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Table of Contents
doi : 10.1016/S1526-5900(21)00328-X
Volume 22, Issue 10, October 2021, Pages A3-A8
Shifting the National Consciousness about Pain Treatment: The Critical Need for a National Public Education Campaign
Diana J.Burgess*†DonnaVallone‡§¶Matthew J.Bair???††Marianne S.Matthias???††Brent C.Taylor*†Stephanie L.Taylor‡‡§§
doi : 10.1016/j.jpain.2021.03.156
Volume 22, Issue 10, October 2021, Pages 1129-1133
The failure of past practices and policies related to opioid prescribing for chronic pain has led federal agencies and professional organizations to recommend multimodal approaches that prioritize evidence-based nonpharmacological pain treatments (NPTs). These multimodal approaches, which include both traditional and complementary/integrative approaches, hold great promise for reducing the burden of chronic pain and reducing opioid use. Unfortunately, NPT approaches are underutilized due to a daunting array of interrelated barriers including the public's attitudes and beliefs about chronic pain and its treatment. Given the dual crises of chronic pain and opioid use, there is a critical need for a national public health campaign on chronic pain and its treatment to help educate the American public about NPT pain management options, while countering the misleading messages promulgated by the pharmaceutical industry, including but not limited to messages promoting the broad use of prescription opioids and minimizing its risks. Despite these dual crises of chronic pain and opioid use in the U.S., there has never been a concerted effort to broadly educate the American public about these issues and NPT pain management options.
Prevalence and Interference of Chronic Pain Among People With Hemophilia: A Systematic Review and Meta-Analysis
Ana CristinaParedes*†PedroTeixeira*†ArmandoAlmeida*†Patrícia RibeiroPinto*†
doi : 10.1016/j.jpain.2021.03.157
Volume 22, Issue 10, October 2021, Pages 1134-1145
Chronic pain is a common condition among people with hemophilia (PWH), associated with joint deterioration due to repeated joint bleeds. This systematic review and meta-analysis aimed to determine the prevalence of chronic pain due to haemophilia and to analyze its interference in the lives of patients. A systematic search was performed in May and June 2019 and updated in February 2021, using PubMed, EMBASE, Web of Science and SciElo. The search included terms related to hemophilia, pain, pain prevalence and pain interference. Studies were included if they reported data referring to hemophilia-related chronic pain among adult males (age ?18). From 3,258 identified studies, 11 met the inclusion criteria. Three studies used a proposed definition for hemophilia-related chronic pain and 8 used direct questions developed by the authors. For the global samples, prevalence ranged from 17% to 84%. The random-effects meta-analysis including all studies demonstrated a pooled prevalence of chronic pain of 46% (95% Confidence Interval, CI = 34%–58%). Subgroup analysis of samples including all disease severities or including only severe patients revealed a pooled prevalence of 48% (95% CI = 29%–67%) and 53% (95% CI = 38%–69%), respectively. High heterogeneity between studies was observed in all models. Information concerning chronic pain interference was retrieved from 1 study, reporting a mean interference of 3.7 (0–10 numerical rating scale from the Brief Pain Inventory). This systematic review revealed a wide prevalence range of hemophilia-related chronic pain across studies, varying methodologies and sample characteristics. Research in the hemophilia field should clearly distinguish between acute and chronic pain and provide complete characterization of study samples.
The Persistent Pain Transcriptome: Identification of Cells and Molecules Activated by Hyperalgesia
Matthew R.Sapio?Jenny J.Kim?Amelia J.Loydpierson?DraganMaric†TaichiGoto?‡§Fernando A.Vazquez?Mary K.Dougherty?RadhikaNarasimhan?Wallis T.Muhly‡¶Michael J.Iadarola?Andrew J.Mannes?
doi : 10.1016/j.jpain.2021.03.155
Volume 22, Issue 10, October 2021, Pages 1146-1179
During persistent pain, the dorsal spinal cord responds to painful inputs from the site of injury, but the molecular modulatory processes have not been comprehensively examined. Using transcriptomics and multiplex in situ hybridization, we identified the most highly regulated receptors and signaling molecules in rat dorsal spinal cord in peripheral inflammatory and post-surgical incisional pain models. We examined a time course of the response including acute (2 hours) and longer term (2 day) time points after peripheral injury representing the early onset and instantiation of hyperalgesic processes. From this analysis, we identify a key population of superficial dorsal spinal cord neurons marked by somatotopic upregulation of the opioid neuropeptide precursor prodynorphin, and 2 receptors: the neurokinin 1 receptor, and anaplastic lymphoma kinase. These alterations occur specifically in the glutamatergic subpopulation of superficial dynorphinergic neurons. In addition to specific neuronal gene regulation, both models showed induction of broad transcriptional signatures for tissue remodeling, synaptic rearrangement, and immune signaling defined by complement and interferon induction. These signatures were predominantly induced ipsilateral to tissue injury, implying linkage to primary afferent drive. We present a comprehensive set of gene regulatory events across 2 models that can be targeted for the development of non-opioid analgesics.
Predictors of Sickness Absence in a Clinical Population With Chronic Pain
RiccardoLoMartire*†ÖrjanDahlström‡MathildaBjörk§LindaVixner†PaoloFrumento¶LeaConstan?BjörnGerdle§Björn OlovÄng*†#
doi : 10.1016/j.jpain.2021.03.145
Volume 22, Issue 10, October 2021, Pages 1180-1194
Chronic pain-related sickness absence is an enormous socioeconomic burden globally. Optimized interventions are reliant on a lucid understanding of the distribution of social insurance benefits and their predictors. This register-based observational study analyzed data for a 7-year period from a population-representative sample of 44,241 chronic pain patients eligible for interdisciplinary treatment (IDT) at specialist clinics. Sequence analysis was used to describe the sickness absence over the complete period and to separate the patients into subgroups based on their social insurance benefits over the final 2 years. The predictive performance of features from various domains was then explored with machine learning-based modeling in a nested cross-validation procedure. Our results showed that patients on sickness absence increased from 17% 5 years before to 48% at the time of the IDT assessment, and then decreased to 38% at the end of follow-up. Patients were divided into 3 classes characterized by low sickness absence, sick leave, and disability pension, with eight predictors of class membership being identified. Sickness absence history was the strongest predictor of future sickness absence, while other predictors included a 2008 policy, age, confidence in recovery, and geographical location. Information on these features could guide personalized intervention in the specialized healthcare.
Specialized Pro-resolving Mediators Reduce Pro-nociceptive Inflammatory Mediator Production in Models of Localized Provoked Vulvodynia
Megan L.Falsetta*†Ronald W.Wood*Mitchell A.Linder*Adrienne D.Bonham*Kenneth V.Honn‡Krishna RaoMaddipati‡Richard P.Phipps§Constantine G.Haidaris¶David C.Foster*
doi : 10.1016/j.jpain.2021.03.144
Volume 22, Issue 10, October 2021, Pages 1195-1209
Localized provoked vulvodynia (LPV) is the most common cause of chronic dyspareunia in premenopausal women, characterized by pain with light touch to the vulvar vestibule surrounding the vaginal opening. The devastating impact of LPV includes sexual dysfunction, infertility, depression, and even suicide. Yet, its etiology is unclear. No effective medical therapy exists; surgical removal of the painful vestibule is the last resort. In LPV, the vestibule expresses a unique inflammatory profile with elevated levels of pro-nociceptive proinflammatory mediators prostaglandin E2 (PGE2) and interleukin-6 (IL-6), which are linked to lower mechanical sensitivity thresholds. Specialized pro-resolving mediators (SPMs), lipids produced endogenously within the body, hold promise as an LPV treatment by resolving inflammation without impairing host defense. Ten of 13 commercially available SPMs reduced IL-6 and PGE2 production by vulvar fibroblasts, administered either before or after inflammatory stimulation. Using a murine vulvar pain model, coupling proinflammatory mediator quantification with mechanical sensitivity threshold determination, topical treatment with the SPM, maresin 1, decreased sensitivity and suppressed PGE2 levels. Docosahexaenoic acid, a precursor of maresin 1, was also effective in reducing PGE2 in vulvar fibroblasts and rapidly restored mouse sensitivity thresholds. Overall, SPMs and their precursors may be a safe and efficacious for LPV.
Adverse Childhood Experiences (ACEs) and Internalizing Mental Health, Pain, and Quality of Life in Youth With Chronic Pain: A Longitudinal Examination
SarahNelson*†Jaimie K.Beveridge‡RichelleMychasiuk‡§¶?MelanieNoel‡§¶
doi : 10.1016/j.jpain.2021.03.143
Volume 22, Issue 10, October 2021, Pages 1210-1220
The aims of this longitudinal study were to 1) identify categories of adverse childhood experiences (ACEs) (ie, neglect, abuse, household dysfunction in childhood) that increase risk for internalizing mental health problems, pain-related impairment, and poorer quality of life and 2) examine the moderating role of posttraumatic stress symptoms (PTSS) in these associations, in a clinical sample of youth with chronic pain. At 2 timepoints, youth (N?=?155; aged 10–18 years) completed measures of exposure to ACEs, PTSS, depressive and anxiety symptoms, pain intensity, pain interference, and quality of life. Multivariate analyses of variance, linear mixed modeling, and moderation analyses were conducted. Results from cross-sectional and longitudinal analyses were similar; youth with a history of 3+ ACEs reported significantly higher PTSS, depressive and anxiety symptoms, and poorer quality of life than youth with no ACE history. Results also revealed differences in functioning between youth exposed to different types of ACEs (ie, maltreatment only, household dysfunction only, both, none). Finally, PTSS was found to moderate the association between ACEs and anxiety and depressive symptoms. Findings underscore the influence that ACEs can have on the long-term functioning of youth with chronic pain as well as the important role of current PTSS in this association.
When Do We Not Face Our Fears? Investigating the Boundary Conditions of Costly Pain-Related Avoidance Generalization
EveliinaGlogan*†#KristofVandael*‡#RenaGatzounis*AnnMeulders*†
doi : 10.1016/j.jpain.2021.03.149
Volume 22, Issue 10, October 2021, Pages 1221-1232
Excessive generalization of fear and avoidance are hallmark symptoms of chronic pain disability, yet research focusing on the mechanisms underlying generalization of avoidance specifically, is scarce. Two experiments investigated the boundary conditions of costly pain-related avoidance generalization in healthy participants who learned to avoid pain by performing increasingly effortful (in terms of deviation and force) arm-movements using a robot-arm (acquisition). During generalization, novel, but similar arm-movements, without pain, were tested. Experiment 1 (N = 64) aimed to facilitate generalization to these movements by reducing visual contextual changes between acquisition and generalization, whereas Experiment 2 (N = 70) aimed to prevent extinction by increasing pain uncertainty. Both experiments showed generalization of pain-expectancies and pain-related fear. However, Experiment 2 was the first and only to also demonstrate generalization of avoidance, ie, choosing the novel effortful arm-movements in the absence of pain. These results suggest that uncertainty about the occurrence of pain may delay recovery, due to reduced disconfirmation of threat beliefs when exploring, resulting in persistent avoidance.
Yoga, Eurythmy Therapy and Standard Physiotherapy (YES-Trial) for Patients With Chronic Non-specific Low Back Pain: A Three-Armed Randomized Controlled Trial
AndreasMichalsen*†2MichaelJeitler*†2Christian S.Kessler*†NicoSteckhan*†SibylleRobens‡ThomasOstermann‡Farid I.Kandil*JosephinStankewitz§BettinaBerger¶SonnyJung¶MatthiasKröz§¶??ArndtBüssing¶
doi : 10.1016/j.jpain.2021.03.154
Volume 22, Issue 10, October 2021, Pages 1233-1245
We aimed to evaluate the effects of yoga and eurythmy therapy compared to conventional physiotherapy exercises in patients with chronic low back pain. In a three-armed, multicentre, randomized controlled trial, patients with chronic low back pain were treated for 8 weeks in group sessions (75 minutes once per week). Primary outcome was patients’ physical disability (measured by RMDQ) from baseline to week 8. Secondary outcome variables were pain intensity and pain-related bothersomeness (VAS), health-related quality of life (SF-12) and life satisfaction (BMLSS). Outcomes were assessed at baseline, after the intervention at 8 weeks and at a 16-week follow up. Data of 274 participants were used for statistical analyses. There were no significant differences between the three groups for the primary and all secondary outcomes. In all groups, RMDQ decreased comparably at 8 weeks, but did not reach clinical meaningfulness. Pain intensity and pain-related bothersomeness decreased, while quality of life increased in all 3 groups. In explorative general linear models for the SF-12’s mental health component participants in the eurythmy arm benefitted significantly more compared to physiotherapy and yoga. Furthermore, within-group analyses showed improvements of SF-12 mental score for yoga and eurythmy therapy only. All interventions were safe.
Should Exercises be Painful or not? Effects on Clinical and Experimental Pain in Individuals with Shoulder Pain
MBalasch-Bernat*†ELluch*†‡HBVaegter§¶LDueñas*†
doi : 10.1016/j.jpain.2021.03.153
Volume 22, Issue 10, October 2021, Pages 1246-1255
Exercise can reduce pain, however the effect of painful versus non-painful exercises is uncertain. The primary aim of this randomized crossover study was to compare the effect of painful versus nonpainful isometric shoulder exercises on pain intensity after exercise in individuals with rotator cuff-related shoulder pain. Secondary exploratory aims were to describe the effects on pressure pain thresholds (PPTs), conditioned pain modulation (CPM) and muscle strength. On separate days, 35 individuals performed painful isometric shoulder exercises (external rotation; 20% above pain threshold), nonpainful isometric shoulder exercises (external rotation; 20% below pain threshold), and a rest condition, in randomised order. Shoulder pain intensity, PPTs, CPM, and external rotation strength were assessed before, immediately after and 45 minutes after conditions. No significant differences were observed between painful and nonpainful exercises. Visual analogue scale scores increased immediately after both painful and non-painful exercises compared with rest (P = .047, partial ?2 = .07), but were similar to preexercise levels after 45 minutes. No changes in PPTs, CPM, or muscle strength after exercises compared with rest were observed. Painful and non-painful isometric exercises caused a moderate but short-lasting increase in shoulder pain in individuals with RCRSP. Isometric exercises had no effect on pain sensitivity and shoulder muscle strength or CPM.
Modulating Brain Rhythms of Pain Using Transcranial Alternating Current Stimulation (tACS) - A Sham-Controlled Study in Healthy Human Participants
Elisabeth S.May*†**Vanessa D.Hohn*†**Moritz M.Nickel*†LauraTiemann*†CristinaGil Ávila*†HenrikHeitmann*†‡PaulSauseng§MarkusPloner*†‡
doi : 10.1016/j.jpain.2021.03.150
Volume 22, Issue 10, October 2021, Pages 1256-1272
Chronic pain is a major health care problem. A better mechanistic understanding and new treatment approaches are urgently needed. In the brain, pain has been associated with neural oscillations at alpha and gamma frequencies, which can be targeted using transcranial alternating current stimulation (tACS). Thus, we investigated the potential of tACS to modulate pain and pain-related autonomic activity in an experimental model of chronic pain in 29 healthy participants. In 6 recording sessions, participants completed a tonic heat pain paradigm and simultaneously received tACS over prefrontal or somatosensory cortices at alpha or gamma frequencies or sham tACS. Concurrently, pain ratings and autonomic responses were collected. Using the present setup, tACS did not modulate pain or autonomic responses. Bayesian statistics confirmed a lack of tACS effects in most conditions. The only exception was alpha tACS over somatosensory cortex where evidence was inconclusive. Taken together, we did not find significant tACS effects on tonic experimental pain in healthy humans. Based on our present and previous findings, further studies might apply refined stimulation protocols targeting somatosensory alpha oscillations.
Sexually Dimorphic Role of Toll-like Receptor 4 (TLR4) in High Molecular Weight Hyaluronan (HMWH)-induced Anti-hyperalgesia
Ivan J.M.Bonet*†DionéiaAraldi*†Paul G.Green*†‡Jon D.Levine*†§
doi : 10.1016/j.jpain.2021.03.152
Volume 22, Issue 10, October 2021, Pages 1273-1282
High molecular weight hyaluronan (HMWH), a prominent component of the extracellular matrix binds to and signals via multiple receptors, including cluster of differentiation 44 (CD44) and toll-like receptor 4 (TLR4). We tested the hypothesis that, in the setting of inflammation, HMWH acts at TLR4 to attenuate hyperalgesia. We found that the attenuation of prostaglandin E2 (PGE2)-induced hyperalgesia by HMWH was attenuated by a TLR4 antagonist (NBP2-26245), but only in male and ovariectomized female rats. In this study we sought to evaluated the role of the TLR4 signaling pathway in anti-hyperalgesia induced by HMWH in male rats. Decreasing expression of TLR4 in nociceptors, by intrathecal administration of an oligodeoxynucleotide (ODN) antisense to TLR4 mRNA, also attenuated HMWH-induced anti-hyperalgesia, in male and ovariectomized female rats. Estrogen replacement in ovariectomized females reconstituted the gonad-intact phenotype. The administration of an inhibitor of myeloid differentiation factor 88 (MyD88), a TLR4 second messenger, attenuated HMWH-induced anti-hyperalgesia, while an inhibitor of the MyD88-independent TLR4 signaling pathway did not. Since it has previously been shown that HMWH-induced anti-hyperalgesia is also mediated, in part by CD44 we evaluated the effect of the combination of ODN antisense to TLR4 and CD44 mRNA. This treatment completely reversed HMWH-induced anti-hyperalgesia in male rats. Our results demonstrate a sex hormone-dependent, sexually dimorphic involvement of TLR4 in HMWH-induced anti-hyperalgesia, that is MyD88 dependent.
Differential Activation of Colonic Afferents and Dorsal Horn Neurons Underlie Stress-Induced and Comorbid Visceral Hypersensitivity in Female Rats
Dong-YuanCao*§#BoHu*§#YangXue*¶ShelbyHanson*DeanDessem*‡1Susan G.Dorsey†‡Richard J.Traub*‡
doi : 10.1016/j.jpain.2021.04.004
Volume 22, Issue 10, October 2021, Pages 1283-1293
Chronic Overlapping Pain Conditions, including irritable bowel syndrome (IBS) and temporomandibular disorder (TMD), represent a group of idiopathic pain conditions that likely have peripheral and central mechanisms contributing to their pathology, but are poorly understood. These conditions are exacerbated by stress and have a female predominance. The presence of one condition predicts the presence or development of additional conditions, making this a significant pain management problem. The current study was designed to determine if the duration and magnitude of peripheral sensitization and spinal central sensitization differs between restraint stress-induced visceral hypersensitivity (SIH) and chronic comorbid pain hypersensitivity (CPH; stress during pre-existing orofacial pain). SIH in female rats, as determined by the visceromotor response, persisted at least four but resolved by seven weeks. In contrast, CPH persisted at least seven weeks. Surprisingly, colonic afferents in both SIH and CPH rats were sensitized at seven weeks. CPH rats also had referred pain through seven weeks, but locally anesthetizing the colon only attenuated the referred pain through four weeks, suggesting a transition to colonic afferent independent central sensitization. Different phenotypes of dorsal horn neurons were sensitized in the CPH rats seven weeks post stress compared to four weeks or SIH rats. The current study suggests differential processing of colonic afferent input to the lumbosacral spinal cord contributes to visceral hypersensitivity during comorbid chronic pain conditions.
Local and Systemic Expression Pattern of MMP-2 and MMP-9 in Complex Regional Pain Syndrome
FabiolaEscolano-Lozano*EvaGries†TanjaSchlereth‡VioletaDimova*PanoraiaBaka*EvaVlckova§SimoneKönig¶FrankBirklein*
doi : 10.1016/j.jpain.2021.04.002
Volume 22, Issue 10, October 2021, Pages 1294-1302
Matrix metalloproteinases (MMP)-2 and MMP-9 play important roles in inflammation as well as in pain processes. For this reason, we compared the concentrations of these enzymes in skin and serum of patients with complex regional pain syndrome (CRPS), other pain diseases and healthy subjects. We analyzed ipsi- and contralateral skin biopsies of 18 CRPS patients, as well as in 10 pain controls and 9 healthy subjects. Serum samples were analyzed from 20 CRPS, 17 pain controls and 17 healthy subjects. All samples were analyzed with ELISA. Concentrations were then compared to clinical data as well as to quantitative sensory testing data.MMP-2 was increased in both ipsi- and contralateral skin biopsies of CRPS patients compared to healthy subjects. While low ipsilateral MMP-2 was associated with trophic changes, contralateral MMP-2 inversely correlated with the CRPS severity. MMP-9 was also locally increased in ipsilateral CRPS skin, and higher ipsi- and contralateral MMP-9 levels correlated with CRPS severity.
The Moderating Role of Attention Control in the Relationship Between Pain Catastrophizing and Negatively-Biased Pain Memories in Youth With Chronic Pain
AlineWauters*MelanieNoel†Dimitri M.L.Van Ryckeghem*‡§SabineSoltani¶TineVervoort*
doi : 10.1016/j.jpain.2021.04.010
Volume 22, Issue 10, October 2021, Pages 1303-1314
The present study examined the role of attention control in understanding the development of negatively-biased pain memories as well as its moderating role in the relationship between pain catastrophizing and negatively-biased pain memories. Youth with chronic pain (N = 105) performed a cold pressor task (CPT) and completed self-report measures of state/trait pain catastrophizing and attention control, with the latter comprising both attention focusing and attention shifting. Two weeks after the CPT, youth's pain-related memories were elicited via telephone allowing to compute pain and anxiety memory bias indices (ie, recalling pain intensity or pain-related anxiety, respectively, as higher than initially reported). Results indicated no main effects of attention control and pain catastrophizing on pain memories. However, both components of attention control (ie, attention focusing and attention shifting) moderated the impact of pain catastrophizing on youth's memory bias, with opposite interaction effects. Specifically, whereas high levels of attention shifting buffered the influence of high pain catastrophizing on the development of pain memory bias, high levels of attention focusing strengthened the influence of high pain catastrophizing on the development of anxiety memory bias. Interaction effects were confined to trait catastrophizing (ie, not state catastrophizing). Theoretical and clinical implications are discussed.
