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Chronic pain affects up to 30% of the adult population Chronic pain affects up to 30% of the adult population […].
Learn More >Voltage-dependent sodium and calcium channels in pain-initiating nociceptor neurons are attractive targets for new analgesics. We made a permanently charged cationic derivative of an N-type calcium channel-inhibitor. Unlike cationic derivatives of local anesthetic sodium channel blockers like QX-314, this cationic compound inhibited N-type calcium channels more effectively with extracellular than intracellular application. Surprisingly, the compound is also a highly effective sodium channel inhibitor when applied extracellularly, producing more potent inhibition than lidocaine or bupivacaine. The charged inhibitor produced potent and long-lasting analgesia in mouse models of incisional wound and inflammatory pain, inhibited release of the neuropeptide calcitonin gene-related peptide (CGRP) from dorsal root ganglion neurons, and reduced inflammation in a mouse model of allergic asthma, which has a strong neurogenic component. The results show that some cationic molecules applied extracellularly can powerfully inhibit both sodium channels and calcium channels, thereby blocking both nociceptor excitability and pro-inflammatory peptide release.
Learn More >The American Registry for Migraine Research (ARMR) is a multicenter, prospective, longitudinal patient registry, biorepository, and neuroimaging repository that collects clinical data, electronic health record (EHR) data, blood samples, and brain imaging data from individuals with migraine or other headache types. In this manuscript, we outline ARMR research methods and report baseline data describing an initial cohort of ARMR participants.
Learn More >Neuropathic pain (NeuP) arises due to injury of the somatosensory nervous system and is both common and disabling, rendering an urgent need for non-addictive, effective new therapies. Given the high evolutionary conservation of pain, investigative approaches from Drosophila mutagenesis to human Mendelian genetics have aided our understanding of the maladaptive plasticity underlying NeuP. Successes include the identification of ion channel variants causing hyper-excitability and the importance of neuro-immune signaling. Recent developments encompass improved sensory phenotyping in animal models and patients, brain imaging, and electrophysiology-based pain biomarkers, the collection of large well-phenotyped population cohorts, neurons derived from patient stem cells, and high-precision CRISPR generated genetic editing. We will discuss how to harness these resources to understand the pathophysiological drivers of NeuP, define its relationship with comorbidities such as anxiety, depression, and sleep disorders, and explore how to apply these findings to the prediction, diagnosis, and treatment of NeuP in the clinic.
Learn More >The paucity of selective agonists for TWIK-related acid-sensitive K 3 (TASK-3) channel, a member of two-pore domain K (K2P) channels, has contributed to our limited understanding of its biological functions. By targeting a druggable transmembrane cavity using a structure-based drug design approach, we discovered a biguanide compound, CHET3, as a highly selective allosteric activator for TASK-3-containing K2P channels, including TASK-3 homomers and TASK-3/TASK-1 heteromers. CHET3 displayed potent analgesic effects in vivo in a variety of acute and chronic pain models in rodents that could be abolished pharmacologically or by genetic ablation of TASK-3. We further found that TASK-3-containing channels anatomically define a unique population of small-sized, transient receptor potential cation channel subfamily M member 8 (TRPM8)-, transient receptor potential cation channel subfamily V member 1 (TRPV1)-, or tyrosine hydroxylase (TH)-positive nociceptive sensory neurons and functionally regulate their membrane excitability, supporting CHET3 analgesic effects in thermal hyperalgesia and mechanical allodynia under chronic pain. Overall, our proof-of-concept study reveals TASK-3-containing K2P channels as a druggable target for treating pain.
Learn More >There is an ongoing need for potent opioids with less adverse effects than commonly used opioids. R-dihydroetorphine is a full opioid receptor agonist with relatively high affinity at the μ-, δ- and κ-opioid receptors and low affinity at the nociception/orphanin FQ receptor. The authors quantified its antinociceptive and respiratory effects in healthy volunteers. The authors hypothesized that given its receptor profile, R-dihydroetorphine will exhibit an apparent plateau in respiratory depression, but not in antinociception.
Learn More >Research suggests that endogenous opioids play a key role in the creation and maintenance of attachment bonds. Opioids acting at the μ-opioid receptor mediate reward and analgesia and are thus thought to underlie feelings of comfort and warmth experienced in the presence of close others. Disruption of μ-opioidergic activity increases separation distress in animals, suggesting that low opioid states may contribute to social pain. Accordingly, a functional μ-opioid receptor (OPRM1) polymorphism (C77G in primates, A118G in humans) affecting opioidergic signaling has been associated with separation distress and attachment behavior in nonhuman primates, and social pain sensitivity in humans. However, no research has examined the effects of this polymorphism on socioemotional experience, and specifically felt security, in daily interactions between romantic partners. Using an event-contingent recording method, members of 92 cohabiting romantic couples reported their felt security and quarrelsome behavior in daily interactions with each other for 20 days. Consistent with prior work, findings suggested that, relative to AA homozygotes, G allele carriers were more sensitive to their partners' self-reported quarrelsome behaviors (e.g., criticism), showing a greater decline in felt security when their partners reported higher quarrelsome behavior than usual. This is the first study to link variation in OPRM1 with felt security toward romantic partners in everyday social interactions. More generally, this research supports the theory that the attachment system incorporated evolutionarily primitive pain-regulating opioidergic pathways. We also discuss implications of this work for understanding of differential vulnerability to health risks posed by social stress.
Learn More >Opioids are the recommended form of analgesia for patients with persistent cancer pain and regular dosing 'by the clock' is advocated in many international guidelines on cancer pain management. The development of sustained release opioid preparations has made regular dosing easier for patients. However, patients report that the intensity and impact of their cancer pain varies considerably day to day, and many try to find a trade-off between acceptable pain control and impact of cognitive (and other) adverse effects on daily activities. In acute care settings, (eg post-operative) as needed dosing and other opioid sparing approaches have resulted in better patient outcomes compared with regular dosing. The aim of this study was to determine whether regular dosing of opioids was superior to as needed dosing for persistent cancer pain. We systematically searched for randomised controlled trials that directly compared pain outcomes from regular dosing of opioids with as needed dosing in adult cancer patients. We identified 4347 records, 25 RCTs meet the inclusion criteria, nine were included in the review and 7 of these included in meta-analysis. We found no clear evidence demonstrating superiority of regular dosing of opioids compared with as needed dosing in persistent cancer pain and regular dosing was associated with significantly higher total opioid doses. There was, however, a paucity of trials directly answering this question and low-quality evidence limits the conclusions that can be drawn. It is clear that further high-quality clinical trials are needed to answer this question and to guide clinical practice.
Learn More >Native Americans (NAs) have a higher prevalence of chronic pain than other U.S. racial/ethnic groups, but there have been few attempts to understand the mechanisms of this pain disparity. This study used a comprehensive battery of laboratory tasks to assess peripheral fiber function (cool/warm detection thresholds), pain sensitivity (eg, thresholds/tolerances), central sensitization (eg, temporal summation), and pain inhibition (conditioned pain modulation) in healthy, pain-free adults (N = 155 NAs, N = 150 non-Hispanic Whites [NHWs]). Multiple pain stimulus modalities were used (eg, cold, heat, pressure, ischemic, and electric), and subjective (eg, pain ratings and pain tolerance) and physiological (eg, nociceptive flexion reflex) outcomes were measured. There were no group differences on any measure, except that NAs had lower cold-pressor pain thresholds and tolerances, indicating greater pain sensitivity than NHWs. These findings suggest that there are no group differences between healthy NAs and NHWs on peripheral fiber function, central sensitization, or central pain inhibition, but NAs may have greater sensitivity to cold pain. Future studies are needed to examine potential within-group factors that might contribute to NA pain risk.
Learn More >High frequency stimulation (HFS) of the sciatic nerve has been reported to produce long term potentiation (LTP) and long-lasting pain hypersensitivity in rats. However, the central underlying mechanism remains unclear. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX) belongs to a group of electron-transporting transmembrane enzymes that produce reactive oxygen species (ROS). Here we found that NOX2 was upregulated in the lumbar spinal dorsal horn after HFS of the left sciatic nerve, which induced bilateral pain and spinal LTP in both male and female rats. Blocking NOX2 with blocking peptide or shRNA prevented the development of bilateral mechanical allodynia, the induction of spinal LTP, and the phosphorylation of N-methyl-d-aspartate (NMDA) receptor 2B (GluN2B) and nuclear factor kappaB (NF-κB) p65 following HFS. Moreover, NOX2 shRNA reduced the frequency and amplitude of both spontaneous excitatory post synaptic currents (sEPSCs) and miniature excitatory postsynaptic currents (mEPSCs) in laminar II neurons. Furthermore, 8-hydroxyguanine (8-OHG), an oxidative stress marker, was increased in the spinal dorsal horn. Spinal application of ROS scavenger, Phenyl-N-tert-butylnitrone (PBN), depressed the already established spinal LTP. Spinal application of H2O2, one ROS, induced LTP and bilateral mechanical allodynia, increased the frequency and amplitude of sEPSCs in laminar II neurons, and phosphorylated GluN2B and p65 in the dorsal horn. The present study provided electrophysiological and behavioral evidence that NOX2- derived ROS in the spinal cord contributed to persistent mirror-image pain by enhancing the synaptic transmission, which was mediated by increasing presynaptic glutamate release and activation of NMDAR and NF-κB in the spinal dorsal horn.
Learn More >Chronic pain is often associated with changes in brain structure and function, and also cognitive deficits. It has been noted that these chronic pain-related alterations may resemble changes found in healthy aging, and thus may represent accelerated or pre-mature aging of the brain. Here we test the hypothesis that patients with chronic non-cancer pain demonstrate accelerated brain aging compared to healthy control subjects. The predicted brain age of 59 patients with chronic pain (mean chronological age ± standard deviation: 53.0 ± 9.0 years; 43 women) and 60 pain-free healthy controls (52.6 ± 9.0 years; 44 women) was determined using the software brainageR. This software segments the individual T1-weighted structural MR images into gray and white matter and compares gray and white matter images to a large (n = 2001) training set of structural images, using machine learning. Finally, brain age delta, which is the predicted brain age minus chronological age, was calculated and compared across groups. This study provided no evidence for the hypothesis that chronic pain is associated with accelerated brain aging (Welch's t-test, p = 0.74, Cohen's d = 0.061). A Bayesian independent samples t-test indicated moderate evidence in favor of the null hypothesis (BF01 = 4.875, i.e. group means were equal). Our results provide indirect support for recent models of pain related-changes of brain structure, brain function, and cognitive functions. These models postulate network-specific maladaptive plasticity, rather than wide-spread or global neural degeneration.
Learn More >This paper addresses the problem of long-term opioid use by chronic pain patients. The study involved a secondary analysis of unanalysed data from a published study of two versions of CBT-based interdisciplinary treatment for chronic pain. In this paper we examined whether the use of opioids by 140 chronic pain patients could be ceased sustainably over 12-months following participation in the comprehensive interdisciplinary pain management program aimed at enhancing pain self-management. On admission to the treatment there were no significant differences between those patients taking or not taking opioids on usual pain, pain interference in daily activities, pain-related disability, depression severity, as well as in pain cognitions. Following the treatment the use of opioids was significantly reduced, both in numbers taking any and in mean doses, and these gains were maintained over the 12-month follow-up. Finally, cessation of opioids during treatment was associated with more substantial and consistent improvements in usual pain, depression severity, pain interference, pain-related disability, and pain cognitions, relative to those who reduced their opioids but did not cease them. These findings support the idea of using training in pain self-management strategies as a viable alternative to long-term opioid use by patients with chronic pain.
Learn More >Drawing on advances in chronic pain metrics, a simplified Graded Chronic Pain Scale Revised (GCPS-R) was developed to differentiate mild, bothersome and high impact chronic pain. GCPS-R was validated among adult enrollees of two health plans (N=2021). In this population, the prevalence of chronic pain (pain present most or every day, prior 3 months) was 40.5%: 15.4% with mild chronic pain (lower pain intensity and interference); 10.1% bothersome chronic pain (moderate to severe pain intensity with lower life activities interference); and 15.0% high impact chronic pain (sustained pain-related activity limitations). Persons with mild chronic pain versus those without chronic pain showed small differences on ten health status indicators (unfavorable health perceptions, activity limitations, receiving long-term opioid therapy), with non-significant differences for 7 of 10 indicators. Persons with bothersome versus mild chronic pain differed significantly on 6 of 10 indicators (e.g., negative pain coping beliefs, psychological distress, unfavorable health perceptions and pain-related interference with overall activities). Persons with high impact chronic pain differed significantly from those with mild chronic pain on all 10 indicators. Persons with high impact chronic pain, relative to those with bothersome chronic pain, were more likely to have substantial activity limitations (significant differences for 4 of 5 disability indicators) and more often received long-term opioid therapy. GCPS-R strongly predicted five activity limitation indicators with area under receiver operating characteristic curve coefficients of 0.76 to 0.89. We conclude that the 5 item GCPS-R and its scoring rules provide a brief, simple and valid method for assessing chronic pain.
Learn More >Approximately 1.7 million youth suffer from debilitating chronic pain in the US alone, conferring risk for continued pain in adulthood. Abberations in threat-safety (T-S) discrimination are proposed to contribute to pain chronicity in adults and youth by interacting with pain-related distress. Yet, few studies have examined the neural circuitry underlying T-S discrimination in patients with chronic pain or how T-S discrimination relates to pain-related distress. In this study, 91 adolescents (10-24 years; 78 females) including 30 chronic pain patients with high pain-related distress, 29 chronic pain patients with low pain-related distress, and 32 healthy peers without chronic pain completed a developmentally-appropriate T-S learning paradigm. We measured self-reported fear, psychophysiology (skin conductance response), and functional MRI responses (N = 72 after fMRI exclusions). After controlling for age and anxiety symptoms, patients with high pain-related distress showed altered self-reported fear and fronto-limbic activity in response to learned threat and safety cues compared to both patients with low pain-related distress and healthy controls. Specifically, adolescent patients with high pain-related distress reported elevated fear and showed elevated limbic (hippocampus, amygdala) activation in response to a learned threat cue (CS+). In addition, they showed decreased frontal (vmPFC) activation and aberrant fronto-limbic connectivity in response to a learned safety cue (CS-). Patients with low pain-related distress and healthy controls appeared strikingly similar across brain and behavior. These findings indicate that altered T-S discrimination, mediated by fronto-limbic activation and connectivity, may be one mechanism maintaining pain chronicity in adolescents with high levels of pain-related distress.
Learn More >Chronic pain is known to alter the brain's network dynamics. These dynamics are often demonstrated by identifying alterations in the brain network topology. A common approach used for this purpose is graph theory. To date, little is known on how these potentially altered networks in chronic pain relate to the symptoms reported by these patients. Here, we applied a graph theoretical approach to identify network changes in patients suffering from chronic neck pain, a group that is often neglected in chronic pain research. Participants with chronic traumatic and non-traumatic neck pain were compared to healthy pain-free controls. They showed higher levels of self-reported symptoms of sensitization, higher levels of disability and impaired sensorimotor control. The brain suffering from chronic neck pain furthermore showed altered network properties in the posterior cingulate cortex, amygdala and pallidum compared to the healthy pain-free brain. These regions have been identified as brain hubs (i.e. regions that are responsible for orchestrating communication between other brain regions) and are therefore known to be more vulnerable in brain disorders including chronic pain. We were furthermore able to uncover associations between these altered brain network properties and the symptoms reported by patients. Our findings indicate that chronic neck pain patients reflect brain network alterations and that targeting the brain in patients might be of utmost importance.
Learn More >(250 WORDS): Repetitive transcranial magnetic stimulation (rTMS) is a procedure increasingly used to treat patients with central neuropathic pain (CNP), but its efficacy is still under debate.Patients with medically refractory chronic CNP were included in two randomized phases (active/sham), separated by a wash-out period of 8 weeks. Each phase consisted of 4 consecutive rTMS sessions and a final evaluation session, all separated from one another by 3 weeks. High-frequency (20Hz) rTMS was delivered over the primary motor cortex (M1) contralateral to the patient's pain using a neuronavigated robotic system. Patients and clinicians assessing outcomes were blinded to treatment allocation during the trial. The primary outcome measured the percentage of pain relief (%R) from baseline. Secondary outcomes were VAS score, Neuropathic Pain Symptom Inventory (NPSI), analgesic drug consumption and quality of life (EQ-5D).Thirty-six patients performed the entire study with no adverse effects. The analgesic effect for the main criterion (%R) was significantly higher in the active (33.8% CI: [23.88-43.74]) than in the sham phase (13.02% CI:[6.64-19.76]). This was also the case for the secondary outcome VAS (-19.34% CI: [14.31-25.27] vs. -4.83% CI: [1.96-8.18]). No difference was observed for quality of life or analgesic drug consumption. Seventeen patients (47%) were identified as responders but no significant interaction was found between clinical and technical factors considered here and the analgesic response.These results provide strong evidence that 3-weeks spaced high-frequency rTMS of M1 results in a sustained analgesic effect and support the clinical interest of this stimulation paradigm to treat refractory chronic pain.
Learn More >Opioid prescription in the treatment of chronic pain is frequent and carries a risk of increased morbidity and mortality in a clinically significant number of patients, particularly those who are using opioids in a hazardous manner. Few treatment options are available that target both pain-related interference and hazardous opioid use among patients with chronic pain. In military Veterans, this issue is of particular importance as numerous reports indicate continued high rates of opioid prescription for chronic pain, as well as significant opioid-related problems. The overall aim of the present study was to determine the feasibility of an integrated psychosocial treatment in Veterans with chronic pain, who also have evidence of hazardous opioid use. To examine this aim, a random design was used to assess the feasibility and initial efficacy of integrating two empirically supported interventions: Acceptance and Commitment Therapy for chronic pain and Mindfulness Based Relapse Prevention for opioid misuse. Half of participants were randomized to the integrated treatment group and all participants received usual care (UC) through a Veteran's Administration co-occurring disorders medical clinic to treat chronic pain and opioid misuse. In total, 37 participants were randomized and included in intent to treat (ITT) analyses and 32 individuals were included in per protocol (PP) analyses with 6-month follow-up serving as the primary study endpoint. Feasibility indicators included recruitment, retention, and treatment completion rates. Recruitment fell short of targeted enrollment, although retention and completion were excellent. Primary outcome measures were opioid misuse, pain interference, and pain behavior. Simultaneous multiple regression analyses controlled for pain duration, baseline opioid dose, and baseline value for outcome measures. Results of both the ITT and PP indicated a significant effect in favor of the integrated intervention for opioid misuse, pain interference, and pain behavior. Results support the feasibility of providing an integrated treatment for both opioid risk and pain interference. PERSPECTIVE: Opioid misuse occurs in some opioid-prescribed individuals with chronic pain. Few treatment options exist that target both pain interference and opioid misuse. This study examined feasibility and initial efficacy of an integrated behavioral treatment for Veterans. Feasibility was supported, except recruitment. Efficacy was supported compared to usual care.
Learn More >In diabetic neuropathy, there is activation of axonal and sensory neuronal degeneration pathways leading to distal axonopathy. The nicotinamide-adenine dinucleotide (NAD+)-dependent deacetylase enzyme, Sirtuin 1 (SIRT1), can prevent activation of these pathways and promote axonal regeneration. In this study, we tested whether increased expression of SIRT1 protein in sensory neurons prevents and reverses experimental diabetic neuropathy induced by a high fat diet (HFD). We generated a transgenic mouse that is inducible and overexpresses SIRT1 protein in neurons (nSIRT1OE Tg). Higher levels of SIRT1 protein were localized to cortical and hippocampal neuronal nuclei in the brain and in nuclei and cytoplasm of small to medium sized neurons in dorsal root ganglia. Wild-type and nSIRT1OE Tg mice were fed with either control diet (6.2% fat) or a HFD (36% fat) for 2 months. HFD-fed wild-type mice developed neuropathy as determined by abnormal motor and sensory nerve conduction velocity, mechanical allodynia, and loss of intraepidermal nerve fibres. In contrast, nSIRT1OE prevented a HFD-induced neuropathy despite the animals remaining hyperglycaemic. To test if nSIRT1OE would reverse HFD-induced neuropathy, nSIRT1OE was activated after mice developed peripheral neuropathy on a HFD. Two months after nSIRT1OE, we observed reversal of neuropathy and an increase in intraepidermal nerve fibre. Cultured adult dorsal root ganglion neurons from nSIRT1OE mice, maintained at high (30 mM) total glucose, showed higher basal and maximal respiratory capacity when compared to adult dorsal root ganglion neurons from wild-type mice. In dorsal root ganglion protein extracts from nSIRT1OE mice, the NAD+-consuming enzyme PARP1 was deactivated and the major deacetylated protein was identified to be an E3 protein ligase, NEDD4-1, a protein required for axonal growth, regeneration and proteostasis in neurodegenerative diseases. Our results indicate that nSIRT1OE prevents and reverses neuropathy. Increased mitochondrial respiratory capacity and NEDD4 activation was associated with increased axonal growth driven by neuronal overexpression of SIRT1. Therapies that regulate NAD+ and thereby target sirtuins may be beneficial in human diabetic sensory polyneuropathy.
Learn More >Itch stimuli are detected by specialized primary afferents, which convey the signal to the spinal cord, but how itch transmission is regulated is still incompletely known. Here, we investigated the roles of the neuropeptide Y (NPY)/Y2 receptor system on scratch behavior. The inhibitory Y2 receptor is expressed on mouse primary afferents and intrathecal administration of the Y2 agonist peptide YY (PYY)3-36 reduced scratch episode frequency and duration induced by compound 48/80, an effect that could be reversed by intrathecal pre-administration of the Y2 antagonist BIIE0246. Also, scratch episode duration induced by histamine could be reduced by PYY3-36. In contrast, scratch behavior induced by α-methyl-5HT, SLIGRL, chloroquine, topical dust mite extract, or mechanical itch induced by von Frey filaments was unaffected by stimulation of Y2. Primary afferent neurons expressing the Npy2r gene were found to co-express itch-associated markers such as natriuretic peptide precursor b, oncostatin M receptor and interleukin (IL) 31 receptor A. Accordingly, intrathecal PYY3-36 reduced the scratch behavior induced by IL-31. Our findings imply that the NPY/Y2 system reduces histaminergic and IL-31-associated itch through presynaptic inhibition of a subpopulation of itch-associated primary afferents. SIGNIFICANCE STATEMENT: The spinal neuropeptide Y system dampens scratching behavior induced by histaminergic compounds and interleukin 31, a cytokine involved in atopic dermatitis, through interactions with the Y2 receptor. The Y2 receptor is expressed by primary afferent neurons that are rich in itch-associated neurotransmitters and receptors such as somatostatin, natriuretic peptide precursor b and interlekin 31 receptors.
Learn More >Post-surgical pain that lingers beyond the initial few-week period of tissue healing is a major predictor of pain chronification, which leads to substantial disability and new persistent opioid analgesic use. We investigated whether postoperative medical complications increase the risk of lingering post-surgical pain.
Learn More >The κ-opioid receptor (KOR) system has been implicated in the regulation of many behaviors including pain. While there are numerous studies suggesting KOR regulation of pain being mediated spinally, there have been reports of pain-like behaviors regulated by central KOR signaling. In particular, oxytocin-induced analgesia appears to be mediated by KOR receptors within the ventrolateral periaqueductal gray (vlPAG). We recently found that activation of dopamine (DA) neurons within the vlPAG is antinociceptive. In this study, we sought to determine the impact of KOR signaling on -GABAergic inputs onto vlPAG DA neurons, and the mechanism through which KOR impacts these inputs. We found that activation of KOR reduced GABAergic transmission onto vlPAG DA neurons. In addition, our data suggest this effect is mediated presynaptically via the G protein βγ-subunit. They raise the possibility that KOR activation disinhibits -vlPAG DA neurons, which could lead to altered regulation of pain-related behaviors.
Learn More >Low back pain is costly and disabling. Prognostic factor evidence can help healthcare providers and patients understand likely prognosis, inform the development of prediction models to identify subgroups, and may inform new treatment strategies. Recent studies have suggested that people who have poor expectations for recovery experience more back pain disability, but study results have differed.
Learn More >Previous studies have indicated a positive relationship between self-compassion and psychological and emotional well-being in chronic pain populations. However, evidence on the role and mechanisms of self-compassion in pain perception is largely limited. The current study was designed to investigate the effects and a potential mechanism of self-compassion on experimental pain. Thirty healthy participants underwent a compassionate self-talk protocol, which was followed by cold pain exposure during which high-frequency heart rate variability (HF-HRV) was evaluated. The compassionate self-talk protocol successfully generated compassionate statements among the participants. Our behavioral data showed lower pain ratings in the self-compassion compared to the control condition. Moreover, self-compassion manipulation resulted in higher HF-HRV during pain, which was associated with lower pain ratings. We present interesting findings that a short period of compassionate self-talk may decrease experimental pain as well as mechanistic evidence surrounding bodily control over pain-related arousal indicated by HF-HRV. PERSPECTIVE: This study presents the first line of evidence that a short period of compassionate self-talk may be sufficient to reduce experimental pain. We also demonstrate increased bodily control as a potential mechanism underlying this effect.
Learn More >Recent research has shown that placebos are effective even if they are openly prescribed to participants. However, it is unclear how such "open-label placebos" (OLPs) compare to deceptive placebo (DP) and what the mechanisms of actions are. In this study, we therefore compared two versions of OLP to DP and no treatment (NT).
Learn More >Chronic pain is a heavy burden disease. Current treatments are generally weakly effective or associated with adverse effects. New therapeutic approaches are therefore needed. Recent studies have suggested T-type calcium channels as an attractive target for the treatment of chronic pain. In this perspective, it was decided to perform a preclinical evaluation of the efficacy of ethosuximide, a T-type channel blocker used clinically as an antiepileptic, as a novel pharmacological treatment for chronic pain. Assessment of the effect of ethosuximide was thus made in both nociception and pain-related comorbidities as anxiety and depression are frequently encountered in chronic pain patients. Our results show that such symptoms occurred in three animal models of chronic pain designed to reflect traumatic neuropathic, chemotherapy-induced neuropathic and inflammatory pain conditions. Administration of ethosuximide reduced both chronic pain and comorbidities with a marked intensity ranging from partial reduction to a complete suppression of symptoms. These results make ethosuximide, and more broadly the inhibition of T-type calcium channels, a new strategy for the management of uncontrolled chronic pain, likely to improve not only pain but also the accompanying anxiety and depression.
Learn More >Oxaliplatin is the first-line chemotherapy for metastatic colorectal cancer. Unlike other platinum anticancer agents, oxaliplatin does not result in significant renal impairment and ototoxicity. Oxaliplatin, however, has been associated with acute and chronic peripheral neuropathies. Despite the awareness of these side-effects, the underlying mechanisms are yet to be clearly established. Therefore, in this study, we aimed to understand the factors involved in the generation of chronic neuropathy elicited by oxaliplatin treatment. We established a rat model of oxaliplatin-induced neuropathic pain (4 mg kg-1 intraperitoneally). The paw withdrawal thresholds were assessed at different time-points after the treatment, and a significant decrease was observed 3 and 4 weeks after oxaliplatin treatment as compared to the vehicle treatment (4.4 ± 1.0 vs. 16.0 ± 4.1 g; P < 0.05 and 4.4 ± 0.7 vs. 14.8 ± 3.1 g; P < 0.05, respectively). We further evaluated the role of different mitogen-activated protein kinases (MAPKs) pathways in the pathophysiology of neuropathic pain. Although the levels of total extracellular signal-regulated kinase (ERK) 1/2 in the dorsal root ganglia (DRG) were not different between oxaliplatin and vehicle treatment groups, phosphorylated ERK (p-ERK) 1/2 was up-regulated up to 4.5-fold in the oxaliplatin group. Administration of ERK inhibitor PD98059 (6 μg day-1 intrathecally) inhibited oxaliplatin-induced ERK phosphorylation and neuropathic pain. Therefore, upregulation of p-ERK by oxaliplatin in rat DRG and inhibition of mechanical allodynia by an ERK inhibitor in the present study may provide a better understanding of intracellular molecular alterations associated with oxaliplatin-induced neuropathic pain and help in the development of potential therapeutics.
Learn More >Whiplash associated disorder (WAD), a common and disabling condition, incurs huge burden and costs to Australia. Yet, current treatments for whiplash are not very effective; improved outcomes are urgently needed. Clinical guidelines recommend simple analgesia (paracetamol and non-steroidal anti-inflammatory drugs) but there have been no trials of guideline-recommended drugs. This study will investigate the effectiveness of evidence-based advice (EBA), paracetamol, naproxen, and both paracetamol and naproxen, in reducing daily neck pain and preventing chronic neck pain after whiplash injury.
Learn More >To develop a multicenter, multistakeholder, prospective clinical registry of children and adolescents with migraine to support the collection of real-world data of sufficient quality to support regulatory submissions and provide site-based infrastructure support for future clinical trials.
Learn More >Background and purpose – Pain catastrophizing contributes to acute and long-term pain after total knee arthroplasty (TKA) but currently there are only limited treatment options. This study investigates the effectiveness of patient education in pain coping among patients with moderate to high pain catastrophizing score before TKA. Secondary outcomes were physical function, quality of life, self-efficacy, and pain catastrophizing.Patients and methods – The study was a parallel-group randomized controlled trial including patients with moderate to high levels of pain catastrophizing. 60 patients were recruited from December 2015 to June 2018. The mean age of the patients was 66 (47-82) years and 40 were women. The patients were randomized to either cognitive-behavioral therapy (CBT) based pain education or usual care. The primary outcome measure was pain under activity measured with the Visual Analog Scale (VAS). All outcomes were measured preoperatively, at 3 months, and at 1 year after surgery.Results – We found no difference in the primary outcome measure, VAS during activity, between the 2 groups but both groups had large reductions over time. The CBT-based pain education group reduced their VAS score by 37 mm (95% CI 27-46) and the control group by 40 mm (CI 31-49). We found no statistically significantly differences between the 2 groups in any of the secondary outcomes.Interpretation – Future research is warranted to identify predictors of persistent pain and interventions for the approximately 20% of patients with persisting pain after a TKA.
Learn More >Abdominal pain is common and is associated with high disease burden and health care costs in pediatric acute recurrent and chronic pancreatitis (ARP/CP). Despite the strong central component of pain in ARP/CP and the efficacy of psychological therapies for other centralized pain syndromes, no studies have evaluated psychological pain interventions in children with ARP/CP. The current trial seeks to 1) evaluate the efficacy of a psychological pain intervention for pediatric ARP/CP, and 2) examine baseline patient-specific genetic, clinical, and psychosocial characteristics that may predict or moderate treatment response.
Learn More >Neural plasticity, especially central sensitization, is essential for developing and maintaining neuropathic pain. Unfortunately, the analgesic potency of morphine is greatly reduced in animal models and patients with neuropathic pain. We hypothesized that pre-activation of spinal N-methyl-D-aspartate receptors (NMDARs) by agonist or neuropathic pain facilitated the development of morphine-induced analgesic tolerance. We therefore investigated the effects of spinal NMDAR activation, induced by neuropathic pain, on the development of morphine-induced analgesic tolerance in male Sprague-Dawley rats. Four days of chronic constriction injury (CCI) induced upregulation of spinal NR1. Once established, spinal central sensitization accelerated the development of morphine-induced analgesic tolerance. Continuous ropivacaine infusion prevented CCI-induced increases in spinal Substance P (SP), NR1, and TRPV1. Blockade of peripheral nociceptive inputs prevented chronic morphine-induced increases in spinal SP, NR1, and TRPV1 and a rightward shift of the morphine dose-response curve in the CCI model. These findings suggest that pre-activation of spinal NMDARs contributes to central sensitization and potentiates the development of morphine-induced analgesic tolerance. Interruption of the peripheral nociceptive inputs during the induction phase could prevent spinal central sensitization and retain morphine efficacy, thereby delaying the development of morphine-induced tolerance in patients with neuropathic conditions.
Learn More >Cannabinoid 1 receptor (CB1R) allosteric ligands hold far-reaching therapeutic promise. We report application of fluoro- and nitrogen-walk approaches to enhance the drug-like properties of GAT211, a prototype CB1R allosteric agonist-positive allosteric modulator (ago-PAM). Several analogs exhibited improved functional potency (cAMP, arrestin2), metabolic stability, and aqueous solubility. Two key analogs, GAT591 (6r) and GAT593 (6s), exhibited augmented allosteric-agonist and PAM activities in neuronal cultures, improved metabolic stability, and enhanced orthosteric agonist binding (CP55,940). Both also exhibited good analgesic potency in the CFA inflammatory-pain model with longer duration of action over GAT211 while devoid of adverse cannabimimetic effects. Another analog, GAT592 (9j), exhibited moderate ago-PAM potency and improved aqueous solubility with therapeutic reduction of intraocular pressure in murine glaucoma models. The SAR findings and the enhanced allosteric activity in this class of allosteric modulators were accounted for in our recently developed computational model for CB1R allosteric activation and positive allosteric modulation.
Learn More >Paclitaxel (Brand name Taxol) is widely used in the treatment of common cancers like breast, ovarian and lung cancer. Although highly effective in blocking tumor progression, paclitaxel also causes peripheral neuropathy as a side effect in 60-70% of chemotherapy patients. Recent efforts by numerous labs have aimed at defining the underlying mechanisms of paclitaxel-induced peripheral neuropathy (PIPN). In vitro models using rodent dorsal root ganglion neurons, human induced pluripotent stem cells, and rodent in vivo models have revealed a number of molecular pathways affected by paclitaxel within axons of sensory neurons and within other cell types, such as the immune system and peripheral glia, as well skin. These studies revealed that paclitaxel induces altered calcium signaling, neuropeptide and growth factor release, mitochondrial damage and reactive oxygen species formation, and can activate ion channels that mediate responses to extracellular cues. Recent studies also suggest a role for the matrix-metalloproteinase 13 (MMP-13) in mediating neuropathy. These diverse changes may be secondary to paclitaxel-induced microtubule transport impairment. Human genetic studies, although still limited, also highlight the involvement of cytoskeletal changes in PIPN. Newly identified molecular targets resulting from these studies could provide the basis for the development of therapies with which to either prevent or reverse paclitaxel-induced peripheral neuropathy in chemotherapy patients.
Learn More >Tolerance to the antinociceptive effects of cannabinoids represents a significant limitation to their clinical use in managing chronic pain. Tolerance likely results from desensitization and down-regulation of the cannabinoid type 1 receptor (CBR), with CBR desensitization occurring via phosphorylation of CBRs by a G protein-coupled receptor kinase and subsequent association with an arrestin protein. Previous studies have shown that (1) desensitization-resistant S426A/S430A mice exhibit a modest delay in tolerance for Δ-THC and CP55,940 but a more pronounced disruption in tolerance for WIN 55,212-2 and (2) that c-Jun N-terminal kinase (JNK) signaling may selectively mediate antinociceptive tolerance to morphine compared to other opioid analgesics. In the current study, we found that pretreatment with the JNK inhibitor SP600125 (3 mg/kg) attenuates tolerance to the antinociceptive and anti-allodynic effects of Δ-THC (6 mg/kg) in wild-type mice using the formalin test and in mice with cisplatin-evoked neuropathic pain, respectively. We also find that SP600125 causes an especially robust reduction in tolerance to the antinociceptive effects of Δ-THC (30 mg/kg) but not WIN 55,212-2 (10 mg/kg) in the tail-flick assay using S426A/S430A mice. Interestingly, SP600125 pretreatment accelerated tolerance to the antinociceptive and anti-allodynic effects of CP55,940 (0.3 mg/kg) in mice with acute and neuropathic pain. These results demonstrate that inhibition of JNK signaling pathways delay tolerance to Δ-THC, but not to CP55,940 or WIN55,212-2, demonstrating that the mechanisms of cannabinoid tolerance are agonist-specific.
Learn More >In recent decades, a growing number of structural neuroimaging studies of grey matter (GM) in trigeminal neuralgia (TN) have reported inconsistent alterations. We carried out a systematic review and meta-analysis to identify consistent and replicable GM volume abnormalities using effect-size signed differential mapping (ES-SDM). Furthermore, we conducted a meta-regression to explore the potential effects of clinical characteristics on GM volume alterations in patients with TN. A total of 13 studies with 15 datasets, representing 407 TN patients and 376 healthy individuals, were included in the present study. The results revealed that TN patients had GM volume abnormalities mainly in the basal ganglia, including the putamen, nucleus accumbens (NAc), caudate nucleus and amygdala, as well as the cingulate cortex (CC), thalamus, insula and superior temporal gyrus (STG). The meta-regression analysis showed that verbal rating scale (VRS) scores were negatively correlated with decreased GM volume in the left striatum and that illness duration was negatively correlated with decreased GM volume in the left STG and left insula. These results provide a thorough profile of GM volume alterations in TN patients and constitute robust evidence that aberrant GM volumes in the brain regions regulating and moderating sensory-motor and affective processing may play an important role in the pathophysiology of TN.
Learn More >Fremanezumab, a fully humanized monoclonal antibody targeting calcitonin gene-related peptide, has demonstrated efficacy for the preventive treatment of migraine in adults.
Learn More >Many medically-refractory trigeminal neuralgia patients are non-responders to surgical treatment. Few studies have explored how trigeminal nerve characteristics relate to surgical outcome, and none have investigated the relationship between subcortical brain structure and treatment outcomes.
Learn More >Juvenile Idiopathic Arthritis (JIA) is the most common rheumatic disease in childhood, with chronic pain being a main symptom. JIA symptoms can lead to substantial disability in children and their families. While preliminary evidence reveals the potential beneficial role of resilience in dealing with chronic pain, research on the role of resilience in how families of a child with JIA cope with pain-related symptoms is scant and dispersed. Using the framework of the Ecological Resilience-Risk Model, this review aims to identify (1) family characteristics that are associated with both risk and resilience in children with JIA and (2) the contribution of individual and parental resilience mechanisms and resources to resilience outcomes in children with JIA and their families. MEDLINE, EMBASE, EBSCO, Psycharticles, and PsycINFO were systematically searched. Longitudinal, cross-sectional, and treatment studies written in English with a focus on resilience resources and/or mechanisms in families of a child (6-18 years) with JIA were included. The original search (July 2016) produced 415 articles, with a final sample of 6 articles remaining after screening. An updated search (July 2018) did not identify new articles, but identified one extra article through personal communications. The 7 articles were included in a narrative review and study quality was assessed. Limited research was available on the role of family characteristics, with just one study revealing how family dysfunction is related to reduced child resilience. Studies evaluating the role of individual resilience mechanisms and resources most commonly assessed resilience outcomes in terms of recovery and sustainability outcomes, such as health-related quality of life (HRQL) and functional disability. The findings revealed that children's psychological flexibility, self-efficacy, adherence, pain acceptance, and perceived social support contribute to resilience outcomes. Findings were inconclusive for the influence of coping strategies, such as seeking social support. While our knowledge is growing, a better understanding of how familial and individual resilience resources and mechanisms influence adjustment to chronic pain as part of JIA is needed and can stimulate development of targeted interventions to enhance outcomes for children with JIA.
Learn More >Small fiber neuropathy (SFN) could cause significant morbidity due to neuropathic pain and autonomic dysfunction. SFN is underdiagnosed and the knowledge on the condition is limited among general public and health care professionals. This review is intended to enhance the understanding of SFN symptoms, causes, diagnostic tools, and therapeutic options.
Learn More >retrospective population-based cohort analysis.
Learn More >We aimed to examine arterial stiffness and vitamin K2 status in migraine subjects by comparison to controls.
Learn More >We recently identified novel small-molecule antagonists of the PACAP type I (PAC1) receptor using docking-based in silico screening followed by in vitro/vivo pharmacological assays. In the present study, we synthesized 18 novel derivatives based on the structure of PA-9, a recently developed antagonist of the PAC1 receptor, with a view to obtain a panel of compounds with more potent antagonistic and analgesic activities. Among them, compound 3d showed improved antagonistic activities. Intrathecal injection of 3d inhibited both pituitary adenylate cyclase-activating polypeptide (PACAP) and spinal nerve ligation-induced mechanical allodynia. The effects were more potent than PA-9. Compound 3d also showed anti-allodynic effects following oral administration. Hence, our results suggest that 3d may become an orally available analgesic in the treatment of the neuropathic pain.
Learn More >The objective of the review is to determine whether conditioned pain modulation (CPM) is impaired in adults with chronic low back pain when compared to pain-free individuals.
Learn More >The aim of this study was to measure the interictal burden (IIB) associated with cluster headache (CH).
Learn More >Almost 40% of individuals with chronic whiplash-associated disorders (WAD) report headache after 5 years, making it one of the most common persistent symptoms besides neck pain, but randomized treatment studies are lacking. This study aimed to evaluate the effect of 3 different exercise approaches on headache in chronic WAD grades 2 and 3, and to identify potential factors associated with such headache, and whether they differ depending on 3 different aspects of such headache (current headache, maximum headache, or headache bothersomeness).
Learn More >Neuropathic low back-related leg pain (LBLP) can be a challenge to healthcare providers to diagnose and treat. Accurate diagnosis of neuropathic pain is fundamental to ensure appropriate intervention is given. However, to date there is no gold standard to diagnose neuropathic LBLP. Patient examination guidelines and screening tools have been developed and validated for the purpose of diagnosing neuropathic pain in LBLP; however, there has been no systematic review conducted to compare the diagnostic validity of these methods. Therefore, this systematic review will investigate the diagnostic utility of patient history, clinical examination and screening tool data to identify neuropathic pain in LBLP.
Learn More >Migraine is highly prevalent and associated with a large socio-economic burden in the United States. Current preventive medications have variable efficacy and their use is often limited by intolerable side effects. Calcitonin gene-related peptide (CGRP) has been identified as an integral part of migraine pathophysiology. There are currently seven CGRP antagonists under investigation, all of which are undergoing or have completed phase 3 clinical trials. Three of the investigated CGRP antagonists are approved for use within and outside of the United States. The trials have resulted in positive efficacy and safety data. The purpose of this review is to evaluate the seven CGRP antagonists and their future place in therapy.
Learn More >The majority of preclinical studies investigating aberrant glial-neuroimmune actions underlying neuropathic pain have focused on male rodent models. Recently, studies have shown peripheral immune cells play a more prominent role than glial cells in mediating pathological pain in females. Here, we compared the onset and duration of allodynia in males and females, and the anti-allodynic action of a potentially novel therapeutic drug (BIRT377) that not only antagonizes the action of lymphocyte function-associated antigen-1 (LFA-1) to reduce cell migration in the periphery, but may also directly alter the cellular inflammatory bias.
Learn More >: Chronic pain is a common comorbid complaint in traumatized refugees seeking treatment for posttraumatic stress disorder (PTSD) and depression. However, the effect of comorbid pain on treatment remains under investigated. : To investigate whether pre-treatment pain (severity/interference) predicts outcomes in a multimodal treatment targeting PTSD, depression, anxiety, somatic complaints, and health-related disability in refugees exposed to torture and organized violence. Additional predictors were gender, age, and number of treatment sessions. : Participants were active cases at a specialist outpatient clinic for tortured refugees (n = 276; 170 men, 106 women) who were either on a treatment waitlist (mean length = 7.4 months, SD = 4.5), in treatment (mean length = 12.2 months, SD = 6.5), or who completed treatment and had (or were waiting for) a follow-up assessment. Participants completed symptom measures at referral, pre- and post-treatment, and 9-month follow-up. Multi-level mixed modelling was used to assess whether outcomes at post-treatment and 9-months were predicted by pain, gender, age, or the number of treatment sessions. : Treatment yielded significant pre-to-post-treatment reductions in PTSD, depression, anxiety, and number of pain locations, but no reductions in pain severity/interference, or health-related disability, except for societal participation. Gains for PTSD, depression, and societal participation were maintained at the 9-month follow-up. Higher levels of pain interference (but not severity) predicted poorer outcomes (PTSD, depression, and anxiety). Age, gender and number of treatment sessions did not predict outcomes, except for a small negative effect of (older) age on PTSD. : A growing body of literature suggests that pain and PTSD symptoms interact in ways to increase the severity and impact of both disorders in refugee and non-refugee populations alike. The present study suggests interference from pain can lessen the effectiveness of standard multi-modal treatments for refugees.
Learn More >While opioids play a critical role in the management of cancer pain, the ongoing opioid epidemic has raised concerns regarding their persistent use and abuse. We lack data-driven tools in oncology to understand the risk of adverse opioid-related outcomes. This project seeks to identify clinical risk factors and create a risk score to help identify patients at risk of persistent opioid use and abuse.
Learn More >Reliable population-based data on the prevalence and characteristics of primary headache across the lifespan are essential. However, robust data are lacking. We utilized questionnaire data from a random general population sample in Germany, that comprised 2,478 participants aged ≥14 years. A standardized questionnaire addressing headache and headache treatment was filled in during the face-to-face survey. The 6-month prevalence of self-reported headache in the total sample amounted to 39.0% (known diagnosis of migraine 7.2%; tension-type headache 12.4%; another diagnosis or unknown diagnosis 23.4%). Age-specific prevalence rates were 37.9% (14-34 years), 44.6% (35-54 years), 38.5% (55-74 years), and 26.9% (≥75 years). Compared to age group 14-34, participants aged 35-54 were more ( = 1.29, 95%- 1.05-1.60, = 0.018) and those aged ≥75 were less ( = 0.55, 95%- 0.40-0.76, < 0.001) likely to have any headache. Of the participants with headache, 79.5% reported headache on <4 days per month, 15.6% on 4-14 days per month and 4.9% on >14 days per month. The frequency of headache did not differ significantly between age groups in men [ = 1.45, > 0.05], but in women [ = 21.57, < 0.001]: women aged ≥75 years were over-represented in the group reporting 4-14 headache days per month. The analgesic use (days per month) differed significantly between age groups among participants with headache on <4 days per month and on >14 days per month: 1.8 (14-34 years), 2.5 (35-54 years), 3.2 (55-74 years), and 3.4 (≥75 years), respectively 7.9 (14-34 years), 11.4 (35-54 years), 18.4 (55-74 years), and 22.8 (≥75 years). In general, the prevalence of headache decreases with age. However, older women suffer from more frequent attacks and older participants take analgesics on more days per month than younger participants. This might put them at risk of medication overuse which may lead to medication overuse headache. More research is needed to understand these specifics in headache frequency and treatment behavior in older people.
Learn More >Mitigating the transition from acute to chronic whiplash-associated disorders (WAD) is fundamental, and this could be achieved through early identification of individuals at risk. Several physical factors such as angular velocity, smoothness of neck movement and coactivation of neck flexors and extensors, have been observed in patients with WAD, but their predictive ability after a whiplash injury have not been considered in previous reviews. Therefore, the aim of the current protocol is to outline the protocol for a systematic review that synthesises the current evidence of which physical factors can predict ongoing pain and disability following a whiplash trauma.
Learn More >Burst and high-frequency spinal cord stimulation (SCS), in contrast to low-frequency stimulation (LFS, < 200 Hz), reduce neuropathic pain without the side effect of paresthesia, yet it is unknown whether these methods' mechanisms of action (MoA) overlap. We used empirically based computational models of fiber threshold accommodation to examine the three MoA.
Learn More >Opioids are the most prescribed analgesics for pain in Inflammatory Bowel Diseases (IBD), however the consequences of opioid use on IBD severity is not well defined. This is the first study investigating consequences of hydromorphone in both dextran sodium sulfate (DSS)-induced colitis and spontaneous colitis [IL-10 knockout (IL-10-/-)] mouse model of IBD.
Learn More >The cannabinoid receptor type 1 (CB1R), a G protein-coupled receptor (GPCR), plays an essential role in the control of many physiological processes such as hunger, memory loss, gastrointestinal activity, catalepsy, fear, depression, and chronic pain. Therefore, it is an attractive target for drug discovery to manage pain, neurodegenerative disorders, obesity, and substance abuse. However, the psychoactive adverse effects, generated by CB1R activation in the brain, limit the use of the orthosteric CB1R ligands as drugs. The discovery of CB1R allosteric modulators during the last decade provided new tools to target the CB1R. Moreover, application of the site-directed mutagenesis in combination with advanced physical methods, especially X-ray crystallography and computational modeling, has opened new horizons for understanding the complexity of the structure, function, and activity of cannabinoid receptors. In this paper, we present the latest advances in research on the CB1R, its allosteric modulation and allosteric ligands, and their translational potential. We focused on structural essentials of the cannabinoid 1 receptor- ligand (drug) interactions, as well as modes of CB1R signaling regulation.
Learn More >Studies point to an increased hereditary risk of cluster headache. HCRTR2 gene rs2653349 and ADH4 gene rs1800759 polymorphisms have been associated with cluster headache susceptibility. Also, GNB3 rs5443 polymorphism, associated with increased signal transduction via GPCRs, seems to influence triptan treatment response. DNA from 114 cluster headache patients and 570 non-related controls, representing a general Southeastern European Caucasian (SEC) population, was extracted from buccal swabs and genotyped using real-time PCR. Gene distribution for the rs2653349 was GG = 79.8%, GA = 18.4%, and AA = 1.8% for patients and GG = 79.1%, GA = 19.1%, and AA = 1.8% for controls. The frequency of the mutated A allele was 11.0% for patients and 11.3% for controls. The frequencies for rs5443 were CC = 44.7%, CT = 44.7%, and TT = 10.5% for patients and CC = 43.9%, CT = 42.6%, and TT = 13.5% for controls. The frequency of the mutated T allele was 32.9% for patients and 34.8% for controls. A 2.7-fold more frequent appearance of the mutated T allele was observed in patients with better triptan treatment response, although not statistically significant. For rs1800759, the frequencies were CC = 36.0%, CA = 43.0%, and AA = 21.0% for patients and CC = 34.0%, CA = 50.2%, and AA = 15.8% for controls. The frequency of the mutated A allele was 42.5% and 40.9% for patients and controls, respectively. The mutated T allele of GNB3 rs5443 polymorphism was more prevalent in patients with better triptan treatment response, indicating a possible trend of association between this polymorphism and triptan treatment response in SEC population. According to our observation, no association of HCRTR2 rs2653349 and ADH4 rs1800759 polymorphisms and cluster headache in SEC population could be documented.
Learn More >Ubrogepant (MK-1602) is a novel, oral, calcitonin gene-related peptide receptor antagonist in clinical development with positive Phase III outcomes for acute treatment of migraine. This paper describes the population exposure-response (E-R) modeling and simulations which were used to inform the Phase III dose-selection rationale, based on approximately 800 participants pooled across two Phase IIb randomized dose-finding clinical trials. The E-R model describes the placebo and ubrogepant treatment effects based on migraine pain endpoints (2-hour pain relief and 2-hour pain freedom) at various dose levels. Sensitivity analyses were conducted to evaluate various assumptions of placebo response in light of the high placebo response observed in one Phase II trial. A population PK model describing the effect of formulations was included in the E-R simulation framework to assess potential dose implications of a formulation switch from Phase II to Phase III. Model-based simulations predict that a dose of 25 mg or higher is likely to achieve significantly better efficacy than placebo with desirable efficacy levels. The understanding of E-R helped support the dose selection for the Phase III clinical trials.
Learn More >The biopsychosocial model claims that illness is generated by biological, psychological, and social factors. The nocebo response, particularly nocebo hyperalgesia, is an excellent model and approach to understand these effects and their psychophysiological underpinnings, as nocebos are made of negative psychological and social factors, such as negative expectations and social interactions. There is today experimental evidence that nocebos can create symptoms and illness from nothing, in particular pain, whereby a combination of biological, psychological and social factors interact with each other in the generation of the global painful experience. Several biochemical pathways have been identified, e.g. cholecystokinin and cyclooxygenase, and the activation of these mechanisms has been specifically investigated in the field of pain, analgesia and hyperalgesia. The study of placebo and nocebo oxygen at high-altitude has been crucial to unravel these mechanisms, as reduction of oxygen pressure (hypoxia) leads to headache pain. Indeed, the investigation of oxygen-related conditions, such as hypoxia, represents today an excellent approach to understand how nocebos can contribute to generate illness and pain. In this review we discuss old and new findings that help us better understand the interplay between biology and psychology.
Learn More >Dementia is an irreversible, progressive form of cognitive dysfunction that can affect memory, learning ability, thinking, orientation, comprehension, calculation, linguistic skills and executive function but which does not impair consciousness. Pain prevalence is high among the elderly who are also at elevated risk for dementia. Pain control for dementia patients is important but can be challenging for clinicians as cognitive deficits can make it difficult to identify, localize and assess pain. Cerebral changes associated with dementia may change how people process and experience pain in ways that are not entirely elucidated. Agitation is a frequent symptom of dementia and may be associated with untreated pain as agitation and aggression symptoms decrease when pain is effectively addressed.
Learn More >Headache is the most common neurologic symptom and affects nearly half the world's population at any given time. Although the prevalence declines with age, headache remains a common neurologic complaint among elderly populations. Headaches can be divided into primary and secondary causes. Primary headaches comprise about two-thirds of headaches among the elderly. They are defined by clinical criteria and are diagnosed based on symptom pattern and exclusion of secondary causes. Primary headaches include migraine, tension-type, trigeminal autonomic cephalalgias, and hypnic headache. Secondary headaches are defined by their suspected etiology. A higher index of suspicion for a secondary headache disorder is warranted in older patients with new-onset headache. They are roughly 12 times more likely to have serious underlying causes and, frequently, have different symptomatic presentations compared to younger adults. Various imaging and laboratory evaluations are indicated in the presence of any "red flag" signs or symptoms. Head CT is the procedure of choice for acute headache presentations, and brain MRI for those with chronic headache complaints. Management of headache in elderly populations can be challenging due to the presence of multiple medical comorbidities, polypharmacy, and differences in drug metabolism and clearance.
Learn More >Background and aims Bariatric surgery remains a mainstay for treatment of morbid obesity. However, long-term adverse outcomes include chronic abdominal pain and persistent opioid use. The aim of this review was to assess the existing data on prevalence, possible mechanisms, risk factors, and outcomes regarding chronic abdominal pain and persistent opioid use after bariatric surgery. Methods PubMed was screened for relevant literature focusing on chronic abdominal pain, persistent opioid use and pharmacokinetic alterations of opioids after bariatric surgery. Relevant papers were cross-referenced to identify publications possibly not located during the ordinary screening. Results Evidence regarding general chronic pain status after bariatric surgery is sparse. However, our literature review revealed that abdominal pain was the most prevalent complication to bariatric surgery, presented in 3-61% of subjects with health care contacts or readmissions 1-5 years after surgery. This could be explained by behavioral, anatomical, and/or functional disorders. Persistent opioid use and doses increased after bariatric surgery, and 4-14% initiated a persistent opioid use 1-7 years after the surgery. Persistent opioid use was associated with severe pain symptoms and was most prevalent among subjects with a lower socioeconomic status. Alteration of absorption and distribution after bariatric surgery may impact opioid effects and increase the risk of adverse events and development of addiction. Changes in absorption have been briefly investigated, but the identified alterations could not be separated from alterations caused solely by excessive weight loss, and medication formulation could influence the findings. Subjects with persistent opioid use after bariatric surgery achieved lower weight loss and less metabolic benefits from the surgery. Thus, remission from comorbidities and cost effectiveness following bariatric surgery may be limited in these subjects. Conclusions Pain, especially chronic abdominal, and persistent opioid use were found to be prevalent after bariatric surgery. Physiological, anatomical, and pharmacokinetic changes are likely to play a role. However, the risk factors for occurrence of chronic abdominal pain and persistent opioid use have only been scarcely examined as have the possible impact of pain and persistent opioid use on clinical outcomes, and health-care costs. This makes it difficult to design targeted preventive interventions, which can identify subjects at risk and prevent persistent opioid use after bariatric surgery. Future studies could imply pharmacokinetic-, pharmacodynamics-, and physiological-based modelling of pain treatment. More attention to social, physiologic, and psychological factors may be warranted in order to identify specific risk profiles of subjects considered for bariatric surgery in order to tailor and optimize current treatment recommendations for this population.
Learn More >Internet-based cognitive behavior therapy (iCBT) can be effective in mental and somatic health care. Research on the feasibility of internet interventions in clinical practice is, however, still scarce. Studies with a focus on the patient regarding usability of interventions and digital health literacy skills are especially lacking.
Learn More >Due to the current absence of a standardized guide for activity pacing, the concept of pacing is interpreted in various ways by healthcare professionals, patients and researchers. Consequently, the effects of pacing across different conditions are unclear. The present study aimed to undertake the second stage in the development of an activity pacing framework for chronic pain/fatigue.
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