I am a
Home I AM A Search Login

Papers: 5 Dec 2020 - 11 Dec 2020

Share this

Self-Reported Disability in Persons With HIV-Related Neuropathy Is Mediated by Pain Interference and Depression.

The purpose of this study was to compare disability in people with HIV and peripheral neuropathy with those without neuropathy and explore how neuropathy and other relevant factors are associated with disability.

Learn More >

Confidence in subjective pain is predicted by reaction time during decision making.

Self-report is the gold standard for measuring pain. However, decisions about pain can vary substantially within and between individuals. We measured whether self-reported pain is accompanied by metacognition and variations in confidence, similar to perceptual decision-making in other modalities. Eighty healthy volunteers underwent acute thermal pain and provided pain ratings followed by confidence judgments on continuous visual analogue scales. We investigated whether eye fixations and reaction time during pain rating might serve as implicit markers of confidence. Confidence varied across trials and increased confidence was associated with faster pain rating reaction times. The association between confidence and fixations varied across individuals as a function of the reliability of individuals' association between temperature and pain. Taken together, this work indicates that individuals can provide metacognitive judgments of pain and extends research on confidence in perceptual decision-making to pain.

Learn More >

USH2A is a Meissner’s corpuscle protein necessary for normal vibration sensing in mice and humans.

Fingertip mechanoreceptors comprise sensory neuron endings together with specialized skin cells that form the end-organ. Exquisitely sensitive, vibration-sensing neurons are associated with Meissner's corpuscles in the skin. In the present study, we found that USH2A, a transmembrane protein with a very large extracellular domain, was found in terminal Schwann cells within Meissner's corpuscles. Pathogenic USH2A mutations cause Usher's syndrome, associated with hearing loss and visual impairment. We show that patients with biallelic pathogenic USH2A mutations also have clear and specific impairments in vibrotactile touch perception, as do mutant mice lacking USH2A. Forepaw rapidly adapting mechanoreceptors innervating Meissner's corpuscles, recorded from Ush2a mice, showed large reductions in vibration sensitivity. However, the USH2A protein was not found in sensory neurons. Thus, loss of USH2A in corpuscular end-organs reduced mechanoreceptor sensitivity as well as vibration perception. Thus, a tether-like protein is required to facilitate detection of small-amplitude vibrations essential for the perception of fine-grained tactile surfaces.

Learn More >

Altered network architecture of functional brain communities in chronic nociplastic pain.

Neuroimaging has enhanced our understanding of the neural correlates of pain. Yet, how neural circuits interact and contribute to persistent pain remain largely unknown. Here, we investigate the mesoscale organization of the brain through intrinsic functional communities generated from resting state functional MRI data from two independent datasets, a discovery cohort of 43 Fibromyalgia (FM) patients and 20 healthy controls (HC) as well as a replication sample of 34 FM patients and 21 HC. Using normalized mutual information, we found that the global network architecture in chronic pain patients is less stable (more variable). Subsequent analyses of node community assignment revealed the composition of the communities differed between FM and HC. Furthermore, differences in network organization were associated with the changes in the composition of communities between patients with varying levels of clinical pain. Together, this work demonstrates that intrinsic network communities differ substantially between patients with FM and controls. These differences may represent a novel aspect of the pathophysiology of chronic nociplastic pain.

Learn More >

Predatory journals enter biomedical databases through public funding.

Learn More >

Regular physical activity reduces the percentage of spinally projecting neurons that express mu-opioid receptors from the rostral ventromedial medulla in mice.

Regular physical activity/exercise is an effective nonpharmacological treatment for individuals with chronic pain. Central inhibitory mechanisms, involving serotonin and opioids, are critical to analgesia produced by regular physical activity. The rostral ventromedial medulla (RVM) sends projections to the spinal cord to inhibit or facilitate nociceptive neurons and plays a key role in exercise-induced analgesia.

Learn More >

How does the brain change in chronic migraine? Developing disease biomarkers.

Validated chronic migraine biomarkers could improve diagnostic, prognostic, and predictive abilities for clinicians and researchers, as well as increase knowledge on migraine pathophysiology.

Learn More >

Racial Inequity in Federal Grant Funding.

Learn More >

Modeling at-level allodynia after mid-thoracic contusion in the rat.

The rat mid-thoracic contusion model has been used to study at-level tactile allodynia, a common type of pain that develops after spinal cord injury (SCI). An important advantage of this model is that not all animals develop hypersensitivity. Therefore, it can be used to examine mechanisms that are strictly related to the development of pain-like behavior separately from mechanisms related to the injury itself. However, how to separate animals that develop hypersensitivity from those that do not is unclear. The aims of the current study were to identify where hypersensitivity and spasticity develop and use this information to identify metrics to separate animals which develop hypersensitivity from those that do not to study differences in their behavior. To accomplish these aims, a grid was used to localize hypersensitivity on the dorsal trunk relative to thoracic dermatomes, and supraspinal responses to tactile stimulation were tallied. These supraspinal responses were used to develop a hypersensitivity score to separate animals that develop hypersensitivity, or pain-like response to nonpainful stimuli. Similar to humans, the development of hypersensitivity could occur with the development of spasticity or hyperreflexia. Moreover, the time course and prevalence of hypersensitivity phenotypes (at-, above-, or below level) produced by this model were similar to that observed in humans with SCI. However, the amount of spared spinal matter in the cord did not explain the development of hypersensitivity, as previously reported. This approach can be used to study the mechanisms underlying the development of hypersensitivity separately from mechanisms related to injury alone.

Learn More >

Antipruritic Effects of Kappa Opioid Receptor Agonists: Evidence from Rodents to Humans.

Centrally administered bombesin induces scratching and grooming in rats. These behaviors were blocked by early benzomorphan kappa opioid receptor (KOR) agonists as reported by Gmerek and Cowan in 1984. This was the first evidence that KORs may be involved in the sensation of itch-like behaviors. Subsequent development of additional animal models for acute and chronic itch has led to important discoveries since then. For example, it was found that (a) gastrin-releasing peptide (GRP), natriuretic polypeptide b and their cognate receptors are keys for the transmission of itch sensation at the spinal cord level, (b) dynorphins (Dyns), the endogenous KOR agonists, work as inhibitory neuromodulators of itch at the spinal cord level, (c) in a mouse model for acute itch, certain KOR antagonists elicit scratching, (d) in mouse models of acute or chronic itch, KOR agonists (e.g., U50,488, nalfurafine, CR 845, nalbuphine) suppress scratching induced by different pruritogens, and (e) nalfurafine, CR 845, and nalbuphine are in the clinic or in clinical trials for pruritus associated with chronic kidney disease and chronic liver disease, as well as pruritus in chronic skin diseases.

Learn More >

Mechanical detection and pain thresholds: comparability of devices using stepped and ramped stimuli.

Quantitative sensory testing is used to assess somatosensory function in humans. The protocol of the German Research Network on Neuropathic Pain (DFNS) provides comprehensive normative values using defined tools; however, some of these may not be feasible in low-resource settings.

Learn More >

Pharmacology and mechanism of action of HSK16149, a selective ligand of α2δ subunit of voltage-gated calcium channel with analgesic activity in animal models of chronic pain.

Chronic pain is a public health problem as current treatments are unsatisfactory with small therapeutic index. Although pregabalin is effective for treating chronic pain, the clinical use is limited due to its side effects. Therefore, improving its therapeutic index is essential. In this study, HSK16149 was found to be a novel ligand of voltage-gated calcium channel (VGCC) αδ subunit. HSK16149 inhibited [H]gabapentin binding to the αδ subunit and was 23 times more potent than pregabalin. In two rat models of neuropathic pain, the minimum effective dose (MED) of HSK16149 was 10 mg/kg and the efficacy was similar to that of 30 mg/kg pregabalin. Moreover, the efficacy of HSK16149 could persist up to 24 h post-administration at 30 mg/kg, while the efficacy of pregabalin lasted only for 12 h at 30 mg/kg in streptozotocin-induced diabetic neuropathy model, indicating that HSK16149 might be a longer-acting drug candidate. HSK16149 could also inhibit mechanical allodynia in intermittent cold stress model and decrease phase II pain behaviors in formalin-induced nociception model. In addition, the locomotor activity test showed that the MED of HSK16149 was similar to that of pregabalin, while in the rotarod test, the MEDs of HSK16149 and pregabalin were 100 mg/kg and 30 mg/kg, respectively. These finding indicated that HSK16149 might have a better safety profile on the central nervous system. In summary, HSK16149 is a potent ligand of VGCC αδ subunit with a better therapeutic index than pregabalin. Hence, it could be an effective and safe drug candidate for treating chronic pain. As a novel potent ligand of VGCC αδ subunit, HSK16149 has the potential to be an effective and safe drug candidate for the treatment of chronic pain.

Learn More >

Socioeconomic status and occurrence of chronic pain: a meta-analysis.

To examine the association between socioeconomic status (SES) and the occurrence of chronic pain, defined as pain that persists or recurs for >3 months.

Learn More >

Relationship between acute pain trajectories after an emergency department visit and chronic pain: a Canadian prospective cohort study.

Inadequate acute pain management can reduce the quality of life, cause unnecessary suffering and can often lead to the development of chronic pain. Using group-based trajectory modelling, we previously identified six distinct pain intensity trajectories for the first 14-day postemergency department (ED) discharge; two linear ones with moderate or severe pain during follow-up (~40% of the patients) and four cubic polynomial order trajectories with mild or no pain at the end of the 14 days (low final pain trajectories). We assessed if previously described acute pain intensity trajectories over 14 days after ED discharge are predictive of chronic pain 3 months later.

Learn More >

Physical Activity as a Predictor of Chronic Pain Following Pediatric Spinal Surgery.

(1) Characterize objective physical activity patterns via actigraphy over 4 months post-spinal fusion surgery, and (2) examine associations between activity patterns at 2-weeks and chronic post-surgical pain (CPSP) status at 4-months.

Learn More >

Offset analgesia is reduced on the palm and increases with stimulus duration.

A noxious stimulus following a more intense stimulus often feels less painful than continuous noxious stimulation. This effect, known as offset analgesia (OA), may be due to descending inhibitory control, to changes in peripheral neural transmission, or both. The timing and location of noxious thermal stimulation were manipulated to better understand the peripheral and central contributions to OA.

Learn More >

Patients with High Chronic Postoperative Knee Pain 5 years after Total Knee Replacement Demonstrate Low-grad Inflammation, Impairment of Function and High Levels of Pain Catastrophizing.

Total knee replacement (TKR) normally provides improvements of physical function and reduces pain. However, approximately 20% of the patients report chronic postoperative knee pain. The aims of the present study were to assess the pain, physical function, and physiological characteristics 5 years after TKR surgery.

Learn More >

Onset hyperalgesia and offset analgesia: Transient increases or decreases of noxious thermal stimulus intensity robustly modulate subsequent perceived pain intensity.

Reported pain intensity depends not only on stimulus intensity but also on previously experienced pain. A painfully hot temperature applied to the skin evokes a lower subjective pain intensity if immediately preceded by a higher temperature, a phenomenon called offset analgesia. Previous work indicated that prior pain experience can also increase subsequent perceived pain intensity. Therefore, we examined whether a given noxious stimulus is experienced as more intense when it is preceded by an increase from a lower temperature. Using healthy volunteer subjects, we observed a disproportionate increase in pain intensity at a given stimulus intensity when this intensity is preceded by a rise from a lower intensity. This disproportionate increase is similar in magnitude to that of offset analgesia. We call this effect onset hyperalgesia. Control stimuli, in which a noxious temperature is held constant, demonstrate that onset hyperalgesia is distinct from receptor or central sensitization. The absolute magnitudes of offset analgesia and onset hyperalgesia correlate with each other but not with the noxious stimulus temperature. Finally, the magnitude of both offset analgesia and onset hyperalgesia depends on preceding temperature changes. Overall, this study demonstrates that the perceptual effect of a noxious thermal stimulus is influenced in a bidirectional manner depending upon both the intensity and direction of change of the immediately preceding thermal stimulus.

Learn More >

Blockade of α1 subtype GABAA receptors attenuates the development of tolerance to the antinociceptive effects of midazolam in rats.

Benzodiazepines bind to and act on α1-3 and α5-containing GABAA receptors. Previous studies suggest that different GABAA receptor α-subtypes mediate the various behavioral effects of benzodiazepines, which raises the possibility of combining benzodiazepines with subtype-selective GABAA receptor antagonists to improve the therapeutic profiles of benzodiazepines. This study examined the GABAA receptor subtype mediation of the tolerance to midazolam-induced antinociception in rats. Midazolam (3.2 mg/kg) significantly reduced the locomotion in rats which was prevented by the selective α1-preferring GABAA receptor antagonist β-carboline-3-carboxylate-t-butyl ester (βCCt) (3.2 mg/kg). Midazolam increased the paw withdrawal threshold as tested by the von Frey filament assay in the complete Freund's adjuvant-induced inflammatory pain model in rats, and this effect was not altered by βCCt or another α1-preferring GABAA receptor antagonist 3-propoxy-β-carboline hydrochloride (3PBC). Repeated treatment with midazolam in combination with vehicle, βCCt or 3PBC (twice daily) for 7 days led to a progressive increase of the ED50 values in the midazolam- and vehicle-treated rats, but not in other rats, suggesting the development of tolerance to midazolam but not to the combination of midazolam with α1-preferring GABAA receptor antagonists. These results suggest the essential role of the α1-subtype of GABAA receptors in mediating the development of tolerance to midazolam-induced antinociceptive effects and raise the possibility of increasing therapeutic profiles of benzodiazepines by selectively blocking specific α-subtypes of GABAA receptors.

Learn More >

Antinociception produced by nonsteroidal anti-inflammatory drugs in female vs male rats.

The primary aim of this study was to examine sex differences in acute antinociceptive and anti-inflammatory effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in rats. Complete Freund's adjuvant (CFA) was administered to adult Sprague-Dawley rats to induce pain and inflammation in one hindpaw; 2.5 h later, vehicle or a single dose of the NSAIDs ibuprofen (1.0-32 mg/kg) or ketoprofen (0.1-10 mg/kg), or the COX-2-preferring inhibitor celecoxib (1.0-10 mg/kg) was injected i.p. Mechanical allodynia, heat hyperalgesia, biased weight-bearing, and hindpaw thickness were assessed 0.5-24 h after drug injection. Ibuprofen and ketoprofen were more potent or efficacious in females than males in reducing mechanical allodynia and increasing weight-bearing on the CFA-injected paw, and celecoxib was longer-acting in females than males on these endpoints. In contrast, ketoprofen and celecoxib were more potent or efficacious in males than females in reducing hindpaw edema. When administered 3 days rather than 2.5 h after CFA, ketoprofen (3.2-32 mg/kg) was minimally effective in attenuating mechanical allodynia and heat hyperalgesia, and did not restore weight-bearing or significantly decrease hindpaw edema, with no sex differences in any effect. Neither celecoxib nor ketoprofen effects were significantly attenuated by cannabinoid receptor 1 or 2 (CB1 or CB2) antagonists in either sex. These results suggest that common NSAIDs administered shortly after induction of inflammation are more effective in females than males in regard to their antinociceptive effects, whereas their anti-inflammatory effects tend to favor males; effect sizes indicate that sex differences in NSAID effect may be functionally important in some cases.

Learn More >

Morphine-Conditioned Placebo Analgesia in Female and Male Rats with Chronic Neuropathic Pain: c-Fos Expression in The Rostral Ventromedial Medulla.

Placebo analgesia has great potential to overcome the inadequacies of current drug therapies to treat conditions of chronic pain. The rostral ventromedial medulla (RVM) has been implicated as a critical relay in the antinociceptive pathway underpinning placebo analgesia in humans. We developed a model of opiate-conditioned placebo analgesia in rats with neuropathic injury to identify medullary nuclei active during placebo analgesia. Using female and male rats the degree of thermal allodynia was first determined following nerve injury, and a pharmacological conditioning procedure, pairing contextual cues with the experience of morphine-induced analgesia, was used to elicit placebo analgesic reactions. This protocol revealed clear subpopulations of placebo reactors (36% of males, 25% of females) and non-reactors in proportions similar to those reported in human studies. We detected injury-specific c-Fos expression in the gracile nucleus and morphine-specific c-Fos expression in the serotonergic midline raphe nuclei and the caudal nuclei of the solitary tract. However, c-Fos expression did not differ between placebo reactors and non-reactors in either serotonergic or non-serotonergic neurons of the RVM. Despite a subpopulation of rats demonstrating placebo reactions, we found no evidence for enhanced activity in the nuclei from which the classical RVM→spinal cord descending analgesic pathways emerge.

Learn More >

Contribution of the P2X4 Receptor in Rat Hippocampus to the Comorbidity of Chronic Pain and Depression.

The hippocampus is an important region for the interaction between depression and pain. Studies show that the P2X4 receptor plays key role in neuropathic pain. This work investigated the potential implication of the P2X4 receptor in the hippocampus in comorbidity of chronic pain and depression. The rat model induced by chronic constriction injury (CCI) plus unpredictable chronic mild stress (UCMS) was used in this study. Our data showed that CCI plus UCMS treatment resulted in abnormal changes in pain and depressive-like behaviors in the rat, accompanied by the upregulated expression of P2X4, NLRP3 (NOD-like receptor protein 3) inflammasome, and interleukin-1β and the activation of p38 MAPK in the hippocampus. The P2X4 antagonist 5-BDBD reversed these abnormal changes in the hippocampus, relieved hippocampal neuronal damage, and alleviated the abnormal pain and depressive-like behaviors in the CCI plus UCMS treated rats. These findings suggest that the P2X4 receptor in the hippocampus may mediate and significantly contribute to the pathological processes of comorbid pain and depression.

Learn More >

ASIC3 inhibition modulates inflammation-induced changes in the activity and sensitivity of Aδ and C fiber sensory neurons that innervate bone.

The Acid Sensing Ion Channel 3 (ASIC3) is a non-selective cation channel that is activated by acidification, and is known to have a role in regulating inflammatory pain. It has pro-algesic roles in a range of conditions that present with bone pain, but the mechanism for this has not yet been demonstrated. We aimed to determine if ASIC3 is expressed in Aδ and/or C fiber bone afferent neurons, and to explore its role in the activation and sensitization of bone afferent neurons after acute inflammation. A combination of retrograde tracing and immunohistochemistry was used to determine expression of ASIC3 in the soma of bone afferent neurons. A novel, electrophysiological bone-nerve preparation was used to make recordings of the activity and sensitivity of bone afferent neurons in the presence of carrageenan-induced inflammation, with and without the selective ASIC3 inhibitor APET×2. A substantial proportion of bone afferent neurons express ASIC3, including unmyelinated (neurofilament poor) and small diameter myelinated (neurofilament rich) neurons that are likely to be C and Aδ nerve fibers respectively. Electrophysiological recordings revealed that application of APET×2 to the marrow cavity inhibited carrageenan-induced spontaneous activity of C and Aδ fiber bone afferent neurons. APET×2 also inhibited carrageenan-induced sensitization of Aδ and C fiber bone afferent neurons to mechanical stimulation, but had no effect on the sensitivity of bone afferent neurons in the absence of inflammation. This evidence supports a role for ASIC3 in the pathogenesis of pain associated with inflammation of the bone.

Learn More >

Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of Vixotrigine in Healthy Volunteers.

Neuropathic pain affects ~ 6.9-10% of the general population and leads to loss of function, anxiety, depression, sleep disturbance, and impaired cognition. Here we report the safety, tolerability, and pharmacokinetics of a voltage- and use-dependent sodium channel blocker, vixotrigine, currently under investigation for the treatment of neuropathic pain conditions. The randomized, placebo-controlled, phase I clinical trials were split into single (SAD) and multiple ascending dose (MAD) studies. Healthy volunteers received oral vixotrigine as either single doses followed by a ≥ 7-day washout period for up to five dosing sessions (SAD, n = 30), or repeat doses (once or twice daily) for 14 and 28 days (MAD, n = 51). Adverse events (AEs), maximum observed vixotrigine plasma concentration (C ), area under the concentration-time curve from predose to 24 hours postdose (AUC ), time to C (T ), and terminal half-life (t ), among others, were assessed. Drug-related AEs were reported in 47% and 53% of volunteers in the SAD and MAD studies, respectively, with dizziness as the most commonly reported drug-related AE. SAD results showed that C and AUC increased with dose, T was 1-2 hours, and t was ~ 11 hours. A two-fold increase in accumulation was observed when vixotrigine was taken twice vs. once daily (MAD). Steady state was achieved from day 5 onward. These data indicate that oral vixotrigine is well tolerated when administered as single doses up to 825 mg and multiple doses up to 450 mg twice daily.

Learn More >

Pleiotropic Effects of Kappa Opioid Receptor-Related Ligands in Non-human Primates.

The kappa opioid receptor (KOR)-related ligands have been demonstrated in preclinical studies for several therapeutic potentials. This chapter highlights (1) how non-human primates (NHP) studies facilitate the research and development of ligands targeting the KOR, (2) effects of the endogenous opioid peptide, dynorphin A-(1-17), and its analogs in NHP, and (3) pleiotropic effects and therapeutic applications of KOR-related ligands. In particular, synthetic ligands targeting the KOR have been extensively studied in NHP in three therapeutic areas, i.e., the treatment for itch, pain, and substance use disorders. As the KORs are widely expressed in the peripheral and central nervous systems, pleiotropic effects of KOR-related ligands, such as discriminative stimulus effects, neuroendocrine effects (e.g., prolactin release and stimulation of hypothalamic-pituitary-adrenal axis), and diuresis, in NHP are discussed. Centrally acting KOR agonists are known to produce adverse effects including dysphoria, hallucination, and sedation. Nonetheless, with strategic advances in medicinal chemistry, three classes of KOR-related agonists, i.e., peripherally restricted KOR agonists, mixed KOR/mu opioid receptor partial agonists, and G protein-biased KOR agonists, warrant additional NHP studies to improve our understanding of their functional efficacy, selectivity, and tolerability. Pharmacological studies in NHP which carry high translational significance will facilitate future development of KOR-based medications.

Learn More >

Neonatal complete Freund’s adjuvant-induced inflammation does not induce or alter hyperalgesic priming or alter adult distributions of C-fibre dorsal horn innervation.

Inflammation during the neonatal period can exacerbate pain severity following reinjury in adulthood. This is driven by alterations in the postnatal development of spinal and supraspinal nociceptive circuitry. However, the contribution of alterations in peripheral nociceptor function remains underexplored.

Learn More >

Targeting G protein-coupled receptors for the treatment of chronic pain in the digestive system.

Chronic pain is a hallmark of functional disorders, inflammatory diseases and cancer of the digestive system. The mechanisms that initiate and sustain chronic pain are incompletely understood, and available therapies are inadequate. This review highlights recent advances in the structure and function of pronociceptive and antinociceptive G protein-coupled receptors (GPCRs) that provide insights into the mechanisms and treatment of chronic pain. This knowledge, derived from studies of somatic pain, can guide research into visceral pain. Mediators from injured tissues transiently activate GPCRs at the plasma membrane of neurons, leading to sensitisation of ion channels and acute hyperexcitability and nociception. Sustained agonist release evokes GPCR redistribution to endosomes, where persistent signalling regulates activity of channels and genes that control chronic hyperexcitability and nociception. Endosomally targeted GPCR antagonists provide superior pain relief in preclinical models. Biased agonists stabilise GPCR conformations that favour signalling of beneficial actions at the expense of detrimental side effects. Biased agonists of µ-opioid receptors (MOPrs) can provide analgesia without addiction, respiratory depression and constipation. Opioids that preferentially bind to MOPrs in the acidic microenvironment of diseased tissues produce analgesia without side effects. Allosteric modulators of GPCRs fine-tune actions of endogenous ligands, offering the prospect of refined pain control. GPCR dimers might function as distinct therapeutic targets for nociception. The discovery that GPCRs that control itch also mediate irritant sensation in the colon has revealed new targets. A deeper understanding of GPCR structure and function in different microenvironments offers the potential of developing superior treatments for GI pain.

Learn More >

The role of deficient pain modulatory systems in the development of persistent post-traumatic headaches following mild traumatic brain injury: an exploratory longitudinal study.

Post-traumatic headache (PTH) is one of the most common and long-lasting symptoms following mild traumatic brain injury (TBI). However, the pathological mechanisms underlying the development of persistent PTH remain poorly understood. The primary purpose of this prospective pilot study was to evaluate whether early pain modulatory profiles (sensitization and endogenous pain inhibitory capacity) and psychological factors after mild TBI predict the development of persistent PTH in mild TBI patients.

Learn More >

Designing a clinical trial of non-steroidal anti-inflammatory drugs for cancer pain: a survey of UK palliative care physicians.

Insufficient quality evidence exists to support or refute the use of non-steroidal anti-inflammatory drugs (NSAIDs) in the management of cancer pain. We aimed to determine the most clinically pragmatic design of a future randominsed controlled trial (RCT), based on how NSAIDs are currently used and perceived efficacy.

Learn More >

Efficacy of motivational-interviewing and guided opioid tapering support for patients undergoing orthopedic surgery (MI-Opioid Taper): A prospective, assessor-blind, randomized controlled pilot trial.

Postoperative opioid use can lead to chronic use and misuse. Few studies have examined effective approaches to taper postoperative opioid use while maintaining adequate analgesia.

Learn More >

Galcanezumab for the prevention of migraine.

Migraine is a common and disabling disorder affecting approximately 1.02 billion people worldwide. Calcitonin gene-related peptide (CGRP) has been identified as playing an important role in the pathophysiology of migraine and several migraine-specific therapies targeting the CGRP ligand or its receptor have been approved since 2018 for the acute and preventive treatment of migraine. This review focuses on the pharmacology, clinical efficacy and safety/tolerability of galcanezumab, an anti-CGRP monoclonal antibody approved for the prevention of migraine.

Learn More >

Clinical spectrum of coronavirus disease 2019 in Iceland: population based cohort study.

To characterise the symptoms of coronavirus disease 2019 (covid-19).

Learn More >

“It’s not my knee” – understanding ongoing pain and discomfort after total knee replacement through (re)embodiment.

Up to 20% of people who undergo total knee replacement surgery have ongoing pain and discomfort. The aim of this study was to understand what role the concepts of embodiment (of both having a body and experiencing the world through one's body) and incorporation (integrating something into one's body) might have in understanding experiences of pain and discomfort after total knee replacement.

Learn More >

Exposure to first-person shooter videogames is associated with multisensory temporal precision and migraine incidence.

Adaptive interactions with the environment require optimal integration and segregation of sensory information. Yet, temporal misalignments in the presentation of visual and auditory stimuli may generate illusory phenomena such as the sound-induced flash illusion, in which a single flash paired with multiple auditory stimuli induces the perception of multiple illusory flashes. This phenomenon has been shown to be robust and resistant to feedback training. According to a Bayesian account, this is due to a statistically optimal combination of the signals operated by the nervous system. From this perspective, individual susceptibility to the illusion might be moulded through prolonged experience. For example, repeated exposure to the illusion and prolonged training sessions partially impact on the reported illusion. Therefore, extensive and immersive audio-visual experience, such as first-person shooter videogames, should sharpen individual capacity to correctly integrate multisensory information over time, leading to more veridical perception. We tested this hypothesis by comparing the temporal profile of the sound-induced illusion in a group of expert first-person shooter gamers and a non-players group. In line with the hypotheses, gamers experience significantly narrower windows of illusion (~87 ms) relative to non-players (~105 ms), leading to higher veridical reports in gamers (~68%) relative to non-players (~59%). Moreover, according to recent literature, we tested whether audio-visual intensive training in gamers could be related to the incidence of migraine, and found that its severity may be directly proportioned to the time spent on videogames. Overall, these results suggest that continued training within audio-visual environments such as first-person shooter videogames improves temporal discrimination and sensory integration. This finding may pave the way for future therapeutic strategies based on self-administered multisensory training. On the other hand, the impact of intensive training on visual-related stress disorders, such as migraine incidence, should be taken into account as a risk factor during therapeutic planning.

Learn More >

Video-based Pain Education in Schools: A Study with Adolescents.

School-based educational programs have shown positive changes in health-related behaviors among adolescents. The aim of this study was to analyze the changes in pain-related knowledge among adolescents and in the use of positive responses to their peers' pain behaviors after watching a brief educational video.

Learn More >

Cannabinoid control of neurogenic inflammation.

A significant number of cannabinoids are known to have analgesic and anti-inflammatory properties in various diseases. Due to their presynaptic/terminal location, cannabinoid receptors can inhibit synaptic transmission and have the potential to regulate neurogenic inflammation. Neurogenic inflammation occurs when a noxious signal is detected in the periphery initiating an antidromic axon reflex in the same sensory neurone leading to depolarization of the afferent terminal. Neuropeptides are subsequently released and contribute to vasodilation, plasma extravasation and modulation of immune cells. Endocannabinoids, synthetic cannabinoids and phytocannabinoids can reduce neuroinflammation by inhibiting afferent firing and inflammatory neuropeptide release. Thus, in addition to a direct effect on vascular smooth muscle and inflammatory cells, cannabinoids can reduce inflammation by silencing small diameter neurones. This review examines the neuropharmacological processes involved in regulating antidromic depolarization of afferent nerve terminals by cannabinoids and the control of neurogenic inflammation in different diseases.

Learn More >

Trigeminal neuropathic pain is alleviated by inhibition of Ca3.3 T-type calcium channels in mice.

In this brief report, we demonstrate that the Ca3.3 T-type voltage-gated calcium channel subtype is involved in our FRICT-ION model of chronic trigeminal neuropathic pain. We first showed that the gene encoding Ca3.3 is significantly upregulated in whole trigeminal ganglia of FRICT-ION mice compared to controls at week 10 post-injury. We confirmed protein upregulation of Ca3.3 compared to controls using Western blot analysis of whole trigeminal ganglia tissues. Finally, we demonstrated that intraperitoneal injection of a selective TAT-based Ca3.3 blocking peptide in FRICT-ION mice significantly reduces Ca3.3 protein expression at the peak anti-allodynic effect (4 hrs post-injection) of the attenuated neuropathic pain behavior. We also suggest that blockade of Ca3.3 may be more effective in attenuating trigeminal neuropathic pain in female than male FRICT-ION mice. Therefore, blocking or attenuating Ca3.3 function may be an effective strategy for treatment of trigeminal neuropathic pain.

Learn More >

Eptinezumab for the preventive treatment of migraine.

Our knowledge of the pathophysiology of migraine and the molecules implicated in the disorder have evolved over time. Among these, calcitonin gene-related peptide has shown a crucial role that led to the development of therapies specifically targeting the molecule. Four monoclonal antibodies targeting the calcitonin gene-related peptide pathway are currently available after the US FDA approval of eptinezumab for the indication of migraine prevention. This is the only one of the class to be administered intravenously. The pharmacology of eptinezumab and the four studies that led to the approval, two Phase II and two Phase III clinical trials, are reviewed in this paper. Eptinezumab has demonstrated efficacy, tolerability and safety in patients with episodic and chronic migraine. Studies including migraineurs who have failed previous preventives, and comparison with other options administered quarterly, as well as real-world experience data will all be welcome.

Learn More >

Hyperalgesia and Central Sensitization in Subjects With Chronic Orofacial Pain: Analysis of Pain Thresholds and EEG Biomarkers.

The presence of a temporomandibular disorder is one of the most frequent causes of orofacial pain (OFP). When pain continues beyond tissue healing time, it becomes chronic and may be caused, among other factors, by the sensitization of higher-order neurons. The aim of this study is to describe psychological characteristics of patients with chronic OFP, their peripheral pain threshold, and electroencephalography (EEG) recording, looking for possible signs of central sensitization (CS). Twenty-four subjects with chronic OFP caused by temporomandibular disorder were evaluated using the Research Diagnostic Criteria for Temporomandibular Disorders Axis I and Axis II. Pain intensity, catastrophizing, and presence of CS were assessed through self-reported questionnaires. Pressure pain threshold (PPT) was recorded in facial and peripheral sites; EEG activity was recorded during open and closed eyes resting state and also during the pain threshold assessment. Pain thresholds and EEG recordings were compared with a cohort of pain-free age- and sex-matched healthy subjects. Patients with chronic OFP showed a significant reduction in their pain threshold compared to healthy subjects in all sites assessed. Greater reduction in pain threshold was recorded in patients with more severe psychological symptoms. Decreased alpha and increased gamma activity was recorded in central and frontal regions of all subjects, although no significant differences were observed between groups. A general reduction in PPT was recorded in people who suffer from chronic OFP. This result may be explained by sensitization of the central nervous system due to chronic pain conditions. Abnormal EEG activity was recorded during painful stimulation compared to the relaxed condition in both chronic OFP subjects and healthy controls.

Learn More >

The CUL3/neddylation inhibitor MLN4924 reduces ethanol-induced locomotor sensitization and inflammatory pain allodynia in mice.

Heterologous sensitization of adenylyl cyclase (AC) is defined by an enhanced cAMP response following persistent activation of Gα-coupled receptors. This phenomenon was first observed in cellular models, and later reported in animal models of inflammatory pain or following chronic exposure to drugs of abuse including opioids and cocaine. Recently, we used genome-wide siRNA screening to identify Cullin3 signaling as a mediator of AC sensitization in cellular models. We also showed that pharmacological inhibition of Cullin3 with the neddylation inhibitor, MLN4924, abolished heterologous sensitization of several AC isoforms, including AC1, AC2, AC5, and AC6. Because ACs, especially AC1, have been implicated in alcohol-induced locomotor sensitization and inflammatory pain, we assessed the potential activity of MLN4924 in both murine models. We found that MLN4924 (30 mg/kg, i.p.) accumulated in the brain and reduced both locomotor sensitization induced by repeated alcohol administration and allodynia in an inflammatory pain model. Based on our previous findings that MLN4924 potently blocks AC sensitization in cellular models, we propose that the activity of MLN4924 in both animal models potentially occurs through blocking AC sensitization. Our findings provide the basis for understanding the molecular mechanism and yield a new pathway for drug development for pathological disorders associated with AC sensitization.

Learn More >

What Have We Learned from Animal Models of Endometriosis and How Can We Use the Knowledge Gained to Improve Treatment of Patients?

Endometriosis is a complex disorder with a high socio-economic impact. Development of effective novel drug therapies which can be given to women to relieve chronic pain symptoms without side effects such as hormone suppression is urgently required, but progress has been slow. Several different rodent models of 'endometriosis' have been developed, the majority of which mimic aspects of peritoneal disease (e.g. 'lesions' in peritoneal cavity either surgically or spontaneously attached to wall, mesentery, fat). Results obtained using these models have informed our understanding of aetiology including evidence for differential expression of regulatory factors in lesions and impacts on pain perception and fertility. Refinement of these models to ensure reproducibility, extension of models to replicate ovarian and deep disease, complementary in vitro approaches and robust experimental design are all needed to ensure preclinical drug testing results in positive findings in clinical trials and translation for patient benefit.

Learn More >

Endometriosis-Associated Pain – Do Preclinical Rodent Models Provide a Good Platform for Translation?

Pelvic pain is a common symptom of endometriosis. Our understanding of its etiology remains incomplete and medical management is limited by poor translation from preclinical models to clinical trials. In this review, we briefly consider the evidence, or lack thereof, that different subtypes of lesion, extra-uterine bleeding, and neuropathic pathways add to the complex and heterogeneous pain experience of women with the condition. We summarize the studies in rodent models of endometriosis that have used behavioral endpoints (evoked and non-evoked) to explore mechanisms of endometriosis-associated pain. Lesion innervation, activation of nerves by pronociceptive molecules released by immune cells, and a role for estrogen in modulating hyperalgesia are key endometriosis-associated pain mechanisms replicated in preclinical rodent models. The presence of ectopic (full thickness uterus or endometrial) tissue may be associated with changes in the spinal cord and brain, which appear to model changes reported in patients. While preclinical models using rats and mice have yielded insights that appear relevant to mechanisms responsible for the development of endometriosis-associated pain, they are limited in scope. Specifically, most studies are based on models that only resulted in the formation of superficial lesions and use induced (evoked) behavioral 'pain' tests. We suggest that translation for patient benefit will be improved by new approaches including models of ovarian and deep infiltrating disease and measurement of spontaneous pain behaviors. Future studies must also capitalize on new advances in the wider field of pain medicine to identify more effective treatments for endometriosis-associated pain.

Learn More >

Neuropathic pain in sickle cell disease: measurement and management.

The identification of chronic pain and neuropathic pain as common contributors to the overall pain experience of patients with sickle cell disease (SCD) has altered the way we should evaluate difficult-to-treat pain. The recognition of these 2 entities is not generally routine among various medical specialties and provider levels that treat SCD. Due to the relative recency with which neuropathic pain was first described in SCD, validated assessment tools and evidence-based treatments remain lacking. Although clinical assessment and judgment must continue to inform all decision making in this understudied area of SCD pain management, a number of validated neuropathic pain assessment tools exist that can make possible a standardized evaluation process. Similarly, investigation of available neuropathic pain treatments for the uniquely complex pain phenotypes of SCD has only just begun and is better established in pain conditions other than SCD. The aim of this review is to briefly summarize the proposed basic pathophysiology, assessment, and treatment of neuropathic pain in patients with SCD. Furthermore, the aim of this review is to encourage an expanded framework for the assessment and treatment of SCD pain that appreciates the hidden complexities of this common complication of SCD.

Learn More >

Prevalence of Postoperative Pain Following Hospital Discharge: Protocol for a Systematic Review.

Pain is one of the most common, feared, and unpleasant symptoms associated with surgery. However, there is a clear gap in patient care after surgical patients are discharged from hospital, resulting in poorly controlled postoperative pain. Inadequate pain management after discharge can have detrimental effects on quality of life and lead to the development of chronic postsurgical pain. The severity of postoperative pain before discharge is well described, but less emphasis has been placed on assessing pain at home after hospital discharge.

Learn More >

Considerations for Cannabis Use to Treat Pain in Sickle Cell Disease.

Pain in Sickle Cell Disease (SCD) is a major comorbidity and unique with acute pain due to recurrent and episodic vaso-occlusive crises as well as chronic pain, which can span an individual's entire life. Opioids are the mainstay treatment for pain in SCD. Due to recent health crises raised by adverse effects including deaths from opioid use, pain management in SCD is adversely affected. Cannabis and its products are most widely used for pain in multiple conditions and also by patients with SCD on their own. With the availability of "Medical Cannabis" and approval to use cannabis as medicine across majority of States in the United States as well as over-the-counter preparations, cannabis products are being used increasingly for SCD. The reliability of many of these products remains questionable, which poses a major health risk to the vulnerable individuals seeking pain relief. Therefore, this review provides up to date insights into available categories of cannabis-based treatment strategies, their mechanism of action and pre-clinical and clinical outcomes in SCD. It provides evidence for the benefits and risks of cannabis use in SCD and cautions about the unreliable and unvalidated products that may be adulterated with life-threatening non-cannabis compounds.

Learn More >

Analysis of the effects of a tricyclic antidepressant on secondary sleep disturbance induced by chronic pain in a preclinical model.

Chronic pain and sleep have a bidirectional relationship that promotes a vicious circle making chronic pain more difficult to treat. Therefore, pain and sleep should be treated simultaneously. In our previous study, we suggested that hyperactivation of ascending serotonergic neurons could cause secondary sleep disturbance in chronic pain. This study aimed to demonstrate the effects of a tricyclic antidepressant (amitriptyline) and a selective 5-hydroxy-tryptamine 2A (5-HT2A) antagonist (MDL 100907) that adjust serotonergic transmission, on secondary sleep disturbance induced in a preclinical chronic pain model. We produced a chronic neuropathic pain model by partial sciatic nerve ligation in mice, analyzed their electroencephalogram (EEG) and electromyogram (EMG) using the SleepSign software, and evaluated the sleep condition of the pain model mice after administration of amitriptyline or MDL 100907. Amitriptyline improved thermal hyperalgesia and the amount of sleep, especially non-REM sleep. Time change of normalized power density of δ wave in the nerve ligation group with amitriptyline administration showed a normal pattern that was similar to sham mice. In addition, MDL 100907 normalized sleep condition similar to amitriptyline, without improvement in pain threshold. In conclusion, amitriptyline could improve sleep quantity and quality impaired by chronic pain. 5-HT2A receptor antagonism could partially contribute to this sleep improvement, but is not associated with pain relief.

Learn More >

Evaluation of the Pain Impact Index for community-dwelling older adults through the application of Rasch modelling.

Evaluate the Pain Impact Index, a simple, brief, easy-to-use and novel tool to assess the impact of chronic pain in community-dwelling older adults.

Learn More >

Risk factors for indicators of opioid-related harms amongst people living with chronic non-cancer pain: Findings from a 5-year prospective cohort study.

The literature suggests patient characteristics and higher opioid doses and long-term duration are associated with problematic opioid behaviours but no one study has examined the role of all these factors simultaneously in a long-term prospective cohort study.

Learn More >

An Experimental Analogue Study on the “Dose-Response Relationship” of Different Therapeutic Instructions for Pain Exposures: The More, The Better?

Novel suggestions derived from the inhibitory learning model on how to optimize exposure therapy have been debated with enthusiasm in the last few years, particularly with respect to the focus on expectancy violations. However, little is known about how this new approach directly compares to the traditional habituation rationale of exposure therapy. In the present study, we examined these two competing therapeutic instructions among healthy female participants in an experimental heat pain paradigm.

Learn More >

Impact of Catastrophizing in Patients with Temporomandibular Disorders-A Systematic Review.

To assess the prevalence of catastrophizing in patients with temporomandibular disorders (TMD) and the possible associations between catastrophizing and treatment outcome.

Learn More >

Effect of Genetic Polymorphisms on Pain Sensitivity in the Orofacial Region: A Systematic Review.

To systematically review the literature to assess whether genetic polymorphisms affect orofacial pain sensitivity in healthy individuals and in patients with chronic orofacial pain disorders.

Learn More >

Targeting nerve growth factor, a new option for treatment of osteoarthritis: a network meta-analysis of comparative efficacy and safety with traditional drugs.

Osteoarthritis (OA) is the most common joint disease and leading cause of pain and disability in the elderly population. Most guidelines recommend the use of non-steroidal anti-inflammatory drugs (NSAIDs) and opioids for the non-operative treatment of OA. Monoclonal nerve growth factor (NGF) antibodies are new drugs with the potential to provide pain relief and functional improvement in OA. We compared the efficacy (pain reduction and functional improvement), and safety of monoclonal NGF antibodies with NSAIDs and opioids in the treatment of OA with a Bayesian network meta-analysis.

Learn More >

Concurrent brain structural and functional alterations in patients with migraine without aura: an fMRI study.

To explore the possible concurrent brain functional and structural alterations in patients with migraine without aura (MwoA) patients compared to healthy subjects (HS).

Learn More >

Could cathodal transcranial direct current stimulation modulate the power spectral density of alpha-band in migrainous occipital lobe?

To identify the correlation between cathodal transcranial direct current stimulation (tDCS) and the power spectral density (PSD) of alpha-band on the occipital lobe of migraineurs.

Learn More >

Executive Functioning in Adolescents with Chronic Musculoskeletal Pain.

Adolescents with chronic pain often suffer significant impairment in physical, emotional, and social domains. Surprisingly little is known about executive functioning (EF) in youth with chronic pain or how EF deficits may contribute to functional impairment. Study participants included 60 adolescents between the ages of 12 and 17 years ( = 14.57). Thirty participants with chronic musculoskeletal pain and 30 age- and gender-matched healthy controls were recruited from a large Midwestern children's hospital in the United States. Participants completed the Behavior Rating Inventory of Executive Functioning (BRIEF-2) as well as multiple measures of functional impairment across key domains: school, social, emotional (anxiety, depression), and physical. Adolescents with chronic musculoskeletal pain reported significantly greater EF impairment compared to healthy age- and gender-matched peers. Clinically elevated risk levels of impairment were reported across all aspects of EF, with many adolescents in the chronic pain group scoring above the clinical risk cut off for working memory (52%), inhibition (45%), and cognitive flexibility (38%). EF was also significantly related to functional impairment across all domains. Findings suggest that EF may have an impact across several critical domains of functioning for youth with chronic pain.

Learn More >

Somatosensory Testing in Pediatric Patients with Chronic Pain: An Exploration of Clinical Utility.

We aimed to evaluate the utility of clinical somatosensory testing (SST), an office adaptation of laboratory quantitative sensory testing, in a biopsychosocial assessment of a pediatric chronic somatic pain sample (N = 98, 65 females, 7-18 years). Stimulus-response tests were applied at pain regions and intra-subject control sites to cutaneous stimuli (simple and dynamic touch, punctate pressure and cool) and deep pressure stimuli (using a handheld pressure algometer, and, in a subset, manually inflated cuff). Validated psychological, pain-related and functional measures were administered. Cutaneous allodynia, usually regional, was elicited by at least one stimulus in 81% of cases, most frequently by punctate pressure. Central sensitization, using a composite measure of deep pressure pain threshold and temporal summation of pain, was implied in the majority (59.2%) and associated with worse sleep impairment and psychological functioning. In regression analyses, depressive symptoms were the only significant predictor of pain intensity. Functional interference was statistically predicted by deep pressure pain threshold and depressive symptoms. Manually inflated cuff algometry had comparable sensitivity to handheld pressure algometry for deep pressure pain threshold but not temporal summation of pain. SST complemented standard biopsychosocial assessment of pediatric chronic pain; use of SST may facilitate the understanding of disordered neurobiology.

Learn More >

Changes in Muscle Morphology in Female Chronic Neck Pain Patients Using Magnetic Resonance Imaging.

Population based cross-sectional study OBJECTIVE.: The aim of this study was to gain a better understanding of changes in muscle morphology in patients with chronic idiopathic neck pain (CINP) and whiplash associated disorder (CWAD).

Learn More >

The presence of aura is not related to changes in the cervical performance and mobility of patients with migraine.

Migraine may be associated with neck impairment and migraine chronicity is related to greater disability. However, whether other subclassifications of migraine, such as migraine with aura, are related to neck impairment is currently unknown. The aim of this study was to assess the musculoskeletal aspects of the neck in patients with migraine with and without aura.

Learn More >

Interventions for itch in people with advanced chronic kidney disease.

Itch in patients with chronic kidney disease (CKD) is common, often very distressing and associated with depression, reduced quality of life, and increased death. The most common first-line treatment has been the use of antihistamines despite the lack of substantial evidence for its use for uraemic itch. Few recommendations and guidelines exist for treatment.

Learn More >

Weighing Distress and Benefit: Understanding the Research Participation Experiences of Bereaved Parents of Children with Complex Chronic Conditions.

Improving end of life (EOL) care for children with complex chronic conditions (CCCs) requires parental perspectives. The vulnerability of bereaved parents has historically been a research barrier and studies describing their research participation experience are lacking.

Learn More >

Interoception and alexithymia are related to differences between the self-reported and the objectively measured physical activity in patients with chronic musculoskeletal pain.

Patients with chronic musculoskeletal pain (CMP) have difficulty estimating their level of physical activity (PA). Factors associated with this difficulty have yet to be identified; however, identification could allow for increased accuracy in large-scale PA surveys, and enhanced self-management. The purpose of this study was to determine the relationship of interoception and alexithymia with differences between self-reported and objectively measured PA, and investigate factors as they relate to accurately self-reporting PA.

Learn More >

A randomized controlled TRIal of cognitive BEhavioral therapy for high Catastrophizing in patients undergoing lumbar fusion surgery: the TRIBECA study.

Around 20% of patients undergoing spinal fusion surgery have persistent back or leg pain despite surgery. Pain catastrophizing is the strongest psychological predictor for chronic postsurgical pain. Psychological variables are modifiable and could be target for intervention. However, randomized controlled trials evaluating the effectiveness of psychological interventions to reduce chronic pain and disability after spinal fusion in a population of patients with high preoperative pain catastrophizing scores are missing. The aim of our study is to examine whether an intervention targeting pain catastrophizing mitigates the risk of chronic postsurgical pain and disability. Our primary hypothesis is that targeted perioperative cognitive behavioral therapy decreases the risk of chronic postsurgical pain and disability after spinal fusion surgery in high catastrophizing patients.

Learn More >

SIGMA-1 RECEPTOR: A DRUG TARGET FOR THE MODULATION OF NEUROIMMUNE AND NEUROGLIAL INTERACTIONS DURING CHRONIC PAIN.

Immune and glial cells play a pivotal role in chronic pain. Therefore, it is possible that the pharmacological modulation of neurotransmission from an exclusively neuronal perspective may not be enough for adequate pain management, and the modulation of complex interactions between neurons and other cell types might be needed for successful pain relief. In this article, we review the current scientific evidence for the modulatory effects of sigma-1 receptors on communication between the immune and nervous systems during inflammation, as well as the influence of this receptor on peripheral and central neuroinflammation. Several experimental models of pathological pain are considered, including peripheral and central neuropathic pain, osteoarthritic, and cancer pain. Sigma-1 receptor inhibition prevents peripheral (macrophage infiltration into the dorsal root ganglion) and central (activation of microglia and astrocytes) neuroinflammation in several pain models, and enhances immune-driven peripheral opioid analgesia during painful inflammation, maximizing the analgesic potential of peripheral immune cells. Therefore, sigma-1 antagonists may constitute a new class of analgesics with an unprecedented mechanism of action and potential utility in several painful disorders.

Learn More >

Efficacy and Safety of the Controlled-release Pregabalin Tablet (GLA5PR GLARS-NF1) and Immediate-release Pregabalin Capsule for Peripheral Neuropathic Pain: a Multicenter, Randomized, Double-blind, Parallel-group, Active-controlled, Phase III Clinical Tri

This study compared the efficacy and safety of controlled-release pregabalin (GLA5PR GLARS-NF1 tablets) with those of an immediate-release pregabalin capsule after 12 weeks' administration to patients with peripheral neuropathic pain.

Learn More >

Oxytocin-Dependent Regulation of TRPs Expression in Trigeminal Ganglion Neurons Attenuates Orofacial Neuropathic Pain Following Infraorbital Nerve Injury in Rats.

We evaluated the mechanisms underlying the oxytocin (OXT)-induced analgesic effect on orofacial neuropathic pain following infraorbital nerve injury (IONI). IONI was established through tight ligation of one-third of the infraorbital nerve thickness. Subsequently, the head withdrawal threshold for mechanical stimulation (MHWT) of the whisker pad skin was measured using a von Frey filament. Trigeminal ganglion (TG) neurons innervating the whisker pad skin were identified using a retrograde labeling technique. OXT receptor-immunoreactive (IR), transient receptor potential vanilloid 1 (TRPV1)-IR, and TRPV4-IR TG neurons innervating the whisker pad skin were examined on post-IONI day 5. The MHWT remarkably decreased from post-IONI day 1 onward. OXT application to the nerve-injured site attenuated the decrease in MHWT from day 5 onward. TRPV1 or TRPV4 antagonism significantly suppressed the decrement of MHWT following IONI. OXT receptors were expressed in the uninjured and Fluoro-Gold (FG)-labeled TG neurons. Furthermore, there was an increase in the number of FG-labeled TRPV1-IR and TRPV4-IR TG neurons, which was inhibited by administering OXT. This inhibition was suppressed by co-administration with an OXT receptor antagonist. These findings suggest that OXT application inhibits the increase in TRPV1-IR and TRPV4-IR TG neurons innervating the whisker pad skin, which attenuates post-IONI orofacial mechanical allodynia.

Learn More >

Search