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The sensory nervous and immune systems work in concert to preserve homeostasis. While this endogenous interplay protects from danger, it may drive chronic pathologies. Currently, genetic engineering of neurons remains the primary approach to interfere selectively with this potentially deleterious interplay. However, such manipulations are not feasible in a clinical setting. Here, this work reports a nanotechnology-enabled concept to silence subsets of unmodified nociceptor neurons that exploits their ability to respond to heat via the transient receptor potential vanilloid type 1 (TRPV1) channel. This strategy uses laser stimulation of antibody-coated gold nanoparticles to heat-activate TRPV1, turning this channel into a cell-specific drug-entry port. This delivery method allows transport of a charged cationic derivative of an N-type calcium channel blocker (CNCB-2) into targeted sensory fibers. CNCB-2 delivery blocks neuronal calcium currents and neuropeptides release, resulting in targeted silencing of nociceptors. Finally, this work demonstrates the ability of the approach to probe neuro-immune crosstalk by targeting cytokine-responsive nociceptors and by successfully preventing nociceptor-induced CD8 T-cells polarization. Overall, this work constitutes the first demonstration of targeted silencing of nociceptor neuron subsets without requiring genetic modification, establishing a strategy for interfering with deleterious neuro-immune interplays.
Learn More >High definition transcranial direct current stimulation (HD-tDCS) targeting brain areas involved in pain processing has shown analgesic effects in some chronic pain conditions, but less modulatory effect on mechanical and thermal pain thresholds in asymptomatic subjects. This double-blinded study assessed the HD-tDCS effects on experimental pain and hyperalgesia maintained for several days in healthy participants. Hyperalgesia and pain were assessed during three consecutive days following provocation of experimental pain (nerve growth factor injected into the right hand muscle) and daily HD-tDCS sessions (20-min). Forty subjects were randomly assigned to Active-tDCS targeting primary motor cortex and dorsolateral prefrontal cortex simultaneously or Sham-tDCS. Tactile and pressure pain sensitivity were assessed before and after each HD-tDCS session, as well as the experimentally-induced pain intensity scored on a numerical rating scale (NRS). Subjects were effectively blinded to the type of HD-tDCS protocol. The Active-tDCS did not significantly reduce the NGF-induced NRS pain score (3.5±2.4) compared to Sham-tDCS (3.9±2.0) on Day3 and both groups showed similarly NGF-decreased pressure pain threshold in the right hand (P<0.001). Comparing Active-tDCS with Sham-tDCS, the manifestation of pressure hyperalgesia was delayed on Day1, and an immediate (pre-HD-tDCS to post-HD-tDCS) reduction in pressure hyperalgesia was found across all days (P<0.05). Perspectives: The non-significant differences between Active-tDCS and Sham-tDCS on experimental prolonged pain and hyperalgesia suggest that HD-tDCS has no effect on moderate persistent experimental pain. The intervention may still have a positive effect in more severe pain conditions, with increased intensity, more widespread distribution, or increased duration and/or involving stronger affective components.
Learn More >An evidence-practice gap exists for cancer pain management, and cancer pain remains prevalent and disabling.
Learn More >Chronic pain has widespread, detrimental effects on the human nervous system. Its prevalence and burden increase with age. Machine learning techniques have been applied on brain images to produce statistical models of brain aging. Specifically, Gaussian process regression is particularly effective at predicting chronological age from neuroimaging data permitting the calculation of a brain age gap estimate (brain-AGE).Pathological biological processes such as chronic pain can influence brain-AGE. As chronic pain disorders can differ in etiology, severity, pain frequency, and sex-linked prevalence, we hypothesize that the expression of brain-AGE may be pain specific and differ between discrete chronic pain disorders.We built a machine learning model using T1-weighted anatomical MRI from 812 healthy controls to extract brain-AGE for 45 trigeminal neuralgia (TN), 52 osteoarthritis (OA), and 50 chronic low-back pain (BP) individuals. False discovery rate corrected Welch's t-tests were conducted to detect significant alterations in brain-AGE between each discrete pain cohort and age- and sex-matched controls.TN and OA, but not BP subjects, have significantly larger brain-AGE. In all 3 pain groups, we observed female-driven elevation in brain-AGE. Furthermore, in TN, a significantly larger brain-AGE is associated with response to Gamma Knife radiosurgery for TN pain and is inversely correlated with the age at diagnosis.Brain-AGE expression differs across distinct pain disorders with a pronounced sex effect for female subjects. In TN, younger females may therefore represent a vulnerable sub-population requiring expedited chronic pain intervention. To this end, brain-AGE holds promise as an effective biomarker of pain treatment response.
Learn More >Chronic pain is sustained by a maladaptive form of neuronal plasticity occurring in all stations of the pain neuraxis, including cortical regions of the pain matrix. We report that chronic inflammatory pain induced by unilateral injection of Complete Freund's Adjuvant (CFA) in the hindpaw of male mice was associated with a progressive build-up of perineuronal nets (PNNs) in the contralateral somatosensory cortex (SSCtx), medial prefrontal cortex (mPFCtx), and reticular thalamic nucleus. In the SSCtx, the density of PNNs labeled by (WFA) was increased at both 3 and 7 days following CFA injection, but only after 7 days in the mPFCtx. The number of parvalbumin (PV)-positive interneurons enwrapped by WFA/PNNs was also increased in all three brain regions of mice injected with CFA. Remarkably, PNN degradation induced by intracortical infusion of chondroitinase-ABC significantly reduced mechanical and thermal pain, and also reversed the increased frequency of inhibitory postsynaptic currents (IPSCs) recorded in layer 5 pyramidal neurons of the contralateral SSCtx in CFA-injected mice. These findings suggest a possible relationship between cortical PNNs and nociceptive sensitization, and support the hypothesis that PNNs maintain their plasticity in the adult life and regulate cortical responses to sensory inputs.The brain extracellular matrix not only provides structural support, but also regulates synapse formation and function, and modulates neuronal excitability. We found that chronic inflammatory pain in mice enhances the density of perineuronal nets (PNNs) in the somatosensory cortex and medial prefrontal cortex. Remarkably, enzymatic degradation of PNNs in the somatosensory cortex caused analgesia and reversed alterations of inhibitory synaptic transmission associated with chronic pain. These findings disclose a novel mechanism of nociceptive sensitization and support a role for PNNs in mechanisms of neuronal plasticity in the adult brain.
Learn More >Addressing severe maternal morbidity (SMM) is a public health priority in the US. Use of labor neuraxial analgesia for vaginal delivery is suggested to reduce the risk of postpartum hemorrhage (PPH), the leading cause of preventable severe maternal morbidity.
Learn More >Ketamine produces potent analgesia combined with psychedelic effects. It has been suggested that these two effects are associated and possibly that analgesia is generated by ketamine-induced dissociation. The authors performed a post hoc analysis of previously published data to quantify the pharmacodynamic properties of ketamine-induced antinociception and psychedelic symptoms. The hypothesis was that ketamine pharmacodynamics (i.e., concentration-effect relationship as well as effect onset and offset times) are not different for these two endpoints.
Learn More >Classical understanding of allergic conjunctivitis (ACJ) suggests that ocular itch results from a mast cell-dependent inflammatory process. However, treatments that target inflammatory mediators or immune cells are often unsatisfying in relieving the stubborn itch symptom. This suggests that additional mechanisms are responsible for ocular itch in ACJ. In this study, we aim to determine the role of neuronal FcεRIa in allergic ocular itch.
Learn More >Studies have suggested dexmedetomidine (DEX) as a potential antidepressant. However, no relevant research exists on its effects and mechanisms in curing depression caused by chronic pain. Therefore, an understanding of DEX's role in depressive disorders proposes new approaches for antidepressant treatment.
Learn More >These updated guidelines present a practical and logical approach to the assessment and management of acute and chronic pain in canine and feline patients. Recognizing pain is fundamental to successful treatment, and diagnostic guides and algorithms are included for assessment of both acute and chronic pain. Particularly for chronic pain, capturing owner evaluation is important, and pain-assessment instruments for pet owners are described. Expert consensus emphasizes proactive, preemptive pain management rather than a reactive, "damage control" approach. The guidelines discuss treatment options centered on preemptive, multimodal analgesic therapies. There is an extensive variety of pharmacologic and nonpharmacologic therapeutic options for the management of acute and chronic pain in cats and dogs. The guidelines include a tiered decision tree that prioritizes the use of the most efficacious therapeutic modalities for the treatment of acute and chronic pain.
Learn More >Little is known about how individuals with chronic pain use tailored internet-based interventions. This study is the first to compare self-reported skill module use to observed module access and to examine each of these in relationship to tailored recommendations to access specific content. Participants (N = 58) enrolled in a 10-week trial of the Pain EASE program, a tailored internet-based intervention that includes 10 pain self-management skill modules. Participants completed a "Self-Assessment," which was used to provide a "Personalized Plan" that encouraged accessing specific modules. Participants self-reported module use during weekly data collection telephone calls. Program log data were extracted to capture "observed" module use during the trial period. Findings indicated significantly greater self-reported use of the Pain EASE modules compared to observed access with log data. Further, log data revealed that participants accessed less than half of the modules recommended to them via tailoring.
Learn More >The Analgesia Nociception Index (ANI), an objective measure of pain based on heart rate variability (HRV), has its usefulness in awake patients still unclear. This systematic review and meta-analysis aimed to assess ANI's accuracy compared to self-reported pain measures in conscious individuals undergoing medical procedures or painful stimuli. PubMed, Ovid, Web of Science, Scopus, Embase, and grey literature were searched until March 2021. Of the 832 identified citations, 16 studies complied with the eligibility criteria. A meta-analysis including nine studies demonstrated a weak negative correlation between ANI and NRS for pain assessment in individuals in the post-anesthetic recovery room (r = - 0.0984, 95% CI = - 0.397 to 0.220, I = 95.82%), or in those submitted to electrical stimulus (r = - 0.089; 95% CI = - 0.390 to 0.228, I = 0%). The evidence to use ANI in conscious individuals is weak compared to self-report measures of pain, yet ANI explains a part of self-report. Therefore, some individuals may be benefited from the use of ANI during procedures or in the immediate postoperative period.
Learn More >Despite a large body of literature on the association between the dietary inflammatory index (DII) and various chronic diseases, limited knowledge is available regarding the association between DII and migraine. Therefore, we assessed the relationship between the DII and migraine characteristics, including duration, frequency, and severity of migraine headaches, Headache Impact Test-6 (HIT-6), and serum levels of nitric oxide (NO). This population-based cross-sectional study was conducted from August 2019 to June 2020 among 262 patients (38 men and 224 women; 20-50 years). A 168-item semiquantitative food frequency questionnaire (FFQ) was gathered to evaluate dietary intake, and subsequently, an energy-adjusted DII score was calculated. After controlling for potential confounders, an increase of 3.48 in headache frequency was observed when the DII score increased from – 4.04 to – 1.83 (β = 3.48; 95% CI 1.43, 5.54). In the crude model, headache duration tended to be inversely associated with DII in the subjects with the pro-inflammatory diet compared to those with the anti-inflammatory diet (β = - 0.22; 95% CI – 0.46, 0.02). After adjustment for confounders, those with the highest DII values were at a higher risk of severe headaches than those with the lowest values (OR = 2.25; 95% CI 1.17, 4.32). No other significant results were found in terms of the association between DII and HIT-6 or serum NO levels. We found evidence suggesting that higher adherence to a diet with anti-inflammatory properties was significantly and inversely related to headache frequency. Furthermore, our results suggest that the DII score is substantially related to migraine severity.
Learn More >Nervous system manifestations caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are of great concern. Neurological symptoms and the neurological effects induced by SARS-CoV-2, such as the loss of various sensory perceptions, indicate direct viral invasion into sensory neurons. Therefore, it is very important to identify the distribution of angiotensin-converting enzyme 2 (ACE2), the receptor of SARS-CoV-2, in human nervous system. However, autofluorescence from lipofuscin obviously impacted immunofluorescence analysis in previous studies. We demonstrated that Sudan Black B (SBB) remarkably reduced the massive lipofuscin-like autofluorescence and the immunofluorescence signal would be sharpened following the exposure compensation. Additionally, we confirmed that ACE2 was expressed in IB4+, CGRP+, and NF200+ sensory subpopulations. The mapping of ACE2 distribution in hDRG would facilitate the understanding of sensory disorder induced by SARS-CoV-2.
Learn More >Alcohol use disorder (AUD) is a major health problem that causes millions of deaths annually world-wide. AUD is considered to be a chronic pain disorder, that is exacerbated by alcohol withdrawal, contributing to a high (∼80%) relapse rate. Chronic alcohol consumption has a marked impact on the gut microbiome, recognized to have a significant effect on chronic pain. We tested the hypothesis that modulating gut microbiota through feeding rats with probiotics can attenuate alcohol-induced muscle mechanical hyperalgesia. To test this hypothesis, rats were fed alcohol (6.5%, 4 days on 3 days off) for 3 weeks, which induced skeletal muscle mechanical hyperalgesia. Following alcohol feeding, at which time nociceptive thresholds were ∼37% below pre-alcohol levels, rats received probiotics in their drinking water, either GG (Culturelle) or De Simone Formulation (a mixture of 8 bacterial species) for 8 days; control rats received plain water to drink. When muscle mechanical nociceptive threshold was evaluated 1 day after beginning probiotic feeding, nociceptive thresholds were significantly higher than rats not receiving probiotics. Mechanical nociceptive thresholds continued to increase during probiotic feeding, with thresholds approaching pre-alcohol levels 5 days after starting probiotics; nociceptive threshold in rats not receiving probiotics remained low. After probiotics were removed from the drinking water, nociceptive thresholds gradually decreased in these two groups, although they remained higher than the group not treated with probiotic (21 days after ending alcohol feeding). These observations suggest that modification of gut microbiota through probiotic feeding has a marked effect on chronic alcohol-induced muscle mechanical hyperalgesia. Our results suggest that administration of probiotics to individuals with AUD may reduce pain associated with alcohol consumption and withdrawal, and may be a novel therapeutic intervention to reduce the high rate of relapse seen in individuals with AUD attempting to abstain from alcohol.
Learn More >Spinal surgeries to treat chronic low back pain (CLBP) have variable success rates, and despite the significant personal and socioeconomic implications, we lack consensus for prognostic factors. This systematic review and meta-analysis evaluated the evidence for preoperative predictors of return to work (RTW) after spinal surgery for CLBP. We searched electronic databases and references (01/1984-03/2021), screened 2622 unique citations, and included 8 reports (5 low and 3 high risk-of-bias) which involved adults with ≥3 months duration of CLBP with/without leg pain undergoing first elective lumbar surgery with RTW assessed ≥3 months later. Narrative synthesis and meta-analysis where possible found that individuals less likely to RTW were older (odds ratio [OR]=0.58; 95% confidence interval [CI]: 0.46 to 0.72), not working before surgery, had longer sick leave (OR=0.95; 95% CI: 0.93 to 0.97), higher physical workload, legal representation (OR=0.61; 95% CI: 0.53 to 0.71), psychiatric comorbidities and depression (moderate quality-of-evidence, QoE), and longer CLBP duration and opioid use (low QoE), independent of potential confounders. Low quality and small number of studies limit our confidence in other associations. In conclusion, RTW after spinal surgery for CLBP likely depends on sociodemographic and affective psychological factors, and potentially also on symptom duration and opioid use. Perspective: This systematic review and meta-analysis synthesizes and evaluates existing evidence for preoperative predictors of return to work after spinal surgery for chronic low back pain. Demonstrated associations between return to work and sociodemographic, health-related, and psychological factors can inform clinical decision-making and guide further research.
Learn More >Chronic pain (CP) patients often display lower heart rate variability (HRV) and baroreceptor sensitivity (BRS), which are associated with increased evoked pain intensity and decreased pain tolerance.
Learn More >Pain plays a central role in endometriosis. The complex relationship among pain characteristics, comorbid pain disorders, and daily life represents a challenge for medical support. This multicenter cross-sectional case-control study analyzed the association between endometriosis-related chronic pain and functions of daily life in 510 women with endometriosis, 265 (52%) of whom experienced chronic pain, either from endometriosis alone (N=134, 26.3%) or in association with additional pain disorders (N=131, 25.7%).
Learn More >Few new drugs have been developed for chronic pain. Drug development is challenged by uncertainty about whether the drug engages the human target sufficiently to have a meaningful pharmacodynamic effect. IMI2-PainCare-BioPain-RCT1 is one of four similarly designed studies that aim to link different functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics. This study focusses on biomarkers derived from nerve excitability testing (NET) using threshold tracking of the peripheral nervous system.
Learn More >Hip osteoarthritis (OA) is characterized by chronic pain, but there remains a mismatch between symptoms and radiological findings. Recently, brain connectivity has been implicated in the modulation of chronic peripheral pain, however its association with perceived pain in hip OA is not understood. We used resting-state functional magnetic resonance imaging (fMRI) to examine functional connectivity associated with pain in hip OA patients. Thirty participants with hip OA and 10 non-OA controls were recruited. Using the visual analogue scale (VAS), pain scores were obtained before and after performing a painful hip activity. All participants underwent 3.0 T resting-state fMRI, and functional connectivity of brain regions associated with pain was determined and compared between participants, and before and after hip activity. Relative to controls, functional connectivity between the secondary somatosensory cortex and left posterior insula was increased, and functional connectivity between the bilateral posterior insula and motor cortices was significantly decreased in hip OA participants. In response to painful hip activity, functional connectivity increased between the thalamus, periaqueductal grey matter and brainstem. Functional connections between brain regions associated with pain are altered in hip OA patients, and several connections are modulated by performing painful activity. Unique lateralization of left posterior insula and linked brain functional connectivity patterns allows assessment of pain perception in hip OA providing an unbiased method to evaluate pain perception and pain modulation strategies.
Learn More >Nonsteroidal anti-inflammatory drugs are among the most commonly administered drugs in the perioperative period due to their prominent role in pain management. However, they potentially have perioperative consequences due to immune-modulating effects through the inhibition of prostanoid synthesis, thereby affecting the levels of various cytokines. These effects may have a direct impact on the postoperative outcome of patients since the immune system aims to restore homeostasis and plays an indispensable role in regeneration and repair. By affecting the immune response, consequences can be expected on various organ systems. This narrative review aims to highlight these potential immune system-related consequences, which include systemic inflammatory response syndrome, acute respiratory distress syndrome, immediate and persistent postoperative pain, effects on oncological and neurologic outcome, and wound, anastomotic, and bone healing.
Learn More >Social risks previously have been associated with arthritis prevalence and costs. Although social risks often cluster among individuals, no studies have examined associations between multiple social risks within the same individual. Our objective was to determine the association between individual and multiple social risks and the prevalence and burden of arthritis by using a representative sample of adults in 17 US states.
Learn More >T lymphocytes are increasingly implicated in pain signaling. A subset of T lymphocytes, termed TChAT, express the rate-limiting enzyme for acetylcholine (ACh) production, choline acetyltransferase (ChAT), and mediate numerous physiological functions. Given that cholinergic signaling has long been known to modulate pain processing and is the basis for several analgesics used clinically, we asked whether TChAT could be the intersection between T lymphocyte and cholinergic mediation of pain signaling. In this study, we used a mouse gene knockout strategy to ablate ChAT specifically from T lymphocytes and examined the development and expression of mechanical and thermal hypersensitivity in a spared nerve injury (SNI) mouse model of neuropathic pain. We found that mice with ChAT knockout in T cells (floxed plus CD4-Cre recombinase) did not differ from control mice with intact ChAT (floxed , but no Cre recombinase) in their expression of mechanical sensitivity before or after injury. Similarly, thermal sensitivity was unaffected after injury, with control mice expressing similar patterns of thermal preference to mice whose T cells do not express ChAT. Our experiments demonstrate that cholinergic signaling initiated by T lymphocytes neither dampens nor exacerbates the expression of mechanical or thermal sensitivity in neuropathic mice. Thus, while both cholinergic signaling and T lymphocytes have established roles in modulating pain phenotypes, it is not cholinergic signaling initiated by T lymphocytes that drive this. Our findings will help to narrow in on which aspects of T-cell modulation may prove useful as therapies.
Learn More >Postpartum depression (PPD) is a common complication of cesarean section. S-ketamine given intravenously during surgery can help prevent PPD. However, whether S-ketamine in patient-controlled intravenous analgesia (PCIA) can reduce the incidence of PPD is unknown. This study assessed the effect of S-ketamine as an adjuvant in PCIA for preventing PPD in women undergoing cesarean delivery.
Learn More >Explaining the onset and maintenance of pain can be challenging in many clinical presentations. Allostasis encompasses the mechanisms through which humans adapt to stressors to maintain physiological stability. Due to related neuro-endocrine-immune system effects, allostasis and allostatic load (the cumulative effects on the brain and body that develop through the maintenance of physiological stability) offer the potential to explain the development and maintenance of musculoskeletal pain in certain cases. This paper outlines the concept of allostatic load, highlights the evidence for allostatic load in musculoskeletal pain conditions to date and discusses mechanisms through which allostatic load influences pain, with particular focus on hypothalamic-pituitary-adrenal axis and sympathetic nervous system function and central, brain-driven governance of these systems. Finally, through case examples, consideration is given as to how allostatic load can be integrated into clinical reasoning, and how it can be used to help explain pain to patients and guide clinical decision-making. Impact: Awareness of the concept of allostatic load, and subsequent assessment of physical and psychological stressors potentially contributing to allostatic load, may facilitate a broader understanding of the multidimensional presentations of many people with pain, both acute and persistent. This may facilitate discussion between clinicians and their patients regarding broader influences on their presentations and drive more targeted and inclusive pain management strategies.
Learn More >Dermal delivery of bioactive molecules remains an attractive route of administration in osteoarthritis (OA) due to the local accumulation of drugs while avoiding their systemic side effects. In this study we propose a proniosome gel comprising non-ionic surfactants that self-assemble into de-hydrated vesicles for the delivery of the natural anti-inflammatory compound berberine. By modulating the hydrating ability of the proniosome gel, berberine can be efficiently released with minimal mechanical force. A combination of sorbitan oleate (S80) and polyethlene glycol sorbitan monolaurate (T20) in a sorbitan stearate (S60)-based proniosome enables a readily hydrated gel to deliver berberine into the skin, as confirmed by skin permeation studies. Concurrently, an model of OA using primary mouse chondrocytes demonstrated that the release of berberine at a concentration as low as 1 μg mL is sufficient to restore the production of sulphated glycosaminoglycans (sGAG) to levels comparable to healthy chondrocytes while avoiding the cytotoxic concentrations (IC = 33 μg mL) on skin keratinocytes. In a mouse model of OA, the optimized formulation is able to attenuate inflammation and pain and minimize cartilage degeneration. Taken together, these data demonstrate the feasibility of adopting proniosome gels as a suitable platform to deliver active molecules for the management of osteoarthritis.
Learn More >Chimeras of botulinum neurotoxin (BoNT) serotype A (/A) combined with /E protease might possess improved analgesic properties relative to either parent, due to inheriting the sensory neurotropism of the former with more extensive disabling of SNAP-25 from the latter. Hence, fusions of /E protease light chain (LC) to whole BoNT/A (LC/E-BoNT/A), and of the LC plus translocation domain (H) of /E with the neuronal acceptor binding moiety (H) of /A (BoNT/EA), created previously by gene recombination and expression in ., were used. LC/E-BoNT/A (75 units/kg) injected into the whisker pad of rats seemed devoid of systemic toxicity, as reflected by an absence of weight loss, but inhibited the nocifensive behavior (grooming, freezing, and reduced mobility) induced by activating TRPV1 with capsaicin, injected at various days thereafter. No sex-related differences were observed. c-Fos expression was increased five-fold in the trigeminal nucleus caudalis ipsi-lateral to capsaicin injection, relative to the contra-lateral side and vehicle-treated controls, and this increase was virtually prevented by LC/E-BoNT/A. In vitro, LC/E-BoNT/A or /EA diminished CGRP exocytosis from rat neonate trigeminal ganglionic neurons stimulated with up to 1 µM capsaicin, whereas BoNT/A only substantially reduced the release in response to 0.1 µM or less of the stimulant, in accordance with the /E protease being known to prevent fusion of exocytotic vesicles.
Learn More >Chronic pain is a leading cause of morbidity in children and adolescents globally, with a significant impact on quality of life. This is the first systematic review and meta-analysis on paediatric chronic pain in low- and middle-income countries (LMICs).
Learn More >Intranasal diamorphine is a potential treatment for breakthrough pain but few paediatric data are available to assist dose estimation.
Learn More >Otalgia can be primary/otogenic or secondary as a referred pain from another site, which can be difficult to establish owing to various causes and the complex innervation of the ear. In our center, we observed a large group of patients with unexplained otalgia that had a higher prevalence of migraine. We hypothesized that migraine may cause secondary otalgia. This study then aimed to determine the prevalence of migraine-associated otalgia and evaluate the efficacy of migraine treatment.
Learn More >Management of acute perioperative pain in the geriatric patient can be challenging as the physiologic and pharmacokinetic changes associated with aging may predispose older patients to opioid-related side effects. Furthermore, elderly adults are more susceptible to postoperative delirium and postoperative cognitive dysfunction, which may be exacerbated by both poorly controlled postoperative pain and commonly used pain medications. This narrative review summarizes the literature published in the past 10 years for several nonopioid analgesics commonly prescribed to the geriatric patient in the perioperative period. Nonopioid analgesics are broken down as follows: medications prescribed throughout the perioperative period (acetaminophen and nonsteroidal anti-inflammatory drugs), medications limited to the acute perioperative setting (N-methyl-D-aspartate receptor antagonists, dexmedetomidine, dexamethasone, and local anesthetics), and medications to be used with caution in the geriatric patient population (gabapentinoids and muscle relaxants). Our search identified 1757 citations, but only 33 specifically focused on geriatric analgesia. Of these, only 21 were randomized clinical trials' and 1 was a systematic review. While guidance in tailoring pain regimens that focus on the use of nonopioid medications in the geriatric patient is lacking, we summarize the current literature and highlight that some nonopioid medications may extend benefits to the geriatric patient beyond analgesia.
Learn More >To assess the safety and efficacy of oral 50mg Zoledronic acid (ZA) bisphosphate once-a-week for 6-weeks to placebo among patients with chronic low back pain (cLBP) and Modic changes (MC) on MRI. A parallel, double-blinded randomized controlled study was performed at a single center, consisted of 25 subjects with cLBP and MC that received ZA (n=13) or placebo (n=12). Evaluation was at baseline, 2-weeks, 4-weeks, 3-months and 6-months for assessment of LBP/leg pain intensity, disability (Oswestry-Disability-Index:ODI), health-related quality-of-life (RAND-36), and mental component summary scores (MCS). Type 2 MC at baseline (56%) were prevalent. In the ZA group, LBP intensity was lower at 4-weeks in comparison to placebo (5.1±1.9 vs. 6.9±1.8, p=0.038) (minimal clinically important difference (MCID)=1.5). LBP intensity reduced at 4-weeks and 3-months in the ZA-treated group in comparison to baseline. Although there was no difference in ODI, subscale RAND-36 metrics for physical function (p=0.038), energy/fatigue (p=0.040) and pain (p=0.003) were improved at 3-months compared to placebo, with moderate significant difference for pain at 6-months (p=0.051). Correlated MCS scores to baseline also improved at 3-months (p=0.035) and 6-months (p=0.028) by 6.9 and 6.8, respectively, (MCID=3.8). A reduction in MC endplate affected area at 6-month follow-up was noted in the ZA group (-0.67±0.69 cm ), while in the placebo group no change in size was observed (0.0±0.15; p=0.041). Three subjects withdrew from the study and no long-lasting adverse events. Oral ZA was a safe and effective treatment that reduced MC volume, improved LBP symptoms and quality-of-life measures in cLBP subjects with MCs. This article is protected by copyright. All rights reserved.
Learn More >The paper from Steiner et al. suggests that an outcome measure expressed in time units may be an adequate method to assess the impact of headache disorders, regardless of diagnosis or health care setting, proving useful for cost-benefit analysis and health policy definition. Using time lost to each attack – weighted by disability – may prove to be a reliable measure to establish the effectiveness of acute treatment, but if considering also the attack frequency it could evaluate the effects of preventive strategies. A measure such as the Headache Gauge, which translates the proportion of time lost to headache -related disability, has proven to be applicable also in routine clinical practice as well, and can be tested in clinical trials and populational analysis. There are practical limitations, such as disability assessment and the need for prospective data collection to avoid recall bias but it seems consensual that impairment related to primary headache disorders is primarily driven by the TIME stolen from the perfect health status.
Learn More >Immersive Virtual Reality (VR) with head-mounted displays (HMD) can be a promising tool for increasing adherence to exercise in older adults. However, there is little known about the effectiveness of an interactive multimodal therapy in VR for older chronic back pain (CBP) patients. The aim of the exploratory randomized controlled trial was to examine the preliminary effectiveness of a VR multimodal therapy for older adults with CBP in a laboratory setting over a period of four weeks. The intervention group (IG; = 11) received a multimodal pain therapy in VR (movement therapy and psychoeducation) and the control group (CG; = 11) received a conventional multimodal pain therapy (chair-based group exercises and psychoeducation in a group setting). Although the VR therapy (IG) did not reach the pain intensity reduction of the CG (IG: MD = 0.64, = .535; CG: MD = 1.64, = .07), both groups showed a reduction in pain intensity on the Numeric Rating Scale. The functional capacity in the IG improved from Visit 1, = 73.11% to Visit 2, = 81.82% (MD = 8.71%; = .026). In the changes of fear avoidance beliefs and general physical and mental health, no significance was achieved in either group. Although the IG did not reach a significant pain intensity reduction compared to the CG, the results of the present study showed that a pain intensity reduction can be achieved with the current VR application.
Learn More >There is no evidence of effectiveness for interdisciplinary second opinion procedures (ISOP) for recommended back surgery (BS). Since 2015, AOK Nordost has been offering the care program RückenSPEZIAL comprising a preliminary examination, ISOP, and optional interdisciplinary multimodal pain therapy (IMPT). The objective of this study is to determine the effectiveness of RückenSPEZIAL to reduce BS and back pain-related costs (BPRC) compared to patients who likewise received a recommendation for back surgery but not RückenSPEZIAL.
Learn More >Interstitial cystitis/bladder pain syndrome (IC/BPS) is a disorder characterized by bladder pain upon filling which severely affects quality of life. Clinical presentation can vary. Local inflammatory events typify the clinical presentation of IC/BPS patients with Hunner lesions (IC/BPS-HL). It has previously been proposed that B cells are more prevalent in HL, but understanding their exact role in this environment requires a more complete immunological profile of HL. We characterized immunological dysfunction specifically in HL using immunohistochemistry. We detected significantly more plasma cells (50× increase, p < 0.0001), B cells (28× increase, p < 0.0001), T cells (3× increase, p < 0.0001), monocytes/macrophages (6× increase, p < 0.0001), granulocytes (4× increase, p < 0.0001), and natural killer cells (2× increase, p = 0.0249) in IC/BPS patients with HL than in unaffected controls (UC). Patients with IC/BPS-HL also had significantly elevated urinary levels of IL-6 (p = 0.0054), TNF-α (p = 0.0064) and IL-13 (p = 0.0304) compared to patients with IC/BPS without HL (IC/BPS-NHL). In contrast, IL-12p70 levels were significantly lower in the patients with HL than in those without these lesions (p = 0.0422). Different cytokines were elevated in the urine of IC/BPS patients with and without HL, indicating that different disease processes are active in IC/BPS patients with and without HL. Elevated levels of CD138+, CD20+, and CD3+ cells in HL are consistent B and T-cell involvement in disease processes within HL.
Learn More >This systematic review and meta-analysis aims to identify and quantify the current available evidence of hypnosis efficacy to manage pain in patients with chronic musculoskeletal and neuropathic pain. Randomized Control Trials (RCTs) with hypnosis and/or self-hypnosis treatment used to manage musculoskeletal and/or neuropathic chronic pain in adults and assessing pain intensity were included. Reviews, meta-analyses, non-randomized clinical trials, case reports and meeting abstracts were excluded. Five databases, up until May 13 2021, were used to search for RCTs using hypnosis to manage chronic musculoskeletal and/or neuropathic pain. The protocol is registered on PROSPERO register (CRD42020180298) and no specific funding was received for this review. The risk of bias asessement was conducted according to the revised Cochrane risk of bias tool for randomized control trials (RoB 2.0). Nine eligible RCTs including a total of 530 participants were considered. The main analyses showed a moderate decrease in pain intensity (Hedge's g: -0.42; p=0.025 after intervention, Hedge's g: -0.37; p=0.027 after short-term follow-up) and pain interference (Hedge's g: -0.39; p=0.029) following hypnosis compared to control interventions. A significant moderate to large effect size of hypnosis compared to controls was found for at 8 sessions or more (Hedge's g: -0.555; p=0.034), compared to a small and not statistically significant effect for fewer than 8 sessions (Hedge's g: -0.299; p=0.19). These findings suggest that a hypnosis treatment lasting a minimum of 8 sessions could offer an effective complementary approach to manage chronic musculoskeletal and neuropathic pain. Future research is needed to delineate the relevance of hypnosis in practice and its most efficient prescription.
Learn More >The uppermost superficial zone of articular cartilage is the first line of defense against the initiation of osteoarthritis (OA). We previously used Col2-Cre to demonstrate that EGFR, a tyrosine kinase receptor, plays an essential role in maintaining superficial chondrocytes during articular cartilage development. Here, we showed that EGFR activity in the articular cartilage decreased as mice age. In mouse and human OA samples, EGFR activity was initially reduced at the superficial layer and then resurged in cell clusters within the middle and deep zone in late OA. To investigate the role of EGFR signaling in postnatal and adult cartilage, we constructed an inducible mouse model with cartilage-specific EGFR inactivation (Aggrecan-CreER Egfr , Egfr iCKO). EdU incorporation revealed that postnatal Egfr iCKO mice contained fewer slow-cycling cells than controls. EGFR deficiency induced at 3 months of age reduced cartilage thickness and diminished superficial chondrocytes, in parallel to alterations in lubricin production, cell proliferation and survival. Furthermore, male Egfr iCKO mice developed much more severe OA phenotypes, including cartilage erosion, subchondral bone plate thickening, cartilage degeneration at the lateral site, and mechanical allodynia, after receiving destabilization of the medial meniscus (DMM) surgery. Similar OA phenotypes were also observed in female iCKO mice. Moreover, Tamoxifen injections of iCKO mice at 1 month post surgery accelerated OA development 2 months later. In summary, our data demonstrated that chondrogenic EGFR signaling maintains postnatal slow-cycling cells and plays a critical role in adult cartilage homeostasis and OA progression. This article is protected by copyright. All rights reserved.
Learn More >A clinical ability to describe the response trajectory of patients receiving preventive migraine treatment could expedite and improve therapeutic management decisions. This post hoc analysis of the PROMISE-2 study evaluated the consistency and predictive power of Month 1 treatment response on later response in patients with chronic migraine.
Learn More >Spinal cord stimulation is a promising therapy for patients with treatment refractory pain syndromes, and a viable alternative to chronic opioid therapy. Racial disparities are well-documented in the field of pain medicine. This study seeks to determine whether racial disparities are present in spinal cord stimulator (SCS) surgery involving inpatient hospital stays in the United States.
Learn More >Preclinical evidence suggests the potential of Ph1, a toxin obtained from the venom of spider , as a new analgesic drug. Molecular brain imaging techniques have afforded exciting opportunities to examine brain processes in clinical pain conditions. This paper aims to study the brain regions involved in the analgesic effects of Ph1 compared with Morphine, in a model of acute pain induced by formalin in Sprague Dawley rats. We used F-fluorodeoxyglucose as a metabolic radiotracer to perform brain imaging of rats pretreated with Ph1 or Morphine in a model of acute inflammatory pain caused by intraplantar injection of formalin. The rats' hind paw's formalin stimulation resulted in a brain metabolic increase at the bilateral motor cortex, visual cortex, somatosensory cortex, thalamus, and cingulate cortex.In rats treated with Ph1, selective inhibition of unilateral motor cortex and cingulate cortex was observed. Morphine treatment leads to small and selective inhibition at the bilateral amygdala striatum and accumbens. Our results indicate that the analgesic effect of Ph1 and Morphine possesses a differential profile of central processing in the pain state.
Learn More >The calcium/calmodulin-dependent protein phosphase calcineurin (CaN) regulates synaptic plasticity by controlling the phosphorylation of synaptic proteins including AMPA type glutamate receptors. The regulator of calcineurin 1 (RCAN1) is characterized as an endogenous inhibitor of CaN and its dysregulation is implicated in multiple neurological disorders. However, whether RCAN1 is engaged in nociceptive processing in the spinal dorsal horn remains unrevealed. In this study, we found that RCAN1 was predominately expressed in pain-related neurons in the superficial dorsal horn of the spinal cord. Intraplantar injection of complete Freund's adjuvant (CFA) specifically increased the total and synaptic expression of the RCAN1.4 isoform in spinal dorsal horn. The CFA-induced inflammation also caused an increased binding of RCAN1.4 to CaN. Overexpression of RCAN1.4 in spinal dorsal horn of intact mice produced both mechanical allodynia and thermal hyperalgesia, which were accompanied by increased synaptic expression and phosphorylation of GluA1 subunit. Furthermore, the siRNA-mediated knockdown of RCAN1.4 significantly attenuated the development of pain hypersensitivity, meanwhile, decreased the synaptic expression of GluA1 in mice with peripheral inflammation. These data suggested that the increased expression of RCAN1.4 contributed to the development of inflammatory pain hypersensitivity, at least in part by promoting the synaptic recruitment of GluA1-containing AMPA receptor.
Learn More >Joint pain is a complex phenomenon that involves multiple endogenous mediators and pathophysiological events. In addition to nociceptive and inflammatory pain, some patients report neuropathic-like pain symptoms. Examination of arthritic joints from humans and preclinical animal models have revealed axonal damage which is likely the source of the neuropathic pain. The mediators responsible for joint peripheral neuropathy are obscure, but lysophosphatidic acid (LPA) has emerged as a leading candidate target. In the present study, male and female Wistar rats received an intra-articular injection of LPA into the right knee and allowed to recover for 28 days. Joint pain was measured by von Frey hair algesiometry, while joint pathology was determined by scoring of histological sections. Both male and female rats showed comparable degenerative changes to the LPA-treated knee including chondrocyte death, focal bone erosion, and synovitis. Mechanical withdrawal thresholds decreased by 20-30% indicative of secondary allodynia in the affected limb; however, there was no significant difference in pain sensitivity between the sexes. Treatment of LPA animals with the neuropathic pain drug amitriptyline reduced joint pain for over 2 hours with no sex differences being observed. In summary, intra-articular injection of LPA causes joint degeneration and neuropathic pain thereby mimicking some of the characteristics of neuropathic osteoarthritis.
Learn More >Despite accumulating evidence in rodents, the functional role of neuromedin B (NMB) in regulating somatosensory systems in primate spinal cord is unknown. We aimed to compare the expression patterns of NMB and its receptor (NMBR) and the behavioral effects of intrathecal (i.t.) NMB with gastrin-releasing peptide (GRP) on itch or pain in non-human primates (NHPs). We used six adult rhesus monkeys. The mRNA or protein expressions of NMB, GRP, and their receptors were evaluated by quantitative reverse transcription polymerase chain reaction, immunohistochemistry, or in situ hybridization. We determined the behavioral effects of NMB or GRP via acute thermal nociception, capsaicin-induced thermal allodynia, and itch scratching response assays. NMB expression levels were greater than those of GRP in the dorsal root ganglia and spinal dorsal horn. Conversely, NMBR expression was significantly lower than GRP receptor (GRPR). I.t. NMB elicited only mild scratching responses, whereas GRP caused robust scratching responses. GRP- and NMB-elicited scratching responses were attenuated by GRPR (RC-3095) and NMBR (PD168368) antagonists, respectively. Moreover, i.t. NMB and GRP did not induce thermal hypersensitivity and GRPR and NMBR antagonists did not affect peripherally elicited thermal allodynia. Consistently, NMBR expression was low in both itch- and pain-responsive neurons in the spinal dorsal horn. Spinal NMB-NMBR system plays a minimal functional role in the neurotransmission of itch and pain in primates. Unlike the functional significance of the GRP-GRPR system in itch, drugs targeting the spinal NMB-NMBR system may not effectively alleviate non-NMBR-mediated itch.
Learn More >Chronic pain is a significant public health problem, and the prevalence and societal impact continues to worsen annually. Multiple cognitive and emotional factors are known to modulate pain, including pain catastrophizing, which contributes to pain facilitation and is associated with altered resting-state functional connectivity in pain-related cortical and subcortical circuitry. Pain and catastrophizing levels are reported to be higher in non-Hispanic black (NHB) compared with non-Hispanic White (NHW) individuals. The current study, a substudy of a larger ongoing observational cohort investigation, investigated the pathways by which ethnicity/race influences the relationship between pain catastrophizing, clinical pain, and resting-state functional connectivity between anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (dlPFC), insula, and primary somatosensory cortex (S1). Participants included 136 (66 NHBs and 70 NHWs) community-dwelling adults with knee osteoarthritis. Participants completed the Coping Strategies Questionnaire-Revised Pain Catastrophizing subscale and Western Ontario and McMaster Universities Osteoarthritis Index. Magnetic resonance imaging data were obtained, and resting-state functional connectivity was analyzed. Relative to NHW, the NHB participants were younger, reported lower income, were less likely to be married, and self-reported greater clinical pain and pain catastrophizing (ps < 0.05). Ethnicity/race moderated the mediation effects of catastrophizing on the relationship between clinical pain and resting-state functional connectivity between the ACC, dlPFC, insula, and S1. These results indicate the NHB and NHW groups demonstrated different relationships between pain, catastrophizing, and functional connectivity. These results provide evidence for a potentially important role of ethnicity/race in the interrelationships among pain, catastrophizing, and resting-state functional connectivity.
Learn More >Allergic contact dermatitis (ACD) is a common skin condition characterized by contact hypersensitivity to allergens, accompanied with skin inflammation and a mixed itch and pain sensation. The itch and pain dramatically affects patients' quality of life. However, still little is known about the mechanisms triggering pain and itch sensations in ACD.
Learn More >Kinesins (KIF's) are the motor proteins which are recently reported to be involved in the trafficking of nociceptors leading to chronic pain. Aurora kinases are known to be involved in the regulation of KIF proteins which are associated with the activation of N-methyl-D-aspartate (NMDA) receptors. Here, we investigated the effect of tozasertib, a pan-Aurora kinase inhibitor, on nerve injury-induced evoked and chronic ongoing pain in rats and the involvement of kinesin family member 17 (KIF17) and NMDA receptor subtype 2B (NR2B) crosstalk in the same. Rats with chronic constriction injury showed a significantly decreased pain threshold in a battery of pain behavioural assays. We found that tozasertib [10, 20, and 40 mg/kg intraperitoneally (i.p.)] treatment showed a significant and dose-dependent inhibition of both evoked and chronic ongoing pain in rats with nerve injury. Tozasertib (40 mg/kg i.p.) and gabapentin (30 mg/kg i.p.) treatment significantly inhibits spontaneous ongoing pain in nerve injured rats but did not produce any place preference behaviour in healthy naïve rats pointing towards their non-addictive analgesic potential. Moreover, tozasertib (10, 20, and 40 mg/kg i.p.) and gabapentin (30 mg/kg i.p.) treatment did not altered the normal pain threshold in healthy naïve rats and didn't produce central nervous system associated side effects as well. Western blotting and reverse transcription polymerase chain reaction studies suggested enhanced expressions of NR2B and KIF-17 along with increased nuclear factor kappa β (NFkβ), tumour necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6) levels in dorsal root ganglion (DRG) and spinal cord of nerve injured rats which was significantly attenuated on treatment with different does of Tozasertib. Findings from the current study suggests that inhibition of pan-Aurora kinase decreased KIF-17 mediated NR2B activation which further leads to significant inhibition of evoked and chronic ongoing pain in nerve-injured rats.
Learn More >Increasing neurophysiological studies had revealed that regional excitation-inhibition imbalance in the brain played a key role in the pathogenesis of migraine. This study aimed to explore the alterations in gamma-aminobutyric acid (GABA) and glutamate/glutamine complex (Glx) levels in the anterior cingulate gyrus (ACC) and medial prefrontal lobe (mPFC) of patients with migraine without aura (MWoA) and investigate the correlation between neurotransmitter levels and clinical indicators. A total of 28 patients with MWoA and 28 sex-, age-, and education level-matched healthy controls (HCs) underwent single-voxel proton magnetic resonance spectroscopy scanning at 3.0 Tesla. MEscher-Garwood Point RESolved Spectroscopy (MEGA-PRESS) sequence was performed to acquire the spectral data of GABA and Glx in the ACC and mPFC. The clinical indicators and anxiety-depression states of all participants were assessed. The acquired GABA signal contained the overlapping signals of macromolecules and homocarnosine, hence expressed as GABA+. The creatine (Cr) signal was applied as an endogenous reference. We observed that GABA+/Cr levels were significantly lower in ACC and mPFC of patients with MWoA than of HCs, with no significant difference in Glx levels. Negative correlations between GABA+/Cr levels and attack frequency were found in the ACC and mPFC regions of patients. These results suggested that there might be a close relationship between ACC and mPFC GABAergic neurons abnormalities and the pathophysiological mechanisms of MWoA. It might be beneficial to targeted treatment for patients with MWoA.
Learn More >Bradykinin (BK) is an endogenous peptide involved in vascular permeability and inflammation. It has opposite effects (inducing hyperalgesia or antinociception) when administered directly in the central nervous system. The aim of this study was to evaluate whether BK may also present this dual effect when injected peripherally in a PGE-induced nociceptive pain model, as well as to investigate the possible mechanisms of action involved in this event in mice.
Learn More >There is growing interest in identifying and developing interventions aimed at reducing the risk of increased, long-term opioid use among surgical patients. While understanding how these interventions impact health care spending has important policy implications and may facilitate the widespread adoption of these interventions, the extent to which they may impact health care spending among surgical patients who utilize opioids chronically is unknown.
Learn More >Migraine is a complex and highly disabling neurological disease whose treatment remains challenging in many patients, even after the recent advent of the first specific-preventive drugs, namely monoclonal antibodies that target calcitonin gene-related peptide. For this reason, headache researchers are actively searching for new therapeutic targets. Cannabis has been proposed for migraine treatment, but controlled clinical studies are lacking. A major advance in cannabinoid research has been the discovery of the endocannabinoid system (ECS), which consists of receptors CB1 and CB2; their endogenous ligands, such as N-arachidonoylethanolamine; and the enzymes that catalyze endocannabinoid biosynthesis or degradation. Preclinical and clinical findings suggest a possible role for endocannabinoids and related lipids, such as palmitoylethanolamide (PEA), in migraine-related pain treatment. In animal models of migraine-related pain, endocannabinoid tone modulation via inhibition of endocannabinoid-catabolizing enzymes has been a particular focus of research.
Learn More >To compare the effects of dry needling or manual pressure release on an active trigger point in the upper trapezius on cranio-cervical flexion test performance, pressure pain thresholds, and cervical range of motion in chronic neck pain.
Learn More >Despite spinal cord stimulation's (SCS) proven efficacy, failure rates are high with no clear understanding of which patients benefit long term. Currently, patient selection for SCS is based on the subjective experience of the implanting physician.
Learn More >5-Hydroxytryptamine (5-HT) receptors 1B, 1D and 1F have key roles in migraine pharmacotherapy. Selective agonists targeting these receptors, such as triptans and ditans, are effective in aborting acute migraine attacks and inhibit the in vivo release of calcitonin gene-related peptide (CGRP) in human and animal models. The study aimed to examine the localization, genetic expression and functional aspects of 5- HT receptors in the trigeminal system in order to further understand the molecular sites of action of triptans (5-HT) and ditans (5-HT).
Learn More >Chronic pain affects 20% of the global population and is incredibly complex to treat. The burden of chronic pain is physical, emotional and financial, and prevalence rates continue to rise. Current treatments are ineffective long-term against pain and common comorbidities, including anxiety and depression, mood and sleep disorders, and social isolation. While a large body of evidence supports regular physical exercise as an effective long-term treatment for chronic pain and its comorbidities, exercise-induced pain and kinesiophobia are significant barriers to participation and adherence. Immersive virtual reality is a powerful short-term pain reliever, that, when combined with exercise, can help overcome these barriers. This perspective argues for the use of combined exercise and virtual reality treatment techniques to mitigate chronic pain.
Learn More >A gap remains in understanding the association among the symptoms of distal sensory peripheral neuropathy (DSPN) (pain, aching, burning, pins and needles, numbness), comorbidities, and medication use among persons living with People Living with HIV/AIDS (PLWH) with DSPN. This report describes the symptom characteristics associated with prescribed treatment regimens (HIV and non-HIV medications) and comorbidities from a cohort of PLWH experiencing symptoms of DSPN who reside in New York City.
Learn More >Cannabinoid receptor 2 (CB2R) is a potential target for anti-inflammatory and pain therapeutics given its significant immunomodulatory and analgesic effects. However, the role of CB2R in imiquimod (IMQ)-induced psoriasiform dermatitis (PsD) and itch is poorly understood. To investigate the function and mechanism of CB2R in PsD and itch in mice. Following daily treatment with topical IMQ cream for 5-7 consecutive days in C56BL/6 wild-type (WT) and CB2R gene knockout (KO) mice, we assessed the Psoriasis Area and Severity Index (PASI) scores and the scratch bouts every day, and hematoxylin and eosin (H&E) staining, toluidine blue staining were used to observe the histological changes. mRNA levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). Protein levels were detected by western blotting (WB), immunohistochemistry (IHC), immunofluorescence (IF) and cytometric bead array (CBA). Flow cytometry (FCM) was used to examine the proportion of Th17/Treg cells. We found that CB2R expression levels were increased in mice with psoriasis. Compared with WT mice, CB2R deficiency exacerbated IMQ-induced PsD and scratching bouts and upregulated the expression of proinflammatory cytokines by increasing the infiltration of CD4 T cells and the Th17/Treg ratio. Obvious proliferation and prolongation of nerve fibers and high expression of nerve growth factor (NGF) were observed in PsD and CB2R KO mice. Pretreatment with the CB2R agonist, JWH-133 significantly reversed inflammation and scratching bouts. CB2R didn't participate in the induction of itch in psoriasis by regulating the expression of IL-31, thymic stromal lymphopoietin (TSLP) and mast cells in mouse skins. Our results demonstrate that CB2R plays a pivotal role in the pathophysiology of psoriasis, providing a new potential target for anti-inflammatory and antipruritic drugs.
Learn More >Transcutaneous electrical nerve stimulation (TENS) is a non-invasive therapeutic intervention that is typically used for many years to treat chronic pain in patients who are refractory to pain medications. However, evidence of the efficacy of TENS treatment for neuropathic pain is lacking in humans. To further understand the efficacy of TENS under various intervention conditions and illuminate the current circumstance and future research directions, we systematically reviewed animal studies investigating the efficacy of TENS in relieving pain in neuropathic pain rodent models. We searched the Cochrane Library, EMBASE, MEDLINE (via PubMed), and Web of Science and identified 11 studies. Two meta-analyses were performed. The first meta-analysis showed that a single TENS treatment was capable of temporarily ameliorating neuropathic pain when compared to control groups with a significant effect (standardized mean difference: 1.54; 95% CI: 0.65, 2.42; = 0.0007; = 58%). Significant temporary alleviation in neuropathic pain intensity was also observed in the meta-analysis of repetitive TENS (standardized mean difference: 0.85; 95% CI: 0.31, 1.40; = 0.002; = 75%). Subgroup analysis showed no effect of the timing of the application of TENS (test for subgroup difference, = 0.47). Leave-one-out sensitivity analyses suggested that no single study had an outsized effect on the pooled estimates, which may partly prove the robustness of these findings. Other stratified analyses were prevented by the insufficient number of included studies. Overall, current data suggest that TENS might be a promising therapy to ameliorate neuropathic pain. However, the high risk of bias in the included studies suggests that cautions must be considered when interpreting these findings and it is not reasonable to directly generalize the results obtained from animal studies to clinical practice. Future studies should pay more attention to improving the quality of study design and reporting, thereby facilitating the understanding of mechanisms underlying TENS treatment, reducing more potentially unsuccessful clinical trials, and optimizing the efficacy of TENS for people with neuropathic pain.
Learn More >Musculoskeletal pain patients present similar pain characteristics regardless of the clinical diagnosis. PainDETECT questionnaire is useful for screening neuropathic-like symptoms in many musculoskeletal conditions. However, no previous studies compared pain phenotypes of patients with musculoskeletal pain using the painDETECT. Therefore, the current study aimed to compare the pain characteristics of patients with musculoskeletal pain classified according to the painDETECT as nociceptive pain, unclear, and neuropathic-like symptoms.
Learn More >This cross-sectional study aimed to compare the waveform morphology through noninvasive intracranial pressure (ICP-NI) measurement between patients with migraine and controls, and to analyze the association with clinical variables. Twenty-nine women with migraine, age 32.4 (11.2) years and headache frequency of 12.6 (7.5) days per month and twenty-nine women without headache, age 32.1 (9.0) years, were evaluated. Pain intensity, migraine disability, allodynia, pain catastrophizing, central sensitization and depression were evaluated. The ICP-NI monitoring was performed by a valid method consisting of an extracranial deformation sensor positioned in the patients' scalp, which allowed registration of intracranial pressure waveforms. Heart rate and blood pressure measurements were simultaneously recorded during 20 min in the supine position. The analyzed parameter was the P2/P1 ratio based on mean pulse per minute which P1 represents the percussion wave related to the arterial blood pression maximum and P2 the tidal wave, middle point between the P1 maximum and the dicrotic notch. There was no between-groups difference in the P2/P1 ratio (mean difference: 0.04, IC95%: -0.07 to 0.16, p = 0.352, F (1,1) = 0.881) adjusted by body mass index covariable. The Multiple Linear Regression showed non-statistical significance [F (5,44) = 1.104; p = 0.372; R = 0.11)] between the P2/P1 ratio and body mass index, presence of migraine, central sensitization, pain catastrophizing and depression. We found no correlation (p > 0.05) between P2/P1 ratio and migraine frequency, migraine onset, pain intensity, pain intensity at day of examination, disability, allodynia. Migraine patients did not present alterations in the waveform morphology through ICP-NI compared to women without headache and no association with clinical variables was found.
Learn More >Chronic pain is induced by tissue or nerve damage and is accompanied by pain hypersensitivity (i.e., allodynia and hyperalgesia). Previous studies using two-photon microscopy have shown functional and structural changes in the primary somatosensory (S1) cortex at the cellular and synaptic levels in inflammatory and neuropathic chronic pain. Furthermore, alterations in local cortical circuits were revealed during the development of chronic pain. In this review, we summarize recent findings regarding functional and structural plastic changes of the S1 cortex and alteration of the S1 inhibitory network in chronic pain. Finally, we discuss potential neuromodulators driving modified cortical circuits and suggest further studies to understand the cortical mechanisms that induce pain hypersensitivity.
Learn More >The aim of this study was to investigate the related influencing factors of neuropathic pain (NP) in patients with spinal cord injury (SCI).
Learn More >We aim to compare the clinical characteristics, disease course and visual outcomes between Canadian patients with idiopathic intracranial hypertension (IIH) who were incidentally discovered and those who sought care due to symptoms of IIH.
Learn More >Chronic pain, such as chronic neuropathic pain and chronic inflammatory pain, is often difficult to manage and bring great trouble to patients. 5-HT plays a key role in the process of pain transmission both in centrally and peripherally. Tricyclic antidepressants (TCA) such as amitriptyline are classical 5-HT reuptake inhibitors, are recommended as the first-line treatment for chronic pain. Pizotifen, a 5-HT2 receptor antagonist, is currently used in the prevention of vascular headaches. However, the antinociceptive effect of pizotifen on non-headache pain especially chronic pain in the spinal level is still unknown. Here we find that intrathecal pizotifen attenuates neuropathic and inflammatory pain mainly due to elevated GABAergic synaptic inhibition. Neuropathic pain is induced by segmental spinal nerve ligation (SNL), and inflammatory pain is induced by intraplantar injection of complete Freund's adjuvant (CFA). Both in SNL and CFA mice, spinally administered pizotifen reduced mechanical and thermal hyperalgesia dose-dependently. Since the levels of GAD65/67 were increased, and the frequency of mIPSCs in the spinal dorsal horn was increased, together with the antinociceptive effect being reversed by both GABAR and GAD blockade, this antinociceptive effect might be generated from strengthened GABAergic inhibition. Furthermore, high dose of pizotifen (5μg) weakly affected motor performance and did not influence the locomotor activity in normal animals. In summary, our findings suggest that pizotifen strengthens the inhibitory synaptic transmission and exerts antinociceptive effect on both neuropathic pain and inflammatory pain in the spinal cord, and may serve as a promising remedy for chronic pain.
Learn More >Endometriosis is a chronic pain disorder that affects young women, impairing their physical, mental and social well-being. Apart from personal suffering, it imposes a significant economic burden on the healthcare system. We analyzed studies reporting comorbid mental disorders in endometriosis based on the ICD/DSM criteria, discussing them in the context of available neuroimaging studies. We postulate that at least one-third of endometriosis patients suffer from mental disorders (mostly depression or anxiety) and require psychiatric or psychotherapeutic support. According to three neuroimaging studies involving patients with endometriosis, brain regions related not only to pain processing but also to emotion, cognition, self-regulation and reward likely constitute the so-called "endometriosis brain". It is not clear, however, whether the neurobiological changes seen in these patients are caused by chronic pain, mental comorbidities or endometriosis itself. Given the paucity of high-quality data on mental comorbidities and neurobiological correlates in endometriosis, further research is needed.
Learn More >To evaluate the effectiveness of different interventions in reducing pain-related fear outcomes in people with knee osteoarthritis who have or have not had previous knee surgery, and to analyze whether included trials reported their interventions in full detail.
Learn More >To date, there have been no large studies describing real-world treatment of chronic prurigo (CPG) and pruritus (CPR) in Germany.
Learn More >For centuries, cold temperatures have been used by humans for therapeutic, health and sporting recovery purposes. This application of cold for therapeutic purposes is regularly referred to as cryotherapy. Cryotherapies including ice, cold-water and cold air have been popularised by an ability to remove heat, reduce core and tissue temperatures, and alter blood flow in humans. The resulting downstream effects upon human physiologies providing benefits that include a reduced perception of pain, or analgesia, and an improved sensation of well-being. Ultimately, such benefits have been translated into therapies that may assist in improving post-exercise recovery, with further investigations assessing the role that cryotherapies can play in attenuating the ensuing post-exercise inflammatory response. Whilst considerable progress has been made in our understanding of the mechanistic changes associated with adopting cryotherapies, research focus tends to look towards the future rather than to the past. It has been suggested that this might be due to the notion of progress being defined as change over time from lower to higher states of knowledge. However, a historical perspective, studying a subject in light of its earliest phase and subsequent evolution, could help sharpen one's vision of the present; helping to generate new research questions as well as look at old questions in new ways. Therefore, the aim of this brief historical perspective is to highlight the origins of the many arms of this popular recovery and treatment technique, whilst further assessing the changing face of cryotherapy. We conclude by discussing what lies ahead in the future for cold-application techniques.
Learn More >Current best practice recommends group-based pain management programmes for long-term improvements in persistent pain-related disability. However, there are barriers for people to access in-person delivered pain management programmes in Aotearoa.
Learn More >The Toolkit for Optimal Recovery (TOR) is a mind-body program for patients with acute orthopedic injuries who are at risk for persistent pain/disability. In preparation for a multisite feasibility trial of TOR at three orthopedic trauma centers, we aim to qualitatively identify barriers and facilitators to study implementation and strategies to mitigate the implementation barriers and leverage facilitators.We conducted 18 live video focus groups among providers and three one-on-one interviews with department chiefs at Level 1 trauma centers in three geographically diverse sites (N = 79 participants). Using a content analysis approach, we detected the site-specific barriers and facilitators of implementation of TOR clinical trial. We organized the data according to 26 constructs of the Consolidated Framework for Implementation Research (CFIR), mapped to three Proctor implementation outcomes relevant to the desired study outcomes (acceptability, appropriateness, and feasibility). Across the three sites, we mapped six of the CFIR constructs to acceptability, eight to appropriateness, and three to feasibility. Prominent perceived barriers across all three sites were related to providers' lack of knowledge/comfort addressing psychosocial factors, and organizational cultures of prioritizing workflow efficiency over patients' psychosocial needs (acceptability), poor fit between TOR clinical trial and the fast-paced clinic structure as well as basic needs of some patients (appropriateness), and limited resources (feasibility). Suggestions to maximize the implementation of the TOR trial included provision of knowledge/tools to improve providers' confidence, streamlining study recruitment procedures, creating a learning collaborative, tailoring the study protocol based on local needs assessments, exercising flexibility in conducting research, dedicating research staff, and identifying/promoting champions and using novel incentive structures with regular check-ins, while keeping study procedures as nonobtrusive and language as de-stigmatizing as possible. These data could serve as a blueprint for implementation of clinical research and innovations in orthopedic and other medical settings.
Learn More >Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes. Symptoms of DPN mainly include spontaneous intractable pain that is diffuse and continuous and can last from several weeks to several months. DPN is associated with a high mortality rate and poor prognosis. Its pathogenesis is not fully understood, and clinical treatment is focused on relieving its clinical symptoms, as well as improving blood sugar control and cardiovascular risk factors. DPN and its clinically effective treatments need to be studied. This study discusses the treatment methods and pathogenesis of DPN, summarizes the related research progress, and attempts to provide a reference for DPN research.
Learn More >Chronic pain is common among older people with HIV. Etiologies of chronic pain are multifactorial in this population. A careful and thorough initial assessment of pain is important. Associated conditions that can contribute to pain should be explored and managed as indicated. Special consideration is warranted for some of the unique aspects of pain in people with HIV. Chronic pain management is multimodal; a variety of pharmacologic and nonpharmacologic strategies are effective. Among medications, opioids can be used but carry a risk of significant harms. The use and monitoring of opioids is discussed here, and recommendations are made for the safe prescribing of opioids for chronic pain.
Learn More >The Tampa Scale of Kinesiophobia (TSK) is a valid and reliable tool to assess somatic focus and activity avoidance in patients. Currently, the test-retest reliability and measurement error for the Danish version is unknown. The aim of the study was to determine standard error of measurement (SEM) and smallest detectable change (SDC) for three Danish lengths of the TSK in patients with chronic pain.
Learn More >The digiti quinti sign (DQS) consists of a wider angle between the fourth and fifth fingers (ANG) indicative of subtle hemiparesis that has been found interictally in hemiplegic migraine (HM), suggesting a permanent subtle motor dysfunction. The aim of this study was to find a possible cortical origin for the DQS using blood oxygen level dependent (BOLD) functional (f) MRI.
Learn More >Based on the current understanding of the role of neuropeptide signalling in migraine, we explored the therapeutic potential of a specific cannabinoid agonist. The aim of the present study was to examine the effect of the synthetic endocannabinoid (eCB) analogue, arachidonyl-2'-chloroethylamide (ACEA), on calcitonin gene-related peptide (CGRP) release in the dura and trigeminal ganglion (TG), as cannabinoids are known to activate G-coupled cannabinoid receptors type 1 (CB1), resulting in neuronal inhibition.
Learn More >For this narrative review, we found recent publications on the use and effectiveness of old therapies including nutraceuticals, such as riboflavin, vitamin D, magnesium, melatonin and talking therapies. Recent large trials of established conventional pharmaceuticals such as propranolol, pizotifen, topiramate and amitriptyline for childhood migraine have failed, but the use of a quasi-placebo in future trials could help. We reviewed the evidence for angiotensin antagonists including candesartan in adults, but found a lack of evidence for their use in children. There have been new developments in pharmaceuticals recently, including a more selective 5-HT1F agonist, lasmiditan, an effective acute treatment with no vasoconstrictor activity in adults, currently being tested in children. Also, a number of new calcitonin gene-related peptide (CGRP) antibodies and antagonists, with proven efficacy in acute treatment and/or prevention of migraine in adults, are undergoing trials in children. Peripheral nerve blocks and botulinum toxin are gaining popularity in adult practice, but we really need more good quality evidence for their effectiveness in children. Finally, electroceuticals, that is, therapeutic electric devices, are now marketed for acute and or preventative treatment, including an external trigeminal nerve stimulator (e-TNS), a non-invasive vagal nerve stimulator (nVNS), a single-pulse transcranial magnetic stimulator (sTMS) and a remote electrical neuromodulation device (REN). At the moment, evidence for their effectiveness in children is still lacking. So, there has been much progress, but mostly for adults. We are in urgent need of more migraine trials in children.
Learn More >Many drug trials for chronic pain fail because of high placebo response rates in primary endpoints. Neurophysiological measures can help identify pain-linked pathophysiology and treatment mechanisms. They can also help guide early stop/go decisions, particularly if they respond to verum treatment but not placebo. The neurologic pain signature (NPS), an fMRI-based measure that tracks evoked pain in 40 published samples and is insensitive to placebo in healthy adults, provides a potentially useful neurophysiological measure linked to nociceptive pain.
Learn More >venom (BjV) can induce mast cell degranulation. In order to investigate the role of mast cells and the interference of the host genetic background in the inflammation induced by BjV, we have used mouse strains selected for maximal (AIRmax) or minimal (AIRmin) acute inflammatory response (AIR). Mice were pretreated with an inhibitor of mast cell degranulation, cromolyn (CROM), and injected in footpads or intraperitoneally (i.p.) with BjV. Pain was measured with von Frey hairs, cell migration in the peritoneum by flow cytometry, and reactive oxygen species (ROS) production by chemiluminescence assays. The nociceptive response to BjV was higher in AIRmax than AIRmin mice; however, this difference was abolished by pretreatment with CROM. BjV induced peritoneal neutrophil (CD11b GR-1) infiltration and ROS secretion in AIRmax mice only, which were partially inhibited by CROM. Our findings evidence a role for mast cells in pain, neutrophil migration, and ROS production triggered by BjV in AIRmax mice that are more susceptible to the action of BjV.
Learn More >Autism, attention deficit hyperactivity disorder (ADHD), and tic disorder (Tourette syndrome; TS) are neurodevelopmental conditions that frequently co-occur and impact psychological, social, and emotional processes. Increased likelihood of chronic physical symptoms, including fatigue and pain, are also recognized. The expression of joint hypermobility, reflecting a constitutional variant in connective tissue, predicts susceptibility to psychological symptoms alongside recognized physical symptoms. Here, we tested for increased prevalence of joint hypermobility, autonomic dysfunction, and musculoskeletal symptoms in 109 adults with neurodevelopmental condition diagnoses.
Learn More >Inflammatory pain is one of the most common symptoms of clinical pain that seriously affects patient quality of life, but it currently has limited therapeutic options. Proanthocyanidins, a group of polyphenols enriched in plants and foods, have been reported to exert anti-inflammatory pain-alleviating effects. However, the mechanism by which proanthocyanidins relieve inflammatory pain in the central nervous system is unclear. In the present study, we observed that intrathecal injection of proanthocyanidins inhibited mechanical and thermal pain sensitivity in mice with inflammatory pain induced by Complete Freund's Adjuvant (CFA) injection. Electrophysiological results further showed that proanthocyanidins inhibited the frequency of spontaneous excitatory postsynaptic currents without affecting the spontaneous inhibitory postsynaptic currents or the intrinsic properties of parabrachial nucleus-projecting neurons in the spinal cord. The effect of proanthocyanidins may be mediated by their inhibition of phosphorylated activation of the PI3K/Akt/mTOR pathway molecules in dorsal root ganglia neurons. In summary, intrathecal injection of procyanidin induces an obvious anti-inflammatory pain effect in mice by inhibiting peripheral excitatory inputs to spinal neurons that send nociceptive information to supraspinal areas.
Learn More >New psychoactive substances (NPS), formerly also referred to as "designer drugs", are often synthetic derivatives of existing psychoactive drugs, their diverse structures aiming at circumventing legislation and detection while their effects mimic those of traditional drugs of abuse. Of these, the group of new synthetic opioids (NSOs) has been one of the fastest growing NPS subclasses in the last couple of years, with over 70 new compounds detected in Europe since 2009. Apart from effects such as euphoria and analgesia, opioid use is associated with severe side effects such as constipation and respiratory depression. The μ-opioid receptor (MOR), a class A G protein-coupled receptor, is responsible for most of the therapeutic and adverse opioid effects. Insight into the pharmacology of opioids can aid the implementation of proactive harm reduction strategies, as well as the development of safer opioid analgesics. This review aims at assembling the available information on in vitro MOR agonism of the emerging class of new synthetic opioids, with a special focus on functional assays monitoring G protein and β-arrestin pathways.
Learn More >Opioids are among the most effective analgesics and the mainstay of pain management. However, concerns about safety and abuse liability have challenged their widespread use by the medical community. Opioid-sparing therapies include drugs that in combination with opioids have the ability to enhance analgesia while decreasing opioid requirement as well as their side effects. Sex differences in antinociceptive responses to opioids have received increasing attention in recent years. However, the molecular mechanisms underlying sex differences related to opioid-sparing adjuncts remain largely unexplored. Using warm water tail-withdrawal as a mouse model of acute thermal nociception, our data suggest that adjunctive administration of the serotonin 5-HT receptor (5-HTR) antagonist volinanserin dose-dependently enhanced potency of the opioid analgesic oxycodone in male, but not female, mice. This antinociceptive-like response induced by oxycodone was also augmented in 5-HTR knockout (5-HTR) male, but not female mice; an effect that was reversed by Cre-loxP-mediated selective expression of 5-HTR in dorsal root ganglion (DRG) neurons of 5-HTR littermates. Pharmacological inhibition with volinanserin or genetic deletion in 5-HTR animals potentiated the ability of oxycodone to reduce DRG excitability in male mice. Adjunctive volinanserin did not affect oxycodone-induced conditioned place preference (CPP), whereas it reduced oxycodone-induced locomotor sensitization in male and female mice. Together, these results suggest that adjunctive volinanserin augments opioid-induced antinociception, but not abuse-related behavior, through a sex-specific signaling crosstalk mechanism that requires 5-HTR expression in mouse DRG neurons. Ultimately, our results may pave the way for the clinical evaluation of volinanserin as a potential sex-specific opioid adjuvant.
Learn More >Cannabinoid and endocannabinoid system: a promising therapeutic intervention for multiple sclerosis.
Multiple sclerosis (MS) is a chronic and complex neurodegenerative disease, distinguished by the presence of lesions in the central nervous system (CNS) due to exacerbated immunological responses that inflict oligodendrocytes and the myelin sheath of axons. In recent years, studies have focused on targeted therapeutics for MS that emphasize the role of G protein-coupled receptors (GPCRs), specifically cannabinoids receptors. Clinical studies have suggested the therapeutic potential of cannabinoids derived from Cannabis sativa in relieving pain, tremors and spasticity. Cannabinoids also appear to prevent exaggerated immune responses in CNS due to compromised blood-brain barrier. Both, endocannabinoid system (ECS) modulators and cannabinoid ligands actively promote oligodendrocyte survival by regulating signaling, migration and myelination of nerve cells. The cannabinoid receptors 1 (CB1) and 2 (CB2) of ECS are the main ones in focus for therapeutic intervention of MS. Various CB1/CB2 receptors agonists have been experimentally studied which showed anti-inflammatory properties and are considered to be effective as potential therapeutics for MS. In this review, we focused on the exacerbated immune attack on nerve cells and the role of the cannabinoids and its interaction with the ECS in CNS during MS pathology.
Learn More >Peripheral nerve field stimulation (PNFS) is a tool in the armamentarium of treatment options for trigeminal pain. The efficacy of this modality in mitigating trigeminal pain remains unclear. The aim of this study was to examine the existing literature on PNFS and elucidate pain score outcomes associated with its use in patients with trigeminal pain.
Learn More >This review aims to summarize risks and disparities associated with the prevalence and treatment of opioid use disorder in the perioperative and long-term setting, as well as evidence-based treatment and prevention targeted toward specific vulnerable populations.
Learn More >Toll-like receptors (TLRs) are innate immune receptors that are expressed in immune cells as well as glia and neurons of the central and peripheral nervous systems. They are best known for their role in the host defense in response to pathogens and for the induction of inflammation in infectious and non-infectious diseases. In the central nervous system (CNS), TLRs modulate glial and neuronal functions as well as innate immunity and neuroinflammation under physiological or pathophysiological conditions. The majority of the studies on TLRs in CNS pathologies investigated their overall contribution without focusing on a particular cell type, or they analyzed TLRs in glia and infiltrating immune cells in the context of neuroinflammation and cellular activation. The role of neuronal TLRs in CNS diseases and injuries has received little attention and remains underappreciated. The primary goal of this review is to summarize findings demonstrating the pivotal and unique roles of neuronal TLRs in neuropathic pain, Alzheimer's disease, Parkinson's disease and CNS injuries. We discuss how the current findings warrant future investigations to better define the specific contributions of neuronal TLRs to these pathologies. We underline the paucity of information regarding the role of neuronal TLRs in other neurodegenerative, demyelinating, and psychiatric diseases. We draw attention to the importance of broadening research on neuronal TLRs in view of emerging evidence demonstrating their distinctive functional properties.
Learn More >Chronic musculoskeletal pain and insomnia frequently co-occur and are known independent risk factors for anxiety and depression. However, the interplay between these two conditions on the risk of anxiety and depression has not been explored.
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