Browse by Audience
Inflammatory pain, such as hypersensitivity resulting from surgical tissue injury, occurs as a result of interactions between the immune and nervous systems with the orchestrated recruitment and activation of tissue-resident and circulating immune cells to the site of injury. Our previous studies identified a central role for Ly6C myeloid cells in the pathogenesis of postoperative pain. We now show that the chemokines CCL17 and CCL22, with their cognate receptor CCR4, are key mediators of this response. Both chemokines are up-regulated early after tissue injury by skin-resident dendritic and Langerhans cells to act on peripheral sensory neurons that express CCR4. CCL22, and to a lesser extent CCL17, elicit acute mechanical and thermal hypersensitivity when administered subcutaneously; this response abrogated by pharmacological blockade or genetic silencing of CCR4. Electrophysiological assessment of dissociated sensory neurons from naïve and postoperative mice showed that CCL22 was able to directly activate neurons and enhance their excitability after injury. These responses were blocked using C 021 and small interfering RNA (siRNA)-targeting CCR4. Finally, our data show that acute postoperative pain is significantly reduced in mice lacking CCR4, wild-type animals treated with CCR4 antagonist/siRNA, as well as transgenic mice depleted of dendritic cells. Together, these results suggest an essential role for the peripheral CCL17/22:CCR4 axis in the genesis of inflammatory pain via direct communication between skin-resident dendritic cells and sensory neurons, opening therapeutic avenues for its control.
Learn More >The development of painful paclitaxel-induced peripheral neuropathy (PIPN) represents a major dose-limiting side effect of paclitaxel chemotherapy. Here we report a promising effect of duvelisib (Copiktra™), a novel FDA approved PI3Kδ/γ isoform-specific inhibitor, in preventing paclitaxel-induced pain-like behaviour and pronociceptive signalling in dorsal root ganglia (DRG) and spinal cord dorsal horn (SCDH) in rat and mouse model of PIPN. Duvelisib blocked the development of mechanical hyperalgesia in both males and females. Moreover, duvelisib prevented paclitaxel-induced sensitization of TRPV1 receptors, increased PI3K/Akt-signalling in small-diameter DRG neurons and an increase of CD68 cells within DRGs. Specific optogenetic stimulation of inhibitory neurons combined with patch-clamp recording revealed that duvelisib inhibited paclitaxel-induced weakening of inhibitory, mainly glycinergic control on SCDH excitatory neurons. Enhanced excitatory and reduced inhibitory neurotransmission in the SCDH following PIPN was also alleviated by duvelisib application. In summary, duvelisib showed a promising ability to prevent neuropathic pain in PIPN. The potential use of our findings in human medicine may be augmented by the fact that duvelisib is an FDA approved drug with known side effects.We show that duvelisib, a novel FDA approved PI3Kδ/γ isoform-specific inhibitor, prevents the development of paclitaxel-induced pain-like behaviour in males and females and prevents pronociceptive signalling in dorsal root ganglia and spinal cord dorsal horn in rat and mouse model of paclitaxel-induced peripheral neuropathy.
Learn More >Mechanistic studies principally focusing on primary afferent nociceptive neurons uncovered the upregulation of collapsin response mediator protein 2 (CRMP2)-a dual trafficking regulator of N-type voltage-gated calcium (Cav2.2) as well as Nav1.7 voltage-gated sodium channels-as a potential determinant of neuropathic pain. Whether CRMP2 contributes to aberrant excitatory synaptic transmission underlying neuropathic pain processing after peripheral nerve injury is unknown. Here, we interrogated CRMP2's role in synaptic transmission and in the initiation or maintenance of chronic pain. In rats, short-interfering RNA-mediated knockdown of CRMP2 in the spinal cord reduced the frequency and amplitude of spontaneous excitatory postsynaptic currents, but not spontaneous inhibitory postsynaptic currents, recorded from superficial dorsal horn neurons in acute spinal cord slices. No effect was observed on miniature excitatory postsynaptic currents and inhibitory postsynaptic currents. In a complementary targeted approach, conditional knockout of CRMP2 from mouse neurons using a calcium/calmodulin-dependent protein kinase II alpha promoter to drive Cre recombinase expression reduced the frequency and amplitude of spontaneous excitatory postsynaptic currents, but not miniature excitatory SCss. Conditional knockout of CRMP2 from mouse astrocytes using a glial fibrillary acidic protein promoter had no effect on synaptic transmission. Conditional knockout of CRMP2 in neurons reversed established mechanical allodynia induced by a spared nerve injury in both male and female mice. In addition, the development of spared nerve injury-induced allodynia was also prevented in these mice. Our data strongly suggest that CRMP2 is a key regulator of glutamatergic neurotransmission driving pain signaling and that it contributes to the transition of physiological pain into pathological pain.
Learn More >Intrathecal application of contulakin-G (CGX), a conotoxin peptide and a neurotensin analogue, has been demonstrated to be safe and potentially analgesic in humans. However, the mechanism of action for CGX analgesia is unknown. We hypothesized that spinal application of CGX produces antinociception through activation of the presynaptic neurotensin receptor (NTSR)2. In this study, we assessed the mechanisms of CGX antinociception in rodent models of inflammatory and neuropathic pain. Intrathecal administration of CGX, dose dependently, inhibited thermal and mechanical hypersensitivities in rodents of both sexes. Pharmacological and clustered regularly interspaced short palindromic repeats/Cas9 editing of NTSR2 reversed CGX-induced antinociception without affecting morphine analgesia. Electrophysiological and gene editing approaches demonstrated that CGX inhibition was dependent on the R-type voltage-gated calcium channel (Cav2.3) in sensory neurons. Anatomical studies demonstrated coexpression of NTSR2 and Cav2.3 in dorsal root ganglion neurons. Finally, synaptic fractionation and slice electrophysiology recordings confirmed a predominantly presynaptic effect. Together, these data reveal a nonopioid pathway engaged by a human-tested drug to produce antinociception.
Learn More >Chronic pain is a major healthcare issue posing a large burden on individuals and society. Converging lines of evidence indicate that chronic pain is associated with substantial changes of brain structure and function. However, it remains unclear which neuronal measures relate to changes of clinical parameters over time and could thus monitor chronic pain and treatment responses. We therefore performed a longitudinal study in which we assessed clinical characteristics and resting-state electroencephalography data of 41 patients with chronic pain before and 6 months after interdisciplinary multimodal pain therapy. We specifically assessed electroencephalography measures that have previously been shown to differ between patients with chronic pain and healthy people. These included the dominant peak frequency; the amplitudes of neuronal oscillations at theta, alpha, beta, and gamma frequencies; as well as graph theory-based measures of brain network organization. The results show that pain intensity, pain-related disability, and depression were significantly improved after interdisciplinary multimodal pain therapy. Bayesian hypothesis testing indicated that these clinical changes were not related to changes of the dominant peak frequency or amplitudes of oscillations at any frequency band. Clinical changes were, however, associated with an increase in global network efficiency at theta frequencies. Thus, changes in chronic pain might be reflected by global network changes in the theta band. These longitudinal insights further the understanding of the brain mechanisms of chronic pain. Beyond, they might help to identify biomarkers for the monitoring of chronic pain.
Learn More >Endometriosis is a chronic and debilitating condition, commonly characterised by chronic pelvic pain (CPP) and infertility. Chronic pelvic pain can be experienced across multiple pelvic organs, with comorbidities commonly effecting the bowel, bladder, and vagina. Despite research efforts into endometriosis pathophysiology, little is known about how endometriosis induces CPP, and as such, therapeutic interventions are lacking. The aim of this study was to characterise a syngeneic mouse model of endometriosis that mimics naturally occurring retrograde menstruation, thought to precede endometriosis development in patients, and determine whether these mice exhibit signs of CPP and altered behaviour. We characterised the development of endometriosis over 10 weeks following uterine tissue inoculation, measured in vivo and ex vivo hypersensitivity to mechanical stimuli across multiple visceral organs, and assessed alterations in animal spontaneous behaviour. We confirmed that inoculated uterine horn tissue formed into endometriosis lesions throughout the peritoneal cavity, with significant growth by 8 to 10 weeks post inoculation. Additionally, we found that mice with fully developed endometriosis displayed hypersensitivity evoked by (1) vaginal distension, (2) colorectal distension, (3) bladder distension, and (4) cutaneous thermal stimulation, compared to their sham counterparts. Moreover, endometriosis mice displayed alterations in spontaneous behaviour indicative of (5) altered bladder function and (6) anxiety. This model creates a foundation for mechanistical studies into the diffuse CPP associated with endometriosis and the development of targeted therapeutic interventions to improve the quality of life of women with endometriosis.
Learn More >Experimental studies have suggested that nitrous oxide-induced analgesia depends on interactions with opioids. On the basis of these results, we hypothesized that the effects of inhaled nitrous oxide/oxygen (N2O/O2) 50%-50% equimolar mixture (EMONO) on patients with neuropathic pain would be higher in those receiving concomitant opioids. To test this hypothesis, we did exploratory post hoc analyses of our recently published ProtoTOP study to compare the effects of EMONO and placebo in patients with or without concomitant opioid treatment. A total of 92 patients of the 221 (ie, 41.6%) included in the ProtoTOP study were concomitantly treated with opioids. In contrast with our previous analyses, average pain intensity was significantly decreased in comparison with placebo one week after the last treatment administration in patients treated with opioids, but not in those treated without opioid, and this effect was maintained over the 4-week follow-up period. Neuropathic pain symptom inventory (NPSI total and subscores) was also significantly more decreased after inhalation of EMONO in comparison with placebo only in patients receiving opioids. The proportion of patients with at least 30% pain reduction and of those reporting an overall improvement with the Patient Global Impression of Change were significantly higher only in this population of patients. In conclusion, these results complement our previous analyses with the identification of a specific population of responders to EMONO inhalation in patients with neuropathic pain. As suggested by experimental studies, we hypothesized that these long-lasting analgesic effects could depend on the anti-N-methyl-D-aspartate properties of N2O.
Learn More >National strategies from North America call for substantive improvements in entry-level pain management education to help reduce the burden of chronic pain. Past work has generated a valuable set of interprofessional pain management competencies to guide the education of future health professionals. However, there has been very limited work that has explored the development of such competencies for individual professions in different regions. Developing profession-specific competencies tailored to the local context is a necessary first step to integrate them within local regulatory systems. Our group is working toward this goal within the context of entry-level physiotherapy (PT) programs across Canada.
Learn More >Chronic pain is the most common neurological disorder of HIV patients. Multiple neuropathologies were identified in the pain pathway. Among them is the prominent astrocytic reaction (a.k.a. astrogliosis). However, the pathogenic role and mechanism of the astrogliosis are unclear. Here, we show that the astrogliosis is crucial for the pain development induced by a key neurotoxic HIV protein gp120 and that a neuron-to-astrocyte Wnt5a signal controls the astrogliosis. Ablation of astrogliosis blocked the development of gp120-induced mechanical hyperalgesia, and concomitantly the expression of neural circuit polarization (NCP) in the spinal dorsal horn (SDH). We demonstrated that conditional knockout (CKO) of either Wnt5a in neurons or its receptor ROR2 in astrocytes abolished not only gp120-induced astrogliosis but also hyperalgesia and NCP. Furthermore, we found that the astrogliosis promoted expression of hyperalgesia and NCP via IL-1β regulated by a Wnt5a-ROR2-MMP2 axis. Our results shed light on the role and mechanism of astrogliosis in the pathogenesis of HIV-associated pain.
Learn More >Effectiveness of implementing interventions to optimise guideline-recommended medical prescription in low back pain is not well established.
Learn More >We conducted a Mendelian randomization study to assess whether alcohol and coffee consumption and smoking are causally associated with risk of developing migraine. Independent single-nucleotide polymorphisms associated with the potential risk factors at P < 5 × 10-8 in large-scale genome-wide association studies were selected as instrumental variables. Summary-level data for the associations of the selected single-nucleotide polymorphisms with migraine were obtained from the FinnGen consortium comprising 6687 cases and 144,780 noncases and the UK Biobank study comprising 1072 cases and 360,122 noncases. Estimates derived from the FinnGen and UK Biobank cohorts were combined using fixed-effects meta-analysis. We found evidence for associations of genetically predicted alcohol consumption (odds ratio [OR] 0.54 per SD increase in log-transformed alcoholic drinks per week, 95% confidence interval [CI], 0.35-0.82; P = 0.004), coffee consumption (OR 0.56 per 50% increase in coffee consumption, 95% CI, 0.45-0.70; P < 0.001), and smoking initiation (OR 1.15 for one SD increase in the prevalence of smoking initiation, 95% CI, 1.01-1.31; P = 0.038). These associations persisted in sensitivity analyses, including mutual adjustment in multivariable Mendelian randomization analyses. In reverse Mendelian randomization analyses, genetic liability to migraine was inversely associated with alcohol consumption but was not associated with coffee consumption or smoking initiation. This study provides genetic evidence in support of a protective role of moderate coffee consumption and a detrimental role of cigarette smoking in the etiology of migraine. The inverse association between alcohol consumption and migraine risk may be attributable to reverse causality.
Learn More >Primary sensory neurons in dorsal root ganglia (DRG) are wrapped by satellite glial cells (SGCs), and neuron-SGC interaction may affect somatosensation, especially nociceptive transmission. P2-purinergic receptors (P2Rs) are key elements in the two-way interactions between DRG neurons and SGCs. However, because the cell types are in such close proximity, conventional approaches such as in vitro culture and electrophysiologic recordings are not adequate to investigate the physiologically relevant responses of these cells at a population level. Here, we performed in vivo calcium imaging to survey the activation of hundreds of DRG neurons in Pirt-GCaMP6s mice and to assess SGC activation in GFAP-GCaMP6s mice in situ. By combining pharmacologic and electrophysiologic techniques, we investigated how ganglionic purinergic signaling initiated by α,β-methyleneadenosine 5'-triphosphate (α,β-MeATP) modulates neuronal activity and excitability at a population level. We found that α,β-MeATP induced robust activation of small neurons-likely nociceptors-through activation of P2X3R. Large neurons, which are likely non-nociceptive, were also activated by α,β-MeATP, but with a delay. Blocking pannexin 1 channels attenuated the late phase response of DRG neurons, indicating that P2R stimulation may subsequently induce paracrine ATP release, which could further activate cells in the ganglion. Moreover, ganglionic α,β-MeATP treatment in vivo sensitized small neurons and enhanced responses of spinal wide-dynamic-range neurons to subsequent C-fiber inputs, suggesting that modulation via ganglionic P2R signaling could significantly affect nociceptive neuron excitability and pain transmission. Therefore, targeting functional P2Rs within ganglia may represent an important new strategy for pain modulation.
Learn More >The experience of pain and pain behaviors is not only determined by physiological but also psychosocial factors. In this context, the learning history of the individual and specifically operant reinforcement related to spouse responses might play an important role. We investigated the effect of a solicitous and habitually pain-reinforcing spouse for the processing of pain in patients with chronic pain. Using multichannel electroencephalography, pain behaviors, and self-reports of pain, we examined 20 patients with chronic back pain (10 with solicitous and 10 with nonsolicitous spouses) and 10 matched healthy controls. The participants received a series of painful and nonpainful electrical stimuli applied to the site of pain (back) and a control area (finger) in the presence vs absence of the spouse. The global field power of the electroencephalogram with a focus in the frontal region was enhanced in patients with chronic back pain who had a solicitous spouse compared to those with a nonsolicitous spouse and the healthy controls. This was specific for the painful stimulation at the back and occurred only in the presence but not the absence of the spouse. Pain ratings of intensity and unpleasantness were also higher in the patients with solicitous spouses when the spouse was present during painful stimulation. These data suggest that significant other responses indicative of operant reinforcement may have a direct effect on the cerebral processing of pain and related pain perception.
Learn More >The Pain Coping Questionnaire (PCQ) has support for its validity and reliability as a tool to understand how a child copes with pain of an extended duration. However, measure length may limit feasibility in clinical settings.
Learn More >Carpal tunnel syndrome (CTS) is the most common nerve compression in the arm. A mix of peripheral and central contributions on quantitative sensory testing (QST) has been reported in the literature. Thus, this systematic review or meta-analysis aimed to identify the dominant sensory phenotype and draw conclusive evidence about the presence of central sensitization (CS) in CTS. Based on an a priori published protocol and using PRISMA guidelines, 7 databases were searched (Embase, Web of Science, Scopus, PubMed, SAGE, EBSCOhost, and ProQuest). Eligible studies compared the QST findings of individuals with subacute and chronic CTS with those of healthy controls through thermal, mechanical, and vibration detection thresholds; thermal, pressure, and mechanical pain thresholds; mechanical pain sensitivity; presence of allodynia; wind-up ratio; and conditioned pain modulation. Thirty-seven studies were included in the qualitative analysis. Results showed a significant loss of all detection thresholds of hand median nerve territories and hand extramedian areas (little finger and hand dorsum) in CTS (P < 0.05) but no significant difference (P > 0.05) in wind-up ratio, cold, heat, or mechanical pain thresholds of the median nerve territories. Furthermore, there was a significant increase in mechanical pain sensitivity in median nerve territories and remotely in the forearm (P < 0.05) and a significant gain in pressure and heat pain thresholds in the carpal area (P < 0.05). Conditioned pain modulation was impaired in CTS. Hypoesthesia and increased thermal and mechanical pain ratings are the dominant sensory phenotype with inconclusive evidence about CS in CTS due to the heterogenous results of thermal and mechanical pain thresholds.
Learn More >Neuropathic pain is a prevalent and debilitating chronic disease that is characterized by activation in glial cells in various pain-related regions within the central nervous system. Recent studies have suggested a sexually dimorphic role of microglia in the maintenance of neuropathic pain in rodents. Here, we utilized RNA sequencing analysis and in vitro primary cultures of microglia to identify whether there is a common neuropathic microglial signature and characterize the sex differences in microglia in pain-related regions in nerve injury and chemotherapy-induced peripheral neuropathy mouse models. While mechanical allodynia and behavioral changes were observed in all models, transcriptomic analysis of microglia revealed no common transcriptional changes in spinal and supraspinal regions and in the different neuropathic models. However, there was a substantial change in microglial gene expression within the ipsilateral lumbar spinal cord 7 days after chronic constriction injury (CCI) of the sciatic nerve. Both sexes upregulated genes associated with inflammation, phagosome, and lysosome activation, though males revealed a prominent global transcriptional shift not observed in female mice. Transcriptomic comparison between male spinal microglia after CCI and data from other nerve injury models and neurodegenerative microglia demonstrated a unique CCI-induced signature reflecting acute activation of microglia. Further, in vitro studies revealed that only male microglia from nerve-injured mice developed a reactive phenotype with increased phagocytotic activity. This study demonstrates a lack of a common neuropathic microglial signature and indicates distinct sex differences in spinal microglia, suggesting they contribute to the sex-specific pain processing following nerve injury.
Learn More >In their Matters Arising article, McMullan et al. (2022) offer alternative explanations for the phenotypes we observed upon stimulation and ablation of TrkC-positive neurons in mice. Their interpretations are focused on two aspects: first, whether the vasoconstriction we observed upon activation of TrkC neurons is really mediated by TrkC/TH-positive neurons, or whether it might stem from stimulation of somatic nociceptors that also express TrkC; and second, whether the lethality observed after ablation of TrkC neurons might be a result of ablation of vagal afferents and not TrkC/TH neurons located in the spinal ganglia. Central to both of these concerns is the expression and recombination efficiency of the TrkC transgene in these other cell types. This Matters Arising Response paper addresses the McMullan et al. (2022) Matters Arising paper, published concurrently in Cell Reports.
Learn More >The effect of spinal cord stimulation (SCS) using differential target multiplexed programming (DTMP) on proteins involved in the regulation of ion transport in spinal cord (SC) tissue of an animal model of neuropathic pain was evaluated in comparison to low rate (LR) SCS. Rats subjected to the spared nerve injury model (SNI) and implanted with a SCS lead were assigned to DTMP or LR and stimulated for 48 h. A No-SCS group received no stimulation, and a Sham group received no SNI or stimulation. Proteins in the dorsal ipsilateral quadrant of the stimulated SC were identified and quantified using mass spectrometry. Proteins significantly modulated by DTMP or LR relative to No-SCS were identified. Bioinformatic tools were used to identify proteins related to ion transport regulation. DTMP modulated a larger number of proteins than LR. More than 40 proteins significantly involved in the regulation of chloride (Cl), potassium (K), sodium (Na), or calcium (Ca) ions were identified. SNI affected proteins that promote the increase of intracellular Ca, Na, and K and decrease of intracellular Cl. DTMP modulated proteins involved in glial response to neural injury that affect Ca signaling. DTMP decreased levels of proteins related to Ca transport that may result in the reduction of intracellular Ca. Presynaptic proteins involved in GABA vesicle formation and release were upregulated by DTMP. DTMP also upregulated postsynaptic proteins involved with elevated intracellular Cl, while modulating proteins, expressed by astrocytes, that regulate postsynaptic Cl inhibition. DTMP downregulated K regulatory proteins affected by SNI that affect neuronal depolarization, and upregulated proteins that are associated with a decrease of intracellular neuronal K and astrocyte uptake of extracellular K. DTMP treatment modulated the expression of proteins with the potential to facilitate a reversal of dysregulation of ion transport and signaling associated with a model of neuropathic pain.
Learn More >Large-scale procedural safety data on pterygopalatine fossa nerve blocks (PPFB) using a suprazygomatic, ultrasound-guided approach are lacking, leading to hesitancy surrounding this technique. The aim of this study was to characterize the safety of PPFB.
Learn More >Tyrosine-arginine (kyotorphin), an opioid analgesic dipeptide, was discovered more than 40 years ago in 1979. The evidence accumulated during this period has established the physiological significance of kyotorphin as a neuromodulating peptide, and pharmacological applications. Some of the following important findings have been discussed in this review: (1) kyotorphin is unevenly distributed in the brain; it is found in high concentrations in the pain pathway, which involves the regions associated with morphine analgesia; (2) kyotorphin is subcellularly localized in the synaptosome fraction or nerve-ending particles; (3) a specific synthetase generates kyotorphin from tyrosine and arginine; (4) kyotorphin may be also processed from calpastatin by a novel calcium-activated neutral protease or calpain; (5) kyotorphin preloaded into the synaptosome is released by high K depolarization in a Ca-dependent manner; (6) kyotorphin has a specific G protein coupled receptor, which mediates the activation of phospholipase C (PLC) and inhibition of adenylyl cyclase through G; (7) leucine-arginine works as a specific kyotorphin receptor antagonist; 8) membrane-bound aminopeptidase or excretion through a peptide transporter, PEPT2, may contribute to the inactivation of kyotorphin; and (9) kyotorphin causes increased Met-enkephalin release from brain and spinal slices. It is also known that the opening of plasma membrane Ca channels through a conformational coupling of the InsP receptor with the transient receptor potential C1, which is downstream of the kyotorphin receptor-mediated activation of G and PLC, could be a potential underlying mechanism of Met-enkephalin release. Considering these findings, translational research is an exciting domain that can be explored in the future. As kyotorphin is a small molecule, we could design function-added kyotorphin derivatives. These studies would include not only the brain-permeable kyotorphin derivatives but also hybrid kyotorphin derivatives conjugated with small compounds that have additional pharmacological actions. Further, since there are reports of kyotorphin being involved in either the etiology or treatment of Alzheimer's disease, epilepsy, inflammation, and chronic pain, studies on the beneficial effects of kyotorphin derivatives should also be expected in the future.
Learn More >Clinically relevant pain is often associated with functional impairment and behavioral depression, including depression of social behavior. Moreover, recovery of function is a major goal in pain treatment. We used a recently developed model of operant responding for social interaction in rats to evaluate the vulnerability of social behavior to an experimental pain manipulation and the sensitivity of pain-depressed social behavior to treatment with clinically effective analgesics.
Learn More >Aripiprazole is an antipsychotic drug used to treat schizophrenia and bipolar disorder. Recently, its peripheral analgesic component was evaluated, however, the mechanism involved in this effect is not fully established. Therefore, the aim of the study was to obtain pharmacological evidence for the involvement of the nitric oxide system in the peripheral antinociceptive effect induced by aripiprazole. The hyperalgesia was induced via intraplantar injection of prostaglandin E in mice and the nociceptive thresholds evaluated using the paw pressure test. All drugs were injected locally into the right hind paw. The PI3K inhibitor (AS605240), but not rapamycin (mTOR kinase inhibitor), reversed the peripheral antinociceptive effect induced by Aripiprazole. Antinociception was antagonized by the non-selective inhibitor of the nitric oxide synthase (L-NOarg). The same response was observed using the selective iNOS, but not with the selective nNOS inhibitors. The selective guanylyl cyclase enzyme inhibitor (ODQ) and the non-selective potassium channel blocker tetraethylammonium were able to reverse the antinociceptive effect of aripiprazole. The same was seen using glibenclamide, an ATP-dependent K channel blocker. However, calcium-activated potassium channel blockers of small and high conductance, dequalinium chloride and paxilline respectively, did not reverse this effect. The injection of cGMP-specific phosphodiesterase type 5 inhibitor zaprinast, potentiated the antinociceptive effect induced by a low dose of aripiprazole. The results provide evidence that aripiprazole induces peripheral antinociceptive effects via PI3K/NO/cGMP/K pathway activation.
Learn More >Previous research has established links between chronic pain and impaired cognitive ability, as well as between chronic pain and anxiety, in osteoarthritis. Furthermore, there is evidence linking risk of osteoarthritis to lower educational attainment. However, the inter-play of these factors with key social factors (e.g., social deprivation) at the early stages of osteoarthritis are not understood. Here, we used data from waves 4, 5, 6 and 7 of the Survey of Health, Ageing and Retirement in Europe (SHARE) (n = 971) and selected a subsample of respondents who initially did not report a diagnosis of osteoarthritis until wave 6. We used path models to test how social deprivation, education and anxiety, before diagnosis (waves 4 and 5), affect the relationship between cognitive ability, pain and limitations in activities of daily living following diagnosis (waves 6 and 7). We show that high social deprivation before diagnosis predicts greater limitations in activities of daily living after diagnosis, with this effect partly mediated by impaired cognitive ability. We also find that higher educational attainment before diagnosis may protect against limitations in activities of daily living after diagnosis via better cognitive ability and lower anxiety. Therefore, improving cognitive ability and managing anxiety may mitigate the associations of social deprivation and low educational attainment with limitations in activities of daily living.
Learn More >Trigeminal neuropathic pain has been modeled in rodents through the constriction of the infraorbital nerve (CCI-ION). Sensory alterations, including spontaneous pain, and thermal and mechanical hyperalgesia are well characterized, but there is a notable lack of evidence about the affective pain component in this model. Evaluation of the emotional component of pain in rats has been proposed as a way to optimize potential translational value of non-clinical studies. In rats, 22 and 50 kHz ultrasonic vocalizations (USVs) are considered well-established measures of negative and positive emotional states, respectively. Thus, this study tested the hypothesis that trigeminal neuropathic pain would result, in addition to the sensory alterations, in a decrease of 50 kHz USV, which may be related to altered function of brain areas involved in emotional pain processing. CCI-ION surgery was performed on 60-day-old male Wistar rats. 15 days after surgery, von Frey filaments were applied to detect mechanical hyperalgesia, and USV was recorded. At the same timepoint, systemic treatment with d,l-amphetamine (1 mg/kg) allowed investigation of the involvement of the dopaminergic system in USV emission. Finally, brain tissue was collected to assess the change in tyrosine hydroxylase (TH) expression in the nucleus accumbens (NAc) and c-Fos expression in brain areas involved in emotional pain processing, including the prefrontal cortex (PFC), amygdala, and NAc. The results showed that CCI-ION rats presented mechanical hyperalgesia and a significant reduction of environmental-induced 50 kHz USV. Amphetamine caused a marked increase in 50 kHz USV emission in CCI-ION rats. In addition, TH expression was lower in constricted animals and c-Fos analysis revealed an increase in neuronal activation. Taken together, these data indicate that CCI-ION causes a reduction in the emission of environmental-induced appetitive calls concomitantly with facial mechanical hyperalgesia and that both changes may be related to a reduction in the mesolimbic dopaminergic activity.
Learn More >Randomized trial of three IVIg doses for treating chronic inflammatory demyelinating polyneuropathy.
Intravenous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy usually starts with a 2.0 g/kg induction dose followed by 1.0 g/kg maintenance doses every 3 weeks. No dose-ranging studies with intravenous immunoglobulin maintenance therapy have been published. The Progress in Chronic Inflammatory Demyelinating polyneuropathy (ProCID) study was a prospective, double-blind, randomised, parallel-group, multicentre, phase III study investigating the efficacy and safety of 10% liquid intravenous immunoglobulin (panzyga®) in patients with active chronic inflammatory demyelinating polyneuropathy. Patients were randomised 1:2:1 to receive the standard intravenous immunoglobulin induction dose and then either 0.5, 1.0 or 2.0 g/kg maintenance doses every 3 weeks. The primary endpoint was the response rate in the 1.0 g/kg group, defined as an improvement ≥ 1 point in adjusted Inflammatory Neuropathy Cause and Treatment score at Week 6 versus baseline and maintained at Week 24. Secondary endpoints included dose response and safety. This trial was registered with EudraCT (Number 2015-005443-14) and clinicaltrials.gov (NCT02638207). Between August 2017 and September 2019, the study enrolled 142 patients. All 142 were included in the safety analyses. As no post infusion data were available for three patients, 139 were included in the efficacy analyses, of whom 121 were previously on corticosteroids. The response rate was 80% (55/69 patients) (95% confidence interval: 69-88%) in the 1.0 g/kg group, 65% (22/34; confidence interval: 48-79%) in the 0.5 g/kg group, and 92% (33/36; confidence interval 78-97%) in the 2.0 g/kg group. While the proportion of responders was higher with higher maintenance doses, logistic regression analysis showed that the effect on response rate was driven by a significant difference between the 0.5 and 2.0 g/kg groups, whereas the response rates in the 0.5 and 2.0 g/kg groups did not differ significantly from the 1.0 g/kg group. Fifty-six percent of all patients had an adjusted Inflammatory Neuropathy Cause and Treatment score improvement 3 weeks after the induction dose alone. Treatment-related adverse events were reported in 16 (45.7%), 32 (46.4%) and 20 (52.6%) patients in the 0.5, 1.0 and 2.0 g/kg dose groups, respectively. The most common adverse reaction was headache. There were no treatment-related deaths. Intravenous immunoglobulin 1.0 g/kg was efficacious and well tolerated as maintenance treatment for patients with chronic inflammatory demyelinating polyneuropathy. Further studies of different maintenance doses of intravenous immunoglobulin in chronic inflammatory demyelinating polyneuropathy are warranted.
Learn More >Orofacial pain disorders are predominately experienced by women. Progesterone, a major ovarian hormone, is neuroprotective and antinociceptive. We recently reported that progesterone attenuates estrogen-exacerbated orofacial pain behaviors, yet it remains unclear what anatomical substrate underlies progesterone's activity in the trigeminal system. Progesterone has been reported to exert protective effects through actions at intracellular progesterone receptors (iPR), membrane-progesterone receptors (mPR), or sigma 1 receptors (Sig-1R). Of these, the iPR and Sig-1R have been reported to have a role in pain. Progesterone can also have antinociceptive effects through its metabolite, allopregnanolone. Two enzymes, 5α-reductase and 3α-hydroxysteroid dehydrogenase (3α-HSD), are required for the metabolism of progesterone to allopregnanolone. Both progesterone and allopregnanolone rapidly attenuate pain sensitivity, implicating action of either progesterone at Sig-1R and/or conversion to allopregnanolone which targets GABA receptors. In the present study, we investigated whether Sig-1 Rs are expressed in nociceptors within the trigeminal ganglia of cycling female rats and whether the two enzymes required for progesterone metabolism to allopregnanolone, 5α-reductase and 3α-hydroxysteroid dehydrogenase, are also present. Adult female rats from each stage of the estrous cycle were rapidly decapitated and the trigeminal ganglia collected. Trigeminal ganglia were processed by either fluorescent immunochemistry or western blotting to for visualization and quantification of Sig-1R, 5α-reductase, and 3α-hydroxysteroid dehydrogenase. Here we report that Sig-1Rs and both enzymes involved in progesterone metabolism are highly expressed in a variety of nociceptive sensory neuron populations in the female rat trigeminal ganglia at similar levels across the four stages of the estrous cycle. These data indicate that trigeminal sensory neurons are an anatomical substrate for the reported antinociceptive activity of progesterone via Sig-1R and/or conversion to allopregnanolone.
Learn More >The most common treatment for osteoarthritis is daily oral administration of a nonsteroidal anti-inflammatory drug such as diclofenac. This daily dosage regime is often associated with severe side effects. In this study, we explored the potential of utilizing a high molecular weight cross-linked polyurethane polymer covalently linked to diclofenac () for intra-articular administration. We aim to exploit the advantages of local drug delivery by developing an implant with improved efficacy and reduced side effects. The polymer was synthesized from a diclofenac-functionalized monomer unit in a simple one-pot reaction, followed by cross-linking. drug release studies showed zero-order drug release for 4 days, followed by a gradual decline in drug release rate until diclofenac was depleted after 15 days. The cross-linked polymer was triturated to yield an injectable microgel formulation for administration. Whole animal fluorescence imaging of the rhodamine-labeled showed good retention of the polymer in the knee joints of healthy rats, with approximately 30% of the injected dose still present 2 weeks post intra-articular administration. In a reactivation arthritis animal model, the formulation reduced pain and significantly reduced inflammation after a short lag phase, showing that this drug delivery system warrants further development for long-term treatment of osteoarthritis with the benefit of reduced side effects.
Learn More >Orofacial pain patients often report that the painful facial area is "swollen" without clinical signs – known as perceptual distortion (PD). The neuromodulatory effect of facilitatory repetitive transcranial magnetic stimulation (rTMS) on PD in healthy individuals was investigated, to provide further support that the primary somatosensory cortex (SI) is involved in facial PD. Participants were allocated to active (n=26) or sham (n=26) rTMS group in this case-control study. PD was induced experimentally by injecting local anesthesia (LA) in the right infraorbital region. PD was measured at baseline, 6 min after LA, immediately, 20 and 40 min after rTMS. Intermittent theta-burst stimulation (iTBS) as active rTMS and sham rTMS was applied to the face representation area of SI at 10 min after LA. The magnitude of PD was compared between the groups. The magnitude of PD significantly increased immediately after iTBS compared with sham rTMS (P=0.009). The PD was significantly higher immediately after iTBS compared to 6 min after LA (P=0.004) in the active rTMS group, but not in the sham rTMS group (P=0.054). iTBS applied to a somatotopic-relevant cortical region appears to facilitate facial PD further supporting the involvement of SI in the processing of one´s own face and PD. PERSPECTIVE: This study provides information on neural substrate responsible for processing of perceptual distortion of the face which is speculated to contribute to the chronification of orofacial pain. The findings of this study may aid in mechanism-based management of the condition in orofacial pain disorders and possibly other chronic pain states.
Learn More >Migraine is a common, chronic, disorder that is typically characterized by recurrent disabling attacks of headache and accompanying symptoms, including aura. The aetiology is multifactorial with rare monogenic variants. Depression, epilepsy, stroke and myocardial infarction are comorbid diseases. Spreading depolarization probably causes aura and possibly also triggers trigeminal sensory activation, the underlying mechanism for the headache. Despite earlier beliefs, vasodilation is only a secondary phenomenon and vasoconstriction is not essential for antimigraine efficacy. Management includes analgesics or NSAIDs for mild attacks, and, for moderate or severe attacks, triptans or 5HT receptor agonists. Because of cardiovascular safety concerns, unreliable efficacy and tolerability issues, use of ergots to abort attacks has nearly vanished in most countries. CGRP receptor antagonists (gepants) and lasmiditan, a selective 5HT1 receptor agonist, have emerged as effective acute treatments. Intramuscular onabotulinumtoxinA may be helpful in chronic migraine (migraine on ≥15 days per month) and monoclonal antibodies targeting CGRP or its receptor, as well as two gepants, have proven effective and well tolerated for the preventive treatment of migraine. Several neuromodulation modalities have been approved for acute and/or preventive migraine treatment. The emergence of new treatment targets and therapies illustrates the bright future for migraine management.
Learn More >Opioid analgesics are widely used to treat acute, postoperative, and chronic pain. However, opioid receptor activation can result in severe respiratory depression. In this study, we demonstrated that Tandospirone (TS), a selective serotonin-1A receptor partial agonist, is effective against opioid-induced respiratory depression. Fentanyl was used to establish a respiratory depression model in rodents. We observed the effects of TS on respiratory depression in rats by using plethysmographic recordings and arterial oxygen saturation. In addition, we evaluated the effects of TS on fentanyl-induced sedation and analgesia by using the loss of righting reflex (LORR) and hot-plate tests, respectively. Rats (n = 5) were treated with TS or saline 5 min prior to fentanyl administration. TS [2 mg/kg, intravenous (i.v.)] dose-dependently attenuated fentanyl-induced respiratory depression versus saline + fentanyl group. Furthermore, pre-treatment with TS (2 mg/kg, i.v.) increased arterial oxygen saturation to 76.5 ± 2.0% at 5 min after fentanyl injection, compared with 35.9 ± 2.5% in saline pre-treated rats (P < 0.001), whereas the time to induction of LORR (P > 0.99) and duration of LORR (P = 0.95) did not differ between the "TS + fentanyl" and "saline + fentanyl" group. The antinociceptive effect of fentanyl was not affected by the administration of TS (P = 0.99) in mice (n = 10). In conclusion, we found that TS, a novel non-benzodiazepine anxiolytic/antidepressant drug, could attenuate severe fentanyl-induced respiratory depression and did not affect the analgesic/sedative effect of fentanyl. The clinical application of TS could significantly improve pain management.
Learn More >Altered periaqueductal gray matter (PAG) functional connectivity contributes to brain hyperexcitability in migraine. Although tryptophan modulates neurotransmission in PAG projections through its metabolic pathways, the effect of plasma tryptophan on PAG functional connectivity (PAG-FC) in migraine has not been investigated yet. In this study, using a matched case-control design PAG-FC was measured during a resting-state functional magnetic resonance imaging session in migraine without aura patients (n = 27) and healthy controls (n = 27), and its relationship with plasma tryptophan concentration (TRP) was assessed. In addition, correlations of PAG-FC with age at migraine onset, migraine frequency, trait-anxiety and depressive symptoms were tested and the effect of TRP on these correlations was explored. Our results demonstrated that migraineurs had higher TRP compared to controls. In addition, altered PAG-FC in regions responsible for fear-cascade and pain modulation correlated with TRP only in migraineurs. There was no significant correlation in controls. It suggests increased sensitivity to TRP in migraine patients compared to controls. Trait-anxiety and depressive symptoms correlated with PAG-FC in migraine patients, and these correlations were modulated by TRP in regions responsible for emotional aspects of pain processing, but TRP did not interfere with processes that contribute to migraine attack generation or attack frequency.
Learn More >Mesenchyme homeobox protein 2 (MEOX2) is a transcription factor involved in mesoderm differentiation, including development of bones, muscles, vasculature and dermatomes. We have previously identified dysregulation of MEOX2 in fibroblasts from Congenital Insensitivity to Pain (CIP) patients, and confirmed that btn, the Drosophila homologue of MEOX2, plays a role in nocifensive responses to noxious heat stimuli. To determine the importance of MEOX2 in the mammalian peripheral nervous system, we used a Meox2 heterozygous (Meox2 ) mouse model to characterize its function in the sensory nervous system, and more specifically, in nociception. MEOX2 is expressed in the mouse dorsal root ganglia (DRG) and spinal cord, and localizes in the nuclei of a subset of sensory neurons. Functional studies of the mouse model, including behavioral, cellular and electrophysiological analyses, showed altered nociception encompassing impaired action potential initiation upon depolarization. Mechanistically, we noted decreased expression of Scn9a and Scn11a genes encoding Na 1.7 and Na 1.9 voltage gated sodium channels, respectively, that are crucial in subthreshold amplification and action potential initiation in nociceptors. Further transcriptomic analyses of Meox2 DRG revealed downregulation of a specific subset of genes including those previously associated with pain perception, such as PENK and NPY. Based on these observations, we propose a novel role of MEOX2 in primary afferent nociceptor neurons for the maintenance of a transcriptional program required for proper perception of acute and inflammatory noxious stimuli.
Learn More >Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), which causes Coronavirus Disease 2019 (COVID-19), emerged in December 2019 and became a devastating pandemic. Although its respiratory effects can be deadly and debilitating, it can lead to other systemic disorders, such as those causing eye pain and headache. This literature review aims to describe presentations of eye pain and headache in relation to COVID-19, with an emphasis on how these disorders help us to understand the pathophysiology of COVID-19.
Learn More >Neuropathic pain following brachial plexus avulsion injury (BPAI) induces plastic changes in multiple brain regions associated with somatosensory function, pain, or cognition at the group level. The alternation of the whole pattern of resting-state brain activity and the feasibility of a brain imaging, information-based diagnosis of pain following BPAI is poorly investigated.
Learn More >Chronic opioid therapy (COT) has been used to treat many chronic pain conditions even with poor evidence for its long-term effectiveness. Medical cannabis has emerged with certain pain-relieving properties, which has led to questions as to its' potential application, especially in relation to its effect on opioid use.
Learn More >Cervical epidural steroid injections have long been utilized to treat intraspinal inflammation causing cervicalgia and/or cervical radiculopathy, and much has been written about safety and efficacy. There are published opinions, without evidence basis, that these injections should not be performed above C7-T1 for fear of dural puncture, spinal cord injury, and other complications that might occur more frequently at higher spinal levels. However, many experienced interventional pain physicians believe that epidural injections targeted to the level of spinal inflammation may be more effective. Although medication injected at the lowest cervical level C7-T1 may ascend to higher spinal levels, it often does not since inflammation and swelling at the cervical level of pathology may increase epidural pressure causing the injectate to move caudally down the path of least resistance.
Learn More >Trigeminal neuralgia (TN) is a devastating neuropathic condition. This work tests whether radiomics features derived from MRI of the trigeminal nerve can distinguish between TN-afflicted and pain-free nerves.
Learn More >Intensive interdisciplinary chronic pain treatment programs have demonstrated that pain acceptance predicts positive treatment outcomes, but limited research has focused on less-intensive programs. This study aimed to examine associations between changes in pain acceptance and pain interference among youth participating in an outpatient interdisciplinary chronic pain treatment program.
Learn More >In this narrative review, we summarize clinical and experimental data on the effect of light in migraine and discuss future prospects.
Learn More >Vestibular migraine (VM) is an increasingly recognized pathology yet remains as an underdiagnosed cause of vestibular disorders. While current diagnostic criteria are codified in the 2012 Barany Society document and included in the third edition of the international classification of headache disorders, the pathophysiology of this disorder is still elusive. The Association for Migraine Disorders hosted a multidisciplinary, international expert workshop in October 2020 and identified seven current care gaps that the scientific community needs to resolve, including a better understanding of the range of symptoms and phenotypes of VM, the lack of a diagnostic marker, a better understanding of pathophysiologic mechanisms, as well as the lack of clear recommendations for interventions (nonpharmacologic and pharmacologic) and finally, the need for specific outcome measures that will guide clinicians as well as research into the efficacy of interventions. The expert group issued several recommendations to address those areas including establishing a global VM registry, creating an improved diagnostic algorithm using available vestibular tests as well as others that are in development, conducting appropriate trials of high quality to validate current clinically available treatment and fostering collaborative efforts to elucidate the pathophysiologic mechanisms underlying VM, specifically the role of the trigemino-vascular pathways.
Learn More >High-impact chronic pain is suffered by 1 in 5 patients in the USA and globally. Effective, non-addictive, non-opioid therapeutics are urgently needed for the treatment of chronic pain. Slc7a5 (Lat1), also known as system L-neutral amino acid transporter, is involved in a number of physiological processes related to inflammation. Transcriptomics studies have shown that Slc7a5 and its binding partner Slc3a2 are expressed in neurons of the dorsal root ganglia (DRG) and spinal dorsal horn, which are critical to the initiation and maintenance of nociception and pathophysiology of chronic pain. In addition, Slc7a5 is a transporter for the first-line anti-allodynic gabapentinoid drugs and binds to ion channels implicated in nociception and chronic pain including the voltage-gated sodium channel Nav1.7 and the voltage-gated potassium channels K1.1 and K1.2. We found that blocking Slc7a5 with intrathecal administration of the drug JPH203 alleviated allodynia in the spared nerve injury (SNI) rodent model of neuropathic pain. Western blot and immunohistochemistry studies revealed an increase in Slc7a5 protein levels in the spinal cord and DRGs of SNI mice compared to control mice. Using whole-cell current-clamp electrophysiology, we observed that JPH203 treatment reduced excitability of small-diameter (< 30 µm) DRG neurons from SNI mice, in agreement with its behavioral effects. Voltage-clamp recordings from JPH203-treated naïve rat DRGs identified an effect on tetrodotoxin-resistant (TTX-R) sodium currents. Altogether, these results demonstrate that Slc7a5 is dysregulated in chronic neuropathic pain and can be targeted to provide relief of hypersensitivity.
Learn More >Noxious stimuli like cold, heat, pH change, tissue damage, and inflammation depolarize a membrane of peripheral endings of specialized nociceptive neurons which eventually results in the generation of an action potential. The electrical signal is carried along a long axon of nociceptive neurons from peripheral organs to soma located in dorsal root ganglions and further to the dorsal horn of the spinal cord where it is transmitted through a chemical synapse and is carried through the spinal thalamic tract into the brain. Two subtypes of voltage-activated calcium play a major role in signal transmission: a low voltage-activated Ca3.2 channel and a high voltage-activated Ca2.2 channel. The Ca3.2 channel contributes mainly to the signal conductance along nociceptive neurons while the principal role of the Ca2.2 channel is in the synaptic transmission at the dorsal horn. Both channels contribute to the signal initiation at peripheral nerve endings. This review summarizes current knowledge about the expression and distribution of these channels in a nociceptive pathway, the regulation of their expression and gating during pain pathology, and their suitability as targets for pharmacological therapy.
Learn More >Osteoarthritis (OA) is the leading degenerative joint disease in the western world and leads, if left untreated, to a progressive deterioration of joint functionality, ultimately reducing quality of life. Recent data has shown, that especially OA of the ankle and foot are among the most frequently affected regions. Current research in OA points towards a complex involvement of various cell and tissue types, often accompanied by inflammation. Low-dose radiotherapy (LDRT) is widely used for the treatment of degenerative and inflammatory diseases. While the reported analgesic effects are well known, the underlying molecular mechanisms are only poorly understood. We therefore correlated a clinical approach, looking at pain reduction in 196 patients treated with LDRT with a pre-clinical approach, utilizing the K/BxN serum transfer mouse model using flow cytometry and multiplex ELISA for analysis. While an improvement of symptoms in the majority of patients was found, patients suffering from symptoms within the tarsi transversa show a significantly lower level of improvement. Further, a significant impact of therapy success was detected depending on whether only one or both feet were affected. Further, patients of younger age showed a significantly better outcome than older ones while needing fewer treatment series. When looking on a cellular level within the mouse model, a systemic alteration of immune cells namely a shift from CD8+ to CD4+ T cells and reduced numbers of DCs was observed. A general reduction of inflammatory cytokines was detected, with significant alterations in IL-4 and IL-17 levels, all of which could potentially be responsible for the highly effective clinical improvement in patients. Taken together our data indicate that LDRT can be regarded as a highly effective treatment option for patients suffering from OA of the foot and ankle, in terms of analgesic effects, especially in younger patients. Furthermore, the observed effects are mediated by an interplay of cellular and soluble immune factors, as observed in the K/BxN serum transfer model. With this interdisciplinary approach we aim to encourage the usage of LDRT as an additive treatment strategy not only as a last resort, but also earlier in the course of disease.
Learn More >Type 1 and type 2 cannabinoid receptors (CB1 and CB2, respectively) mediate cannabinoid-induced analgesia. Loss of endogenous CB1 is associated with hyperalgesia. However, the downstream targets affected by ablation of CB1 in primary sensory neurons remain unknown. In the present study, we hypothesized that conditional knockout of CB1 in primary sensory neurons (CB1cKO) alters downstream gene expression in the dorsal root ganglion (DRG) and that targeting these pathways alleviates neuropathic pain. We found that CB1cKO in primary sensory neurons induced by tamoxifen in adult Advillin-Cre:CB1-floxed mice showed persistent hyperalgesia. Transcriptome/RNA sequencing analysis of the DRG indicated that differentially expressed genes were enriched in energy regulation and complement and coagulation cascades at the early phase of CB1cKO, whereas pain regulation and nerve conduction pathways were affected at the late phase of CB1cKO. Chronic constriction injury in mice induced neuropathic pain and changed transcriptome expression in the DRG of CB1cKO mice, and differentially expressed genes were mainly associated with inflammatory and immune-related pathways. Nerve injury caused a much larger increase in CB2 expression in the DRG in CB1cKO than in wildtype mice. Interfering with downstream target genes of CB1, such as antagonizing CB2, inhibited activation of astrocytes, reduced neuroinflammation, and alleviated neuropathic pain. Our results demonstrate that CB1 in primary sensory neurons functions as an endogenous analgesic mediator. CB2 expression is regulated by CB1 and may be targeted for the treatment of neuropathic pain.
Learn More >The objective of this study was to describe patterns in monthly migraine days (MMD) and tablet utilization, and to estimate health-related quality of life (HRQoL) measures in patients treated as needed (PRN) with rimegepant 75 mg over 52-weeks.
Learn More >Extremely low-frequency electromagnetic field (ELF-MF) therapy is a promising treatment for chronic pain, given its ability to interact with body homeostasis using water-mediated transmission mechanisms typical of quantum medicine. The present study aims to assess the effects of ELF-MF therapy on chronic pain in 49 patients suffering from various musculoskeletal disorders. The therapy was applied through a Quec Phisis setup generating the electromagnetic field as the ion cyclotronic resonance. Patients underwent eight therapy sessions of 45 min each performed every other day. The bioimpedance assessment was based on the comparison of the height-adjusted body resistance (R/h) and reactance (Xc/h) measured during the first and last sessions of eight-session treatment. Pain perception was quantified using the standard visual-analog scale. We found significant increases in both R/h and Xc/h parameters of body bioimpedance after electromagnetic therapy corresponding with reductions in pain perception. We conclude that the ELF-MF therapy can restore the body's state of health and thus seems a valid therapeutic approach for the treatment of musculoskeletal-derived pain.
Learn More >The precise underlying mechanisms of migraine remain unknown. Although we have previously shown acute orofacial pain evoked changes within the brainstem of individuals with migraine, we do not know if these brainstem alterations are driven by changes in higher cortical regions. The aim of this investigation is to extend our previous investigation to determine if higher brain centers display altered activation patterns and connectivity in migraineurs during acute orofacial noxious stimuli.
Learn More >Subperception spinal cord stimulation (SCS) is described mostly utilizing waveforms that require high energy. However, the necessity of these waveforms for effective subperception has not been established. We aimed to explore whether effective subperception pain relief can be achieved using frequencies below 1 kHz.
Learn More >Refractory chronic migraine (rCM) is a highly disabling condition for which novel safe and effective treatments are needed. Safety and long-term efficacy of paresthesia-free high cervical 10 kHz spinal cord stimulation (SCS) were here prospectively evaluated for the treatment of rCM.
Learn More >The field of neurostimulation for the treatment of chronic pain is a rapidly developing area of medicine. Although neurostimulation therapies have advanced significantly as a result of technologic improvements, surgical planning, device placement, and postoperative care are of equal importance to optimize outcomes. This Neurostimulation Appropriateness Consensus Committee (NACC) project intends to provide evidence-based guidance for these often-overlooked areas of neurostimulation practice.
Learn More >Neuropathic pain and chronic pain constitute an interdisciplinary problem on the border of medicine, psychology, sociology and economics. While it seems to be underestimated, the scale of this problem will continue to increase due to the population aging and the growing incidence of lifestyle disorders. People employed in various occupational sectors may also wrestle with these disease units, which affect the quality of their life, mental health and work productivity. A narrative review provided an overview of neuropathic pain and chronic pain, and their relationship to such factors as job type, work absenteeism and productivity decline, as well mental well-being. A systematic literature search was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines to identify appropriate literature by searching the electronic databases: PubMed/MEDLINE, Pain Journal and the Cochrane Database of Systematic Reviews. Studies were published in Polish, English and French. Research shows an increasing number of musculoskeletal diseases in professionally active people, which lead to disability or provoke work absences. However, sickness presenteeism and/or absenteeism caused by pain not only leads to economic burdens, but also to burnout, fatigue and depression syndromes in employees. These disorders may require specialized effective interventions to support the return to work or maintaining employment despite experiencing pain. Every patient with chronic or neuropathic pain should be correctly assessed to determine the best method of treatment and its effectiveness.
Learn More >Conventional transcutaneous electrical nerve stimulation (TENS) has been reported to effectively alleviate chronic pain, including phantom limb pain (PLP). Recently, literature has focused on modulated TENS patterns, such as pulse width modulation (PWM) and burst modulation (BM), as alternatives to conventional, non-modulated (NM) sensory neurostimulation to increase the efficiency of rehabilitation. However, there is still limited knowledge of how these modulated TENS patterns affect corticospinal (CS) and motor cortex activity. Therefore, our aim was to first investigate the effect of modulated TENS patterns on CS activity and corticomotor map in healthy subjects. Motor evoked potentials (MEP) elicited by transcranial magnetic stimulation (TMS) were recorded from three muscles before and after the application of TENS interventions. Four different TENS patterns (PWM, BM, NM 40Hz, and NM 100 Hz) were applied. The results revealed significant facilitation of CS excitability following the PWM intervention. We also found an increase in the volume of the motor cortical map following the application of the PWM and NM (40 Hz). Although PLP alleviation has been reported to be associated with an enhancement of corticospinal excitability, the efficiency of the PWM intervention to induce pain alleviation should be validated in a future clinical study in amputees with PLP.
Learn More >Tendons have limited reparative ability and perform a relatively simple mechanical function via the extracellular matrix. Thus, the injured tendon might be treated successfully by stem cell transplantation. We performed a randomized, controlled study to investigate the effects of mesenchymal stem cell injection for treating partial tears in the supraspinatus tendon. We enrolled 24 patients with shoulder pain lasting more than 3 months and partial tears in the supraspinatus tendon. Participants were assigned to three groups: stem cells in fibrin glue, normal saline/fibrin glue mixture, and normal saline only, with which intra-lesional injection was performed. Pain at activity and rest, shoulder function and tear size were evaluated. For safety measures, laboratory tests were taken and adverse events were recorded at every visit. Participants were followed up at 6, 12 weeks, 6, 12 months and 2 years after injection. The primary outcome measure was the improvement in pain at activity at 3 months after injection. Twenty-three patients were included in the final analysis. Primary outcome did not differ among groups (p = 0.35). A mixed effect model revealed no statistically significant interactions. Only time significantly predicted the outcome measure. All participants reported transient pain at the injection site. There were no differences in post-injection pain duration or severity. Safety measures did not differ between groups, and there were no persistent adverse events. Stem cell injection into supraspinatus partial tears in patients with shoulder pain lasting more than 3 months was not more effective than control injections.ClinicalTrials.gov Identifier: NCT02298023.
Learn More >The detailed pathological mechanism of orofacial neuropathic pain remains unknown. We aimed to examine the pannexin 1 (Panx1) signaling in the trigeminal ganglion (TG) involvement in infraorbital nerve injury (IONI)-induced orofacial neuropathic pain.
Learn More >Patients with chronic low back pain radiating to the leg (CLBPr) are sometimes referred to a specialised pain clinic for a precise diagnosis based, for example, on a diagnostic selective nerve root block. Possible interventions are therapeutic selective nerve root block or pulsed radiofrequency. Central pain sensitisation is not directly assessable in humans and therefore the term 'human assumed central sensitisation' (HACS) is proposed. The possible existence and degree of sensitisation associated with pain mechanisms assumed present in the human central nervous system, its role in the chronification of pain and its interaction with diagnostic and therapeutic interventions are largely unknown in patients with CLBPr. The aim of quantitative sensory testing (QST) is to estimate quantitatively the presence of HACS and accumulating evidence suggest that a subset of patients with CLBPr have facilitated responses to a range of QST tests.The aims of this study are to identify HACS in patients with CLBPr, to determine associations with the effect of selective nerve root blocks and compare outcomes of HACS in patients to healthy volunteers.
Learn More >The anterior cingulate cortex (ACC) is a core brain region processing pain emotion. In this study, we performed RNA sequencing analysis to reveal transcriptomic profiles of the ACC in a rat chronic constriction injury (CCI) model. A total of 1628 differentially expressed genes (DEGs) were identified by comparing sham-operated rats with rats of 12 hours, 1, 3, 7, and 14 days after surgery, respectively. Although these inflammatory-related DEGs were generally increased after CCI, different kinetics of time-series expression were observed with the development of neuropathic pain affection. Specifically, the expression of and continued to increase following CCI. The expression of , and were initially upregulated after CCI and subsequently decreased after 12 hours. Similarly, the expression of , and increased after 12 hours but reduced after 1 day. However, the expression of the above genes increased again 7 days after CCI, when the neuropathic pain affection had developed. Furthermore, gene ontology analysis, Kyoto Encyclopedia of Genes and Genomes pathway enrichment and interaction network analyses further showed a high connectivity degree among these chemokine targeting genes. Similar expressional changes in these genes were found in the rat spinal dorsal horn responsible for nociception processing. Taken together, our results indicated chemokines and their targeting genes in the ACC may be differentially involved in the initiation and maintenance of neuropathic pain affection. These genes may be a target for not only the nociception but also the pain affection following nerve injury.
Learn More >During the last decades, platelet-rich plasma has been studied for the treatment of multiple chronic pain conditions, in addition to being employed in the enhancement of healing after tissue injury.
Learn More >We performed a systematic review and meta-analysis of randomised controlled trials (RCTs) conducted from January 2005 to June 2021 to update the evidence of Botulinum toxin A (BoNT-A) in neuropathic pain (NP) in addition to quality of life (QOL), mental health, and sleep outcomes. We conducted a Cochrane Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria analysis of RCTs from the following data sources: EMBASE, CINAHL, WHO International Clinical Trial Registry Platform, ClinicalTrials.gov, Cochrane database, Cochrane Clinical Trial Register, Australia New Zealand Clinical Trials Registry, and EU Clinical Trials Register. Meta-analysis of 17 studies showed a mean final VAS reduction in pain in the intervention group of 2.59 units (95% confidence interval: 1.79, 3.38) greater than the mean for the placebo group. The overall mean difference for sleep, Hospital Anxiety and Depression Scale (HADS) anxiety, HADS depression, and QOL mental and physical sub-scales were, respectively, 1.10 (95% CI: -1.71, 3.90), 1.41 (95% CI: -0.61, 3.43), -0.16 (95% CI: -1.95, 1.63), 0.85 (95% CI: -1.85, 3.56), and -0.71 (95% CI: -3.39, 1.97), indicating no significance. BoNT-A is effective for NP; however, small-scale RCTs to date have been limited in evidence. The reasons for this are discussed, and methods for future RCTs are developed to establish BoNT-A as the first-line agent.
Learn More >The objective of this study was to understand current practice, clinician understanding, attitudes, barriers, and facilitators to optimal headache neuroimaging practices.
Learn More >Consensus guidelines recommend multimodal chronic pain treatment with increased use of non-pharmacological treatment modalities (NPM), including as first-line therapies. However, with many barriers to NPM uptake in US healthcare systems, NPM use may vary across medical care settings. Military veterans are disproportionately affected by chronic pain. Many veterans receive treatment through the Veterans Health Administration (VHA), an integrated healthcare system in which specific policies promote NPM use.
Learn More >Previous studies on the association between weather and pain severity among patients with chronic pain have produced mixed results. In part, this inconsistency may be due to differences in individual pain responses to the weather.
Learn More >The prevalence of chronic pain has reached epidemic levels. In addition to personal suffering chronic pain is associated with psychiatric and medical co-morbidities, notably substance misuse, and a huge a societal cost amounting to hundreds of billions of dollars annually in medical cost, lost wages, and productivity. Chronic pain does not have a cure or quantitative diagnostic or prognostic tools. In this manuscript we provide evidence that this situation is about to change. We first start by summarizing our current understanding of the role of the brain in the pathogenesis of chronic pain. We particularly focus on the concept of learning in the emergence of chronic pain, and the implication of the limbic brain circuitry and dopaminergic signaling, which underly emotional learning and decision making, in this process. Next, we summarize data from our labs and from other groups on the latest brain imaging findings in different chronic pain conditions focusing on results with significant potential for translation into clinical applications. The gaps in the study of chronic pain and brain imaging are highlighted in throughout the overview. Finally, we conclude by discussing the costs and benefits of using brain biomarkers of chronic pain and compare to other potential markers.
Learn More >Transmucosal fentanyl (TF), used for breakthrough cancer pain (BTcP) treatment, has different formulations with distinctive attributes. The hypothesis is that, in shared decision making for the prevention of certain therapeutic problems, doctors and patients assign different value to the characteristics of treatment options. The aim of this study was to assess the discordance between the oncologists' opinion of attributes of TF and patients' expectations in BTcP treatment. This is a multicenter, cross-sectional observational study using simultaneous written surveys of doctors and patients suffering from BTcP episodes. The opinion of Spanish oncologists and patients regarding the importance of 14 different attributes of TF treatment (start of action, potency, duration, presentations and doses available, ease of use, titration, administration time, need for saliva, oral mucositis, rhinitis, adverse events, risk of abuse, evidence available, and need for instructions or health personnel to handle the medication), using two surveys, one for each group. Sixty-three clinical oncologists and 272 patients participated in the study. The patients' satisfaction with and knowledge of BTcP treatment was 6.4 and 6.8 points, respectively (scale 1-9). The attributes with the highest relevance were shared by both groups, although their priority differed. Significant differences were observed in the greater importance given by oncologists (onset and duration of analgesia, need for saliva, presence of mucositis, and time required for patient education) and patients (risk of opioid abuse/aberrant behavior). Our results confirm that some aspects that most concern patients about the treatment of BTcP differ from those to which oncologists attach most importance. Increased patient awareness and education about BTcP and its treatment could lead to greater satisfaction and better patient involvement in therapeutic decisions. Certain barriers need to be overcome, such as lack of time in consultations and poor communication skills of oncologists that hinder patient health education.
Learn More >A scoping review was conducted with the objective to identify and map the available evidence from long-term studies on chronic non-specific low back pain (LBP), to examine how these studies are conducted, and to address potential knowledge gaps.
Learn More >This article discusses publications assessing the prevalence, efficacy, and safety of opioid analgesics in patients with rheumatic diseases, including rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, ankylosing spondylitis, and systemic sclerosis.
Learn More >Although new drugs are being developed for cancer treatment, classical chemotherapeutic agents are still front-line therapies, despite their frequent association with severe side effects that can hamper their use. Cannabinoids may prevent or palliate some of these side effects. The aim of the present study is to review the basic research which has been conducted evaluating the effects of cannabinoid drugs in the treatment of three important side effects induced by classical chemotherapeutic agents: nausea and vomiting, neuropathic pain and cognitive impairment. Several published studies have demonstrated that cannabinoids are useful in preventing and reducing the nausea, vomits and neuropathy induced by different chemotherapy regimens, though other side effects can occur, such as a reduction of gastrointestinal motility, along with psychotropic effects when using centrally-acting cannabinoids. Thus, peripherally-acting cannabinoids and new pharmacological options are being investigated, such as allosteric or biased agonists. Additionally, due to the increase in the survival of cancer patients, there are emerging data that demonstrate an important cognitive deterioration due to chemotherapy, and because the cannabinoid drugs have a neuroprotective effect, they could be useful in preventing chemotherapy-induced cognitive impairment (as demonstrated through studies in other neurological disorders), but this has not yet been tested. Thus, although cannabinoids seem a promising therapeutic approach in the treatment of different side effects induced by chemotherapeutic agents, future research will be necessary to find pharmacological options with a safer profile. Moreover, a new line of research awaits to be opened to elucidate their possible usefulness in preventing cognitive impairment.
Learn More >This article was not intended to be a complete review of the electromyography of pathological muscle states, but it was written to illustrate how the "Coletti Method of EMG ChemoDenervation" (CMECD®) protocol for the treatment of chronic pain resulting from chronic muscle spasm was developed and established. That process led to an unexpected understanding of the underlying pathophysiology of chronic muscle spasm, which represents a paradigm shift in our understanding and ultimately in our treatment of muscle spasm-induced chronic pain. Other investigators had brought to light the presence of spontaneous electrical activity (SEA) in states of muscle spasm. Those findings were all but ignored by standard EMG/Nerve conduction studies in clinical practice. Starting with a simple EMG device I experimented with various medications to treat patients with chronic pain associated with chronic muscle spasm. Suppression of SEA with long-acting medications resolved both the chronic spasm and chronic pain. A successful protocol using phenoxybenzamine was established and clinical outcomes were followed. More than 200 patients were successfully treated during last 12 years. Correlating known exercise muscle physiology with the development of the pathological state of chronic muscle spasm as seen by electromyography led to the postulation of the ischemic model of chronic muscle spasm. Light microscopy pathophysiologic supportive findings are presented and discussed. Predictions from this model to various aspects of treatment were supportive. Implications regarding treatment by the CMECD procedure, as well as other standard therapies, are discussed. Application of the ischemic model to other pain conditions was explored with implications of therapeutic modification. Recommendations for changes in rehabilitation therapy are discussed.
Learn More >The discovery of Mas-related G protein-coupled receptors (MRGPRs) in itch sensation promised a search for novel therapeutics of itch that ultimately met with little success. Recent structural determination of these receptors by Roth and Sun marks a big step forward in the search for therapeutics of debilitating itch.
Learn More >Spinal cord stimulation (SCS) has been shown to be a safe and effective therapy for patients with chronic pain. However, some patients do not obtain or maintain adequate pain relief after SCS. The goal of this study was to identify factors that affect patient outcome with regard to SCS.
Learn More >Phosphorylation of N-methyl-D-aspartate receptor (NMDAR) is widely regarded as a vital modification of synaptic function. Various protein kinases are responsible for direct phosphorylation of NMDAR, such as cyclic adenosine monophosphate-dependent protein kinase A, protein kinase C, Ca/calmodulin-dependent protein kinase II, Src family protein tyrosine kinases, cyclin-dependent kinase 5, and casein kinase II. The detailed function of these kinases on distinct subunits of NMDAR has been reported previously and contributes to phosphorylation at sites predominately within the C-terminal of NMDAR. Phosphorylation underlies both structural and functional changes observed in chronic pain, and studies have demonstrated that inhibitors of kinases are significantly effective in alleviating pain behavior in different chronic pain models. In addition, the exploration of drugs that aim to disrupt the interaction between kinases and NMDAR is promising in clinical research. Based on research regarding the modulation of NMDAR in chronic pain models, this review provides an overview of the phosphorylation of NMDAR-related mechanisms underlying chronic pain to elucidate molecular and pharmacologic references for chronic pain management.
Learn More >Hidradenitis suppurativa (HS) is a painful chronic skin disease characterized by abscesses, nodules, and tunnels in the skin. Adalimumab, a monoclonal antibody against tumor necrosis factor-α, is approved for the treatment of HS in Europe, the USA, and Japan. This multicenter, open-label, post-marketing, observational study (ClinicalTrials.gov: NCT03894956) evaluated the safety and effectiveness of adalimumab in routine clinical practice in Japan (March 2019-May 2021). Patients with HS were treated with s.c. doses of adalimumab according to the dosage described in the package insert. The primary end-point was safety (data cut-off, December 2020). Secondary end-points assessed effectiveness, including HS Clinical Response (HiSCR), skin pain, Dermatology Life Quality Index (DLQI), and C-reactive protein (CRP). Here, we report 12-week interim effectiveness results. A total of 84 eligible patients from 65 sites were enrolled; 83 patients were included in this analysis. Mean age was 42.0 years, mean body mass index was 26.9 kg/m , 78.3% of patients were male, 61.4% had Hurley stage III disease, 39.8% had a disease duration ≥10 years, and 7.2% had a family history of HS. The most common affected sites were the axilla (60.2%), buttocks (59.0%), and the inguinal and femoral regions (47.0%). Mean abscess and inflammatory nodule count was 13.0 (standard deviation, 12.0). Among patients with a comorbidity (57.8%), the most common were diabetes mellitus, hypertension, and chronic kidney disease. No patient reported a serious infection or any safety event of special interest. One patient died from a serious adverse event of cardiac failure unrelated to adalimumab. At week 12, 57.4% of patients achieved HiSCR, and significant reductions from baseline in skin pain, DLQI (both p < 0.0001), and CRP (p = 0.0029) were observed. These results support the administration of adalimumab as a well-tolerated and effective treatment for Japanese patients with HS in real-world clinical practice.
Learn More >To introduce cooled radiofrequency nerve ablation (C-RFA) as an alternative to managing symptomatically moderate to severe glenohumeral osteoarthritis (OA) in patients who have failed other conservative treatments and who are not surgical candidates or refuse surgery.
Learn More >In an attempt to aggregate observations from clinical trials, several meta-analyses have been published examining the effectiveness of systemic, non-opioid, pharmacological interventions to reduce the incidence of chronic postsurgical pain.
Learn More >Fibromyalgia (FM) is a condition characterized by chronic widespread pain whose pathogenesis is still not fully defined. Evidence based on structural and functional neuroimaging methods, electrophysiological, and morphological – skin biopsy – features demonstrated a central and peripheral nervous system involvement. A dysfunction in nociceptive inputs processing at the central level was highlighted as the primary cause of FM, but other data coming from different laboratories contributed to emphasize again the peripheral origin of FM. In fact, small fibers neuropathy (SFN) was observed in a large number of patients submitted to skin biopsy. The complex interaction between central and peripheral factors is opening a new scenario about the management of this neurological disorder. Whether proximal SFN is an initiating event leading to FM or is the consequence of stress-related insular hyper excitability remains unclear. Mild sufferance of peripheral afferents could function as a trigger for an exaggerated response of the so-called "salience matrix" in predisposed individuals. On the other side, the intriguing hypothesis rising from animal models could indicate that the cortical hyper function could cause peripheral small afferent damage. The research should go on the genetic origin of such peripheral and central abnormalities, the acquired facilitating factors, and the presence of different phenotypes in order to search for efficacious treatments, which are still lacking.
Learn More >