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Table of Contents
doi : 10.1016/S1526-5900(21)00364-3
Volume 22, Issue 12, December 2021, Pages A3-A8
Lack of Consensus Across Clinical Guidelines Regarding the Role of Psychosocial Factors Within Low Back Pain Care: A Systematic Review
JesperKnoop?GeertRutten*CatoLever*JaapLeemeijer*Lieke J.de Jong*Arianne P.Verhagen†Wimvan Lankveld*J. BartStaal*
doi : 10.1016/j.jpain.2021.04.013
Volume 22, Issue 12, December 2021, Pages 1545-1559
It is widely accepted that psychosocial prognostic factors should be addressed by clinicians in their assessment and management of patient suffering from low back pain (LBP). On the other hand, an overview is missing how these factors are addressed in clinical LBP guidelines. Therefore, our objective was to summarize and compare recommendations regarding the assessment and management of psychosocial prognostic factors for LBP chronicity, as reported in clinical LBP guidelines. We performed a systematic search of clinical LBP guidelines (PROSPERO registration number 154730). This search consisted of a combination of previously published systematic review articles and a new systematic search in medical or guideline-related databases. From the included guidelines, we extracted recommendations regarding the assessment and management of LBP which addressed psychosocial prognostic factors (ie, psychological factors [“yellow flags”], perceptions about the relationship between work and health, [“blue flags”], system or contextual obstacles [“black flags”) and psychiatric symptoms [“orange flags”]). In addition, we evaluated the level or quality of evidence of these recommendations. In total, we included 15 guidelines. Psychosocial prognostic factors were addressed in 13 of 15 guidelines regarding their assessment and in 14 of 15 guidelines regarding their management. Recommendations addressing psychosocial factors almost exclusively concerned “yellow” or “black flags,” and varied widely across guidelines. The supporting evidence was generally of very low quality. We conclude that in general, clinical LBP guidelines do not provide clinicians with clear instructions about how to incorporate psychosocial factors in LBP care and should be optimized in this respect. More specifically, clinical guidelines vary widely in whether and how they address psychosocial factors, and recommendations regarding these factors generally require better evidence support. This emphasizes a need for a stronger evidence-base underlying the role of psychosocial risk factors within LBP care, and a need for uniformity in methodology and terminology across guidelines.
The Role of Skin Mast Cells in Acupuncture Induced Analgesia in Animals: A Preclinical Systematic Review and Meta-analysis
Sun-JeongBae*†Jeong-YeonJi*†Ju-YoungOh*‡JiyoonWon*‡Yeon-HeeRyu§HyangsookLee*‡Hyuk-SangJung‡Hi-JoonPark*‡
doi : 10.1016/j.jpain.2021.06.006
Volume 22, Issue 12, December 2021, Pages 1560-1577
While mast cells (MCs) are previously well-known as a pathological indicator of pain, their role in alleviating pain is recently emerged in acupuncture research. Thus, this study systematically reviews the role of MC in acupuncture analgesia. Animal studies on MC changes associated with the acupuncture analgesia were searched in PubMed and EMBASE. The MC number, degranulation ratio and pain threshold changes were collected as outcome measures for meta-analyses. Twenty studies were included with 13 suitable for meta-analysis, most with a moderate risk of bias. A significant MC degranulation after acupuncture was indicated in the normal and was significantly higher in the pain model. In the subgroup analysis by acupuncture type, manual (MA) and electrical (EA, each P < .00001) but not sham acupuncture had significant MC degranulation. Meta-regression revealed the linear proportionality between MC degranulation and acupuncture-induced analgesia (P < .001), which was found essential in MA (P < .00001), but not in EA (P = .45). MC mediators, such as adenosine and histamine, are involved in its mechanism. Taken together, skin MC is an essential factor for acupuncture-induced analgesia, which reveals a new aspect of MC as a pain alleviator. However, its molecular mechanism requires further study.
The Imperative for Racial Equality in Pain Science: A Way Forward
Staja Q.Booker?†Emily J.Bartley†‡KeeshaPowell-Roach*†ShreelaPalit†‡CaliaMorais†‡Osheeca J.Thompson†‡YeniselCruz-Almeida†‡Roger B.Fillingim†‡
doi : 10.1016/j.jpain.2021.06.008
Volume 22, Issue 12, December 2021, Pages 1578-1585
Racial equity is imperative to the future and integrity of scientific inquiry. In 2020, citizens of the United States (and globally) witnessed one of the most vile and egregious experiences of police brutality and systemic racism in recent history, the public execution of a Black American man. While some may isolate this and other similar events from influencing the scientific endeavors of pain researchers, events such as this can have a direct impact on the study, lived experience, and expression of pain in Black Americans. To truly understand the biopsychosocial effects of inequality and injustice on pain disparities, we must consider the unintended consequences that our current research approaches have in limiting the reliability and validity of scientific discovery. As we reflect on our current research practices in an effort to improve pain science, this perspective article discusses ways to initiate positive change in order to advance the science of pain in more equitable ways, not just for Black Americans, but for all individuals that identify as part of an underrepresented group.
Dysregulation in Sphingolipid Signaling Pathways is Associated With Symptoms and Functional Connectivity of Pain Processing Brain Regions in Provoked Vestibulodynia
Jennifer SLabus*†Emeran AMayer*KirstenTillisch*Kjersti MAagaard‡§?JeanStains*KatarzynaBroniowska¶CharlotteVan Remortel*GuistinnaTun*AndreaRapkin*#
doi : 10.1016/j.jpain.2021.04.017
Volume 22, Issue 12, December 2021, Pages 1586-1605
Provoked vestibulodynia (PVD) is a chronic pain disorder characterized by local hypersensitivity and severe pain with pressure localized to the vulvar vestibule. Despite decades of study, the lack of identified biomarkers has slowed the development of effective therapies. The primary aim of this study was to use metabolomics to identify novel biochemical mechanisms in vagina and blood underlying brain biomarkers and symptoms in PVD, thereby closing this knowledge gap. Using a cross-sectional case-control observational study design, untargeted and unbiased metabolomic profiling of vaginal fluid and plasma was performed in women with PVD compared to healthy controls. In women with PVD, we also obtained assessments of vulvar pain, vestibular and vaginal muscle tenderness, and 24-hour symptom intensity alongside resting-state brain functional connectivity of brain regions involved in pain processing and modulation. Compared to healthy controls, women with PVD demonstrated differences primarily in vaginal (but not plasma) concentrations of metabolites of the sphingolipid signaling pathways, suggesting localized effects in vagina and vulvar vestibule rather than systemic effects. Our findings reveal that dysregulation of sphingolipid metabolism in PVD is associated with increased vulvar pain and muscle tenderness, sexual dysfunction, and decreased functional connectivity strength in pain processing/modulatory brain regions. This data collectively suggests that alterations in sphingolipid signaling pathways are likely an important molecular biomarker in PVD that could lead to new targets for therapeutic intervention.
Associations of Regional and Network Functional Connectivity With Exercise-Induced Low Back Pain
Nicholas J.Bush*†1VictorSchneider*†1LandrewSevel‡§Mark D.Bishop†¶JeffBoissoneault*†
doi : 10.1016/j.jpain.2021.05.004
Volume 22, Issue 12, December 2021, Pages 1606-1616
Musculoskeletal pain is an aversive experience that exists within a variety of conditions and can result in significant impairment for individuals. Gaining greater understanding of the factors related to pain vulnerability and resilience to musculoskeletal pain may help target at-risk individuals for early intervention. This analysis builds on our previous work identifying regions where greater gray matter density was associated with lower pain following standardized, exercise induced musculoskeletal injury. Here we sought to examine the relationship between baseline resting state functional connectivity in a priori regions and networks, and delayed onset muscle soreness (DOMS) pain intensity following a single session of eccentric exercise in healthy adults. Participants completed a baseline functional MRI scan and a high intensity trunk exercise protocol in the erector spinae. Pain intensity ratings were collected 48-hours later. Resting state functional connectivity from four seed regions and 3 networks were separately regressed on pain intensity scores. Results revealed that connectivity between left middle frontal gyrus, the left occipital gyrus and cerebellar network seeds and clusters associated with discriminative, emotional, and cognitive aspects of pain were associated with lower post-DOMS pain. Results suggest resilience to clinically relevant pain is associated with aspects of regional and network neural coherence. Investigations of pain modulatory capacity that integrate multimodal neuroimaging metrics are called for.
Nerve Excitability and Neuropathic Pain is Reduced by BET Protein Inhibition After Spared Nerve Injury
GeorginaPalomés-Borrajo#JordiBadia#XavierNavarroClaraPenas
doi : 10.1016/j.jpain.2021.05.005
Volume 22, Issue 12, December 2021, Pages 1617-1630
Neuropathic pain is a common disability produced by enhanced neuronal excitability after nervous system injury. The pathophysiological changes that underlie the generation and maintenance of neuropathic pain require modifications of transcriptional programs. In particular, there is an induction of pro-inflammatory neuromodulators levels, and changes in the expression of ion channels and other factors intervening in the determination of the membrane potential in neuronal cells. We have previously found that inhibition of the BET proteins epigenetic readers reduced neuroinflammation after spinal cord injury. Within the present study we aimed to determine if BET protein inhibition may also affect neuroinflammation after a peripheral nerve injury, and if this would beneficially alter neuronal excitability and neuropathic pain. For this purpose, C57BL/6 female mice underwent spared nerve injury (SNI), and were treated with the BET inhibitor JQ1, or vehicle. Electrophysiological and algesimetry tests were performed on these mice. We also determined the effects of JQ1 treatment after injury on neuroinflammation, and the expression of neuronal components important for the maintenance of axon membrane potential. We found that treatment with JQ1 affected neuronal excitability and mechanical hyperalgesia after SNI in mice. BET protein inhibition regulated cytokine expression and reduced microglial reactivity after injury. In addition, JQ1 treatment altered the expression of SCN3A, SCN9A, KCNA1, KCNQ2, KCNQ3, HCN1 and HCN2 ion channels, as well as the expression of the Na+/K+ ATPase pump subunits. In conclusion, both, alteration of inflammation, and neuronal transcription, could be the responsible epigenetic mechanisms for the reduction of excitability and hyperalgesia observed after BET inhibition. Inhibition of BET proteins is a promising therapy for reducing neuropathic pain after neural injury.
Increased GABA+ in People With Migraine, Headache, and Pain Conditions- A Potential Marker of Pain
Aimie LPeek*†Andrew MLeaver*SherylFoster*‡GeorgOeltzschner§¶Nicolaas A.Puts???GrahamGalloway††‡‡MicheleSterling†§§KarlNg*¶¶KathrynRefshauge*Maria-Eliza R.Aguila??TrudyRebbeck*†
doi : 10.1016/j.jpain.2021.06.005
Volume 22, Issue 12, December 2021, Pages 1631-1645
Treatment outcomes for migraine and other chronic headache and pain conditions typically demonstrate modest results. A greater understanding of underlying pain mechanisms may better inform treatments and improve outcomes. Increased GABA+ has been identified in recent studies of migraine, however, it is unclear if this is present in other headache, and pain conditions. We primarily investigated GABA+ levels in the posterior cingulate gyrus (PCG) of people with migraine, whiplash-headache and low back pain compared to age- and sex-matched controls, GABA+ levels in the anterior cingulate cortex (ACC) and thalamus formed secondary aims. Using a cross-sectional design, we studied people with migraine, whiplash-headache or low back pain (n = 56) and compared them with a pool of age- and sex-matched controls (n = 22). We used spectral-edited magnetic resonance spectroscopy at 3T (MEGA-PRESS) to determine levels of GABA+ in the PCG, ACC and thalamus. PCG GABA+ levels were significantly higher in people with migraine and low back pain compared with controls (eg, migraine 4.89 IU ± 0.62 vs controls 4.62 IU ± 0.38; P = .02). Higher GABA+ levels in the PCG were not unique to migraine and could reflect a mechanism of chronic pain in general. A better understanding of pain at a neurochemical level informs the development of treatments that target aberrant brain neurochemistry to improve patient outcomes.
Green Light Antinociceptive and Reversal of Thermal and Mechanical Hypersensitivity Effects Rely on Endogenous Opioid System Stimulation
Laurent F.Martin*†AubinMoutal*KevinCheng*Stephanie M.Washington†HugoCalligaro?VasudhaGoel#TracyKranz†Tally M.Largent-Milnes*RajeshKhanna*†‡§¶AmolPatwardhan*†††¶Mohab M.Ibrahim*†††¶
doi : 10.1016/j.jpain.2021.05.006
Volume 22, Issue 12, December 2021, Pages 1646-1656
Benefits of phototherapy were characterized in multiple diseases including depression, circadian rhythm disruptions, and neurodegeneration. Studies on migraine and fibromyalgia patients revealed that green light-emitting diodes (GLED) exposure provides a pragmatic and safe therapy to manage chronic pain. In rodents, GLED reversed hypersensitivity related to neuropathic pain. However, little is known about the underlying mechanisms of GLED efficacy. Here, we sought to understand how green light modulates the endogenous opioid system. We first characterized how exposure to GLED stimulates release of ?-endorphin and proenkephalin in the central nervous system of male rats. Moreover, by individually editing each of the receptors, we found that µ- and ?-opioid receptors are required for green light's antinociceptive effect in naïve rats and a model of HIV-induced peripheral neuropathy. We investigated how GLED could increase pain thresholds, and explored its potential in reversing hypersensitivity in a model of HIV-related neuropathy. Through behavioral and gene editing approaches, we identified that green light provides antinociception via modulation of the endogenous opioid system in the spinal cord. This work identifies a previously unknown mechanism by which GLED can improve pain management. Clinical translation of these results will advance the development of an innovative therapy devoid of adverse effects.
Moderate to Severe Chronic Pain in Later Life: Risk and Resilience Factors for Recovery
RuiLi*Robert H.Dworkin†‡§Benjamin P.Chapman*§Adan Z.Becerra¶LuoyingYang?Christopher J.Mooney*#Christopher L.Seplaki*§
doi : 10.1016/j.jpain.2021.05.007
Volume 22, Issue 12, December 2021, Pages 1657-1671
Despite extensive research on the development and risk factors of chronic pain, the process of recovery from chronic pain in later life has been rarely studied. We estimated the recovery rate of moderate to severe chronic pain (chronic pain of moderate or severe severity or interfering with usual activities) among older adults and investigated predictors of recovery. Leveraging the longitudinal Health and Retirement Study 2006–2016 data (6 waves), we estimated the biennial national attrition-adjusted recovery rate of moderate to severe chronic pain among 6,132 US adults aged 65–75 at baseline. Generalized estimating equation Poisson models examined pain-related, sociodemographic, psychosocial and health-related factors in relation to recovery within any 2-year interval using longitudinal lagged design. Between 2006–2016, the prevalence of moderate to severe chronic pain increased from 28% to 33% with the incidence increasing from 14% to 18% and the recovery rate approximately 30%. Previous chronic pain duration, age, chronic diseases and a personality trait (agreeableness) were associated with a lower probability of recovery. Greater financial wealth and physical activity, better sleep quality and self-reported health were associated with a greater probability of recovery. Interventions that improve physical activity and sleep quality may be important avenues for reducing chronic pain burden among older adults.
The Role of the Observers’ Perception of a Model's Self-Confidence in Observationally Induced Placebo Analgesia
JustynaBr?czykPrzemys?awB?bel
doi : 10.1016/j.jpain.2021.06.001
Volume 22, Issue 12, December 2021, Pages 1672-1680
The aim of this study was to investigate the effect of a model's self-confidence as well as the observer's self-esteem and self-efficacy on observationally acquired placebo analgesia. In addition, we aimed to verify the stability of the placebo effect induced by observational learning. Participants (n = 60) were randomly assigned to one of three groups: a self-confident model, an unself-confident model, and a control group. In the experimental groups, participants watched a videotaped model who rated the intensity of electrocutaneous pain stimuli applied in the placebo condition as lower than those applied in the non-placebo condition. The different levels of self-confidence in these groups were manifested in the body posture and facial expressions of the model as well as in specific behavior that accompanied the assessment of pain. Then, 16 electrocutaneous pain stimuli of the same intensity, preceded by the placebo or non-placebo, were applied to participants. In both experimental groups, in contrast to the control group, participants experienced less pain in the placebo than in the non-placebo condition. Although the magnitude of placebo analgesia did not differ between the experimental groups, multiple regression analysis revealed that the perceived self-confidence of the model, but not the self-efficacy or self-esteem of the observer, was a significant predictor of the placebo effect. Moreover, placebo analgesia induced by observational learning did not extinguish over the course of the experiment. These results support the premise that the observers’ perception of a model's self-confidence plays a significant role in placebo effects.
Characteristics and Network Influence of Providers Involved in the Treatment of Patients With Chronic Back, Neck or Joint Pain in Arkansas
DivyanChopra*ChenghuiLi*Jacob TPainter*Jonathan PBona†IntawatNookaew†Bradley CMartin?
doi : 10.1016/j.jpain.2021.06.002
Volume 22, Issue 12, December 2021, Pages 1681-1695
Increasing emphasis on guidelines and prescription drug monitoring programs highlight the role of healthcare providers in pain treatment. Objectives of this study were to identify characteristics of key players and influence of opioid prescribers through construction of a referral network of patients with chronic pain. A retrospective cohort study was performed and patients with commercial or Medicaid coverage with chronic back, neck, or joint pain were identified using the Arkansas All-Payer Claims-Database. A social network comprised of providers connected by patient referrals based on 12-months of healthcare utilization following chronic pain was constructed. Network measures evaluated were indegree and eigen (referrals obtained), betweenness (involvement), and closeness centrality (reach). Outcomes included influence of providers, opioid prescribers, and brokerage status. Exposures included provider demographics, specialties and network characteristics. There were 51,941 chronic pain patients who visited 8,110 healthcare providers. Primary care providers showed higher betweenness and closeness whereas specialists had higher indegree. Opioid providers showed higher centrality compared to non-opioid providers, which decreased with increasing volume of opioid prescribing. Non-pharmacologic providers showed significant brokerage scores. Findings from this study such as primary care providers having better reach, non-central positions of high-volume prescribers and non-pharmacologic providers having higher brokerage can aid interventional physician detailing.
Attentional Biases Towards Body Expressions of Pain in Men and Women
EdmundKeogh*†NinaAttridge‡JosephWalsh§JessicaBartlett†RachelFrancis*Janet H.Bultitude*†ChristopherEccleston†¶
doi : 10.1016/j.jpain.2021.06.003
Volume 22, Issue 12, December 2021, Pages 1696-1708
This study investigated whether there are gender differences in attention to bodily expressions of pain and core emotions. Three experiments are reported using the attentional dot probe task. Images of men and women displaying bodily expressions, including pain, were presented. The task was used to determine whether participants’ attention was drawn towards or away from target expressions. Inconsistent evidence was found for an attentional bias towards body expressions, including pain. While biases were affected by gender, patterns varied across the Experiments. Experiment 1, which had a presentation duration of 500 ms, found a relative bias towards the location of male body expressions compared to female expressions. Experiments 2 and 3 varied stimulus exposure times by including both shorter and longer duration conditions (e.g., 100 vs. 500 vs. 1250 ms). In these experiments, a bias towards pain was confirmed. Gender differences were also found, especially in the longer presentation conditions. Expressive body postures captured the attention of women for longer compared to men. These results are discussed in light of their implications for why there are gender differences in attention to pain, and what impact this has on pain behaviour.
Association Between Pain Intensity and Discontinuing Opioid Therapy or Transitioning to Intermittent Opioid Therapy After Initial Long-Term Opioid Therapy: A Retrospective Cohort Study
Corey J.Hayes†‡Erin E.Krebs§¶JoshuaBrown?ChenghuiLi??TeresaHudson†‡Bradley C.Martin??
doi : 10.1016/j.jpain.2021.05.008
Volume 22, Issue 12, December 2021, Pages 1709-1721
The purpose of this study was to evaluate changes in pain intensity among Veterans transitioning from long-term opioid therapy (LTOT) to either intermittent therapy or discontinuation compared to continued LTOT. Pain intensity was assessed using the Numeric Rating Scale in 90-day increments starting in the 90-day period prior to potential opioid transitions and the two ensuing 90-day periods after transition. Primary analyses used a 1:1 greedy propensity matched sample. A total of 29,293 Veterans switching to intermittent opioids and 5,972 discontinuing opioids were matched to Veterans continuing LTOT. Covariates were well balanced after matching except minor differences in baseline mean pain scores. Pain scores were lower in the follow up periods for those switching to intermittent opioids and discontinuing opioids compared to those continuing LTOT (0–90 days: Intermittent: 3.79, 95%CI: 3.76, 3.82; LTOT: 4.09, 95%CI: 4.06, 4.12, P < .0001; Discontinuation: 3.06, 95%CI: 2.99, 3.13; LTOT: 3.86, 95%CI: 3.79, 3.94, P = <.0001; 91–180 days: Intermittent: 3.76, 95%CI: 3.73, 3.79; LTOT: 3.99, 95%CI: 3.96, 4.02, P < .0001; Discontinuation: 3.01, 95%CI: 2.94, 3.09; LTOT: 3.80, 95%CI: 3.73, 3.87, P = <.0001). Sensitivity analyses found similar results. Discontinuing opioid therapy or switching to intermittent opioid therapy was not associated with increased pain intensity.
Slowing in Peak-Alpha Frequency Recorded After Experimentally-Induced Muscle Pain is not Significantly Different Between High and Low Pain-Sensitive Subjects
EnricoDe Martino*†LuisinaGregoret*MatteoZandalasini*‡ThomasGraven-Nielsen*
doi : 10.1016/j.jpain.2021.06.004
Volume 22, Issue 12, December 2021, Pages 1722-1732
Peak alpha frequency (PAF) reduces during cutaneous pain, but no studies have investigated PAF during movement-related muscle pain. Whether high-pain sensitive (HPS) individuals exhibit a more pronounced PAF response to pain than low-pain sensitive (LPS) individuals is unclear. As a pain model, twenty-four participants received nerve growth factor injections into a wrist extensor muscle at Day 0, Day 2, and Day 4. At Day 4, a subgroup of twelve participants also undertook eccentric wrist exercise to induce additional pain. Pain numerical rating scale (NRS) scores and electroencephalography were recorded at Day 0 (before injection), Day 4, and Day 6 for 3 minutes (eyes closed) with wrist at rest (Resting-state) and extension (Contraction-state). The average pain NRS scores in contraction-state across Days were used to divide participants into HPS (NRS-scores?2) and LPS groups. PAF was calculated by frequency decomposition of electroencephalographic recordings. Compared with Day 0, contraction NRS-scores only increased in HPS-group at Day 4 and Day 6 (P < .001). PAF in Contraction-state decreased in both groups at Day 6 compared with Day 0 (P = .011). Across days, HPS-group showed faster PAF than LPS-group during Resting-state and Contraction-state (P < .04). Average pain NRS-scores across days during Contraction-states correlated with PAF at Day 0 (P = .012). Pain NRS-scores were associated with PAF during Contraction-state at Day 4 and Day 6 (P < .05).
