Acute, Chronic, and Everyday Physical Pain in Borderline Personality Disorder.

PURPOSE OF REVIEW: Physical pain is an underrecognized area of dysregulation among those with borderline personality disorder (BPD). Disturbances are observed within the experience of acute, chronic, and everyday physical pain experiences for people with BPD. We aimed to synthesize research findings on multiple areas of dysregulation in BPD in order to highlight potential mechanisms underlying the association between BPD and physical pain dysregulation. RECENT FINDINGS: Potential biological mechanisms include altered neural responses to painful stimuli within cognitive-affective regions of the brain, as well as potentially low basal levels of endogenous opioids. Emotion dysregulation broadly mediates dysregulation of physical pain. Certain psychological experiences may attenuate acute physical pain, such as dissociation, whereas others, such as negative affect, may exacerbate it. Social challenges between patients with BPD and healthcare providers may hinder appropriate treatment of chronic pain. Dysregulated physical pain is common in BPD and important in shaping health outcomes including elevated BPD symptoms, chronic pain conditions, and risk for problematic substance use.

Evoked oscillatory cortical activity during acute pain: Probing brain in pain by transcranial magnetic stimulation combined with electroencephalogram.

Temporal dynamics of local cortical rhythms during acute pain remain largely unknown. The current study used a novel approach based on transcranial magnetic stimulation combined with electroencephalogram (TMS-EEG) to investigate evoked-oscillatory cortical activity during acute pain. Motor (M1) and dorsolateral prefrontal cortex (DLPFC) were probed by TMS, respectively, to record oscillatory power (event-related spectral perturbation and relative spectral power) and phase synchronization (inter-trial coherence) by 63 EEG channels during experimentally induced acute heat pain in 24 healthy participants. TMS-EEG was recorded before, during, and after noxious heat (acute pain condition) and non-noxious warm (Control condition), delivered in a randomized sequence. The main frequency bands (α, ß1, and ß2) of TMS-evoked potentials after M1 and DLPFC stimulation were recorded close to the TMS coil and remotely. Cold and heat pain thresholds were measured before TMS-EEG. Over M1, acute pain decreased α-band oscillatory power locally and α-band phase synchronization remotely in parietal-occipital clusters compared with non-noxious warm (all p < .05). The remote (parietal-occipital) decrease in α-band phase synchronization during acute pain correlated with the cold (p = .001) and heat pain thresholds (p = .023) and to local (M1) α-band oscillatory power decrease (p = .024). Over DLPFC, acute pain only decreased ß1-band power locally compared with non-noxious warm (p = .015). Thus, evoked-oscillatory cortical activity to M1 stimulation is reduced by acute pain in central and parietal-occipital regions and correlated with pain sensitivity, in contrast to DLPFC, which had only local effects. This finding expands the significance of α and ß band oscillations and may have relevance for pain therapies.

Poor lumbar spine coordination in acute low back pain predicts persistent long-term pain and disability.

PURPOSE: Sitting balance on an unstable surface requires coordinated out-of-phase lumbar spine and provides sufficient challenge to expose quality of spine control. We investigated whether the quality of spine coordination to maintain balance in acute low back pain (LBP) predicts recovery at 6 months. METHODS: Participants in an acute LBP episode (n = 94) underwent assessment of sitting balance on an unstable surface. Seat, hip and spine (lower lumbar, lumbar, upper lumbar, thoracic) angular motion and force plate data were recorded. Coordination between the seat and hip/spine segments to maintain balance was quantified in the frequency domain to evaluate coordination (coherence) and relative timing (phase angle: in-phase [segments move together]; out-of-phase [segments move opposite]). Center of pressure (CoP) and upper thorax motion assessed overall balance performance. Hip and spine coordination with the seat were compared between those who did not recover (increased/unchanged pain/disability), partially recovered (reduced pain/disability) or recovered (no pain and disability) at 6 months. RESULTS: In both planes, coherence between the seat and lower lumbar spine was lower (and in-phase-unhelpful for balance) at baseline in those who did not recover than those who recovered. Coherence between the seat and hip was higher in partially recovered in both planes, suggesting compensation by the hip. LBP groups had equal overall balance performance (CoP, upper thorax motion), but non-recovery groups used a less optimal strategy that might have consequences for long-term spine health. CONCLUSION: These longitudinal data revealed that individuals with compromised contribution of the lumbar spine to the balance during unstable sitting during acute LBP are less likely to recover.

Alteration of ankle proprioceptive threshold during gait in the presence of acute experimental pain.

OBJECTIVE: Human gait requires complex somatosensory processing of various inputs such as proprioception. Proprioception can be altered in the presence of pain. This has been shown mostly during controlled tasks, thereby limiting the influence of external perturbations. While controlling the environment is sometimes warranted, it limits the ecological validity of the data. Using robotic orthoses to apply perturbations during movements seems a promising tool to functionally assess proprioception, where the complex somatosensory processing required in real-life situations is at play. The main objective of this study was to compare the proprioceptive threshold of healthy participants during gait in the presence and absence of an acute experimental pain. METHODS: 36 healthy participants walked on a treadmill while wearing a robotized ankle-foot orthosis (rAFO) around their right ankle. The rAFO applied torque perturbations of graded magnitudes during the swing phase of gait. Participants had to report the presence/absence of such perturbations, as a measure of proprioceptive threshold. Following initial assessment, they were randomly assigned to one of three experimental groups: Control (no stimulation), Painless (non-nociceptive stimulation) and Painful (nociceptive stimulation). Electrodes placed on the right lateral malleolus delivered an electrical stimulation during the second assessment for Painless and Painful groups. A Kruskal-Wallis was used to compare the percentage of change of the three groups between the two assessments. RESULTS: A 31.80±32.94% increase in proprioceptive threshold, representing an increase of 1.3±1.2 Nm in the detection threshold, was observed for the Painful group only (p<0.005), with an effect size of 1.6. CONCLUSION: Findings show that the presence of pain at the ankle can alter participants' proprioceptive threshold during gait. Clinical assessment of proprioception should therefore carefully consider the presence of pain when evaluating a patient's performance using clinical proprioceptive test and consider the negative effect of pain on proprioceptive threshold for test interpretation.

Low Somatosensory Cortex Excitability in the Acute Stage of Low Back Pain Causes Chronic Pain.

Determining the mechanistic causes of complex biopsychosocial health conditions such as low back pain (LBP) is challenging, and research is scarce. Cross-sectional studies demonstrate altered excitability and organization of the somatosensory and motor cortex in people with acute and chronic LBP, however, no study has explored these mechanisms longitudinally or attempted to draw causal inferences. Using sensory evoked potential area measurements and transcranial magnetic stimulation derived map volume we analyzed somatosensory and motor cortex excitability in 120 adults experiencing acute LBP. Following multivariable regression modelling with adjustment for confounding, we identified lower primary (OR = 2.08, 95% CI = 1.22-3.57) and secondary (OR = 2.56, 95% CI = 1.37-4.76) somatosensory cortex excitability significantly increased the odds of developing chronic pain at 6-month follow-up. Corticomotor excitability in the acute stage of LBP was associated with higher pain intensity at 6-month follow-up (B = -0.15, 95% CI: -0.28 to -0.02) but this association did not remain after confounder adjustment. These data provide evidence that low somatosensory cortex excitability in the acute stage of LBP is a cause of chronic pain. PERSPECTIVE: This prospective longitudinal cohort study design identified low sensorimotor cortex excitability during the acute stage of LBP in people who developed chronic pain. Interventions that target this proposed mechanism may be relevant to the prevention of chronic pain.

Acute Visceral Pain in Rats: Vagal Nerve Block Compared to Bupivacaine Administered Intramuscularly.

BACKGROUND: Visceral and parietal peritoneum layers have different sensory innervations. Most visceral peritoneum sensory information is conveyed via the vagus nerve to the nucleus of the solitary tract (NTS). We already showed in animal models that intramuscular (i.m.) injection of local anesthetics decreases acute somatic and visceral pain and general inflammation induced by aseptic peritonitis. The goal of the study was to compare the effects of parietal block, i.m. bupivacaine, and vagotomy on spinal cord and NTS stimulation induced by a chemical peritonitis. METHODS: We induced peritonitis in rats using carrageenan and measured cellular activation in spinal cord and NTS under the following conditions, that is, a parietal nerve block with bupivacaine, a chemical right vagotomy, and i.m. microspheres loaded with bupivacaine. Proto-oncogene c-Fos (c-Fos), cluster of differentiation protein 11b (CD11b), and tumor necrosis factor alpha (TNF-α) expression in cord and NTS were studied. RESULTS: c-Fos activation in the cord was inhibited by nerve block 2 hours after peritoneal insult. Vagotomy and i.m. bupivacaine similarly inhibited c-Fos activation in NTS. Forty-eight hours after peritoneal insult, the number of cells expressing CD11b significantly increased in the cord (P = .010). The median difference in the effect of peritonitis compared to control was 30 cells (CI95, 13.5-55). TNF-α colocalized with CD11b. Vagotomy inhibited this microglial activation in the NTS, but not in the cord. This activation was inhibited by i.m. bupivacaine both in cord and in NTS. The median difference in the effect of i.m. bupivacaine added to peritonitis was 29 cells (80% increase) in the cord and 18 cells (75% increase) in the NTS. Our study underlines the role of the vagus nerve in the transmission of an acute visceral pain message and confirmed that systemic bupivacaine prevents noxious stimuli by inhibiting c-Fos and microglia activation. CONCLUSIONS: In rats receiving intraperitoneal carrageenan, i.m. bupivacaine similarly inhibited c-Fos and microglial activation both in cord and in the NTS. Vagal block inhibited activation only in the NTS. Our study underlines the role of the vagus nerve in the transmission of an acute visceral pain message and confirmed that systemic bupivacaine prevents noxious stimuli. This emphasizes the effects of systemic local anesthetics on inflammation and visceral pain.

Determining patient treatment preferences for management of acute pain episodes in irritable bowel syndrome.

BACKGROUND: Many patients with irritable bowel syndrome (IBS) experience acute and unexpected pain episodes over and above chronic background symptoms, and there are emerging medications designed to treat such pain. We aimed to use conjoint analysis-a technique that elucidates how people make complex decisions-to examine patient preferences for emerging medicines for breakthrough IBS pain. METHODS: We conducted a cross-sectional conjoint analysis survey among patients with Rome IV IBS and recurrent episodes of acute pain to assess the relative importance of medication attributes in their decision-making. We also assessed what respondents would require of subcutaneous (SQ) therapies to consider their use. KEY RESULTS: Among 629 patients with Rome IV IBS, 606 (96.3%) reported ≥1 acute pain episodes in the past month. For the 461 participants with multiple attacks who completed the conjoint analysis, they prioritized medication efficacy (importance score 34.9%), avoidance of nausea (24.3%), and avoidance of constipation (12.2%) as most important in their decision-making. These were followed by route of administration (10.3%), avoidance of headache (9.3%), and avoidance of drowsiness (8.9%). Moreover, 431 (93.5%) participants would consider SQ therapies for their acute pain; they had varying expectations on the minimum pain decrease and onset and duration of pain relief needed for considering their use. CONCLUSIONS AND INFERENCES: The vast majority of patients with IBS experience breakthrough pain, and when selecting among therapies, they prioritize efficacy and most are willing to use a rapid-acting SQ treatment. These results support development of novel, effective medications-oral or SQ-for management of acute pain attacks.

The Application of Fascia Iliaca Compartment Block for Acute Pain Control of Hip Fracture and Surgery.

PURPOSE OF REVIEW: Over 300,000 patients are hospitalized annually following hip fractures in the USA. Many patients experienced inadequate analgesia. We will review the perioperative effects of the fascia iliaca compartment block (FICB) in hip fracture patients. RECENT FINDINGS: FICB by injecting local anesthetics beneath the fascia iliaca results in significant pain relief in hip fractures. Neuropathies and vascular injuries are almost unlikely. Single-shot FICB is faster to place, yet providing about 8 h of analgesia when bupivacaine is used. Continuous FICB provides prolonged titratable analgesia, improved patient satisfaction, and leads to faster hospital discharge. FICB reduces opioid consumption, decreases morbidity and mortality, reduces hospital stay, reduces delirium, and improves satisfaction. FICB should form part of a multimodal analgesic regime, in the context of a multidisciplinary approach to the management of hip fracture patients. More clinical investigations are needed to validate the long-term outcome benefits of FICB in hip fracture patients.

Pain in sickle cell disease: current and potential translational therapies.

Pain is a major comorbidity of sickle cell disease (SCD). Patients with SCD may suffer from both acute and chronic pain. Acute pain is caused by recurrent and unpredictable episodes of vaso-occlusive crises (VOC), whereas the exact etiology of chronic pain is still unknown. Opioids are the mainstay for pain treatment, but the opioid epidemic has significantly altered access to prescription opioids and has brought concerns over their long-term use into the forefront, which have negatively impacted the treatment of sickle pain. Opioids remain potent analgesics but growing opioid-phobia has led to the realization of an unmet need to develop nonopioid therapies that can provide relief for severe sickle pain. This realization has contributed to the approval of 3 different drugs by the Food and Drug Administration (FDA) for the treatment of SCD, particularly to reduce VOC and/or have an impact on the pathobiology of SCD. In this review, we outline the challenges and need for validation of side-effects of opioids and provide an update on the development of mechanism-based translational therapies, specifically targeting pain in SCD.

Pain Manifestations of COVID-19 and Their Association With Mortality: A Multicenter Prospective Observational Study.

OBJECTIVES: To determine the prevalence and breakdown of pain symptoms among patients with coronavirus disease 2019 (COVID-19) infection admitted for nonpain symptoms and the association between the presence of pain and intensive care unit (ICU) admission and death. PATIENTS AND METHODS: In this multicenter prospective study, data on the intensity and type of pain were collected on 169 patients with active severe acute respiratory syndrome coronavirus 2 infection at 2 teaching hospitals in the United States and Korea and on 8 patients with acute pain at another large teaching hospital between February 1, 2020, and June 15, 2020. RESULTS: Sixty-five of 169 patients (38.5%) reported an active pain condition. Among the 73 patients with pain, the most common pain symptoms were headache (n=22; 30.1%), chest pain (n=17; 23.3%), spinal pain (n=18; 24.7%), myalgia (n=13; 17.8%), abdominal or pelvic pain (n=13; 17.8%), arthralgia (n=11; 15.1%), and generalized pain (n=9; 12.3%). Those reporting headache as their main symptom were less likely to require ICU admission (P=.003). Acetaminophen or nonsteroidal anti-inflammatory drugs were prescribed to 80.8% (n=59), opioids to 17.8% (n=13), adjuvants to 8.2% (n=6), and ketamine to 5.5% (n=4) of patients with pain. When age 65 years and older and sex were controlled for in multivariable analysis, the absence of pain was associated with ICU admission (odds ratio, 2.92; 95% CI, 1.42 to 6.28; P=.004) and death (odds ratio, 3.49; 95% CI, 1.40 to 9.76; P=.01). CONCLUSION: Acute pain is common during active COVID-19 infection with the most common manifestations being headache, chest pain and spine pain. Individuals without pain were more likely to require intensive care and expire than those with pain. Reasons why pain may be associated with reduced mortality include that an intense systemic stimulus (eg, respiratory distress) might distract pain perception or that the catecholamine surge associated with severe respiratory distress might attenuate nociceptive signaling.

AMPAkines potentiate the corticostriatal pathway to reduce acute and chronic pain.

The corticostriatal circuit plays an important role in the regulation of reward- and aversion-types of behaviors. Specifically, the projection from the prelimbic cortex (PL) to the nucleus accumbens (NAc) has been shown to regulate sensory and affective aspects of pain in a number of rodent models. Previous studies have shown that enhancement of glutamate signaling through the NAc by AMPAkines, a class of agents that specifically potentiate the function of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, reduces acute and persistent pain. However, it is not known whether postsynaptic potentiation of the NAc with these agents can achieve the full anti-nociceptive effects of PL activation. Here we compared the impact of AMPAkine treatment in the NAc with optogenetic activation of the PL on pain behaviors in rats. We found that not only does AMPAkine treatment partially reconstitute the PL inhibition of sensory withdrawals, it fully occludes the effect of the PL on reducing the aversive component of pain. These results indicate that the NAc is likely one of the key targets for the PL, especially in the regulation of pain aversion. Furthermore, our results lend support for neuromodulation or pharmacological activation of the corticostriatal circuit as an important analgesic approach.

Pain Catastrophizing Mediates and Moderates the Link Between Acute Pain and Working Memory.

The bidirectional relationship between pain and working memory (WM) deficits is well-documented but poorly understood. Pain catastrophizing-exaggerated, negative cognitive and emotional responses toward pain-may contribute to WM deficits by occupying finite, shared cognitive resources. The present study assessed the role of pain catastrophizing as both a state-level process and trait-level disposition in the link between acute pain and WM. Healthy, young adults were randomized to an experimentally-induced ischemic pain or control task, during which they completed verbal and non-verbal WM tests. Participants also completed measures of state- and trait-level pain catastrophizing. Simple mediation analyses indicated that participants in the pain group (vs. control) engaged in more state-level catastrophizing about pain, which led to worse verbal and non-verbal WM. Moderated mediation analyses indicated that the indirect (mediation) effect of state-level pain catastrophizing was moderated by trait-level pain catastrophizing for both verbal and non-verbal WM. Participants in the pain group who reported a greater trait-level tendency to catastrophize about pain experienced greater state-level catastrophizing about pain during the ischemic task, which led to worse verbal and non-verbal WM performance. These results provide evidence for pain catastrophizing as an important mechanism and moderating factor of WM deficits in acute pain. Future research should replicate these results in chronic pain samples, investigate other potential mechanisms (e.g., sleep disturbances), and determine if interventions that target pain catastrophizing directly can ameliorate cognitive deficits in people with pain. PERSPECTIVE: This article presents a laboratory study examining the relationships among pain, pain catastrophizing, and working memory in healthy participants. The results shed new light on these relationships and raise the possibility that interventions that reduce catastrophizing may lead to improved cognitive function among people with pain.

Influence of acute pain on valence rating of words.

Numerous studies showed the effect of negative affective and pain-related semantic primes enhancing the perceived intensity of successive painful stimuli. It remains unclear whether and how painful primes are able to influence semantic stimuli in a similar way. Therefore, we investigated the effects of noxious primes on the perception of the valence of subsequent semantic stimuli. In two experiments, 48 healthy subjects were asked to give their valence ratings regarding different semantic stimuli (pain-related, negative, positive, and neutral adjectives) after they were primed with noxious electrical stimuli of moderate intensity. Experiment 1 focused on the existence of the effect, experiment 2 focused on the length of the effect. Valence ratings of pain-related, negative, and positive words (not neutral words) became more negative after a painful electrical prime was applied in contrast to no prime. This effect was more pronounced for pain-related words compared to negative, pain-unrelated words. Furthermore, the priming effect continued to affect the valence ratings even some minutes after the painful priming had stopped. So, painful primes are influencing the perception of semantic stimuli as well as semantic primes are influencing the perception of painful stimuli.

Peripheral Nerve Stimulation in Pain Management: A Systematic Review.

BACKGROUND: Peripheral nerve stimulation (PNS) has been increasingly used to manage acute and chronic pain. However, the level of clinical evidence to support its use is not clear. OBJECTIVES: To assess the clinical evidence of PNS in the treatment of acute or chronic pain. STUDY DESIGN: A systematic review of the efficacy and safety of PNS in managing acute or chronic pain. METHODS: Data sources were PubMed, Cochrane Library, Scopus, CINAHL Plus, Google Scholar, and reference lists. The literature search was performed up to December 2019. Study selection included randomized trials, observational studies, and case reports of PNS in acute or chronic pain. Data extraction and methodological quality assessment were performed utilizing Cochrane review methodologic quality assessment and Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB) and Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment for Nonrandomized Studies (IPM-QRBNR). The evidence was summarized utilizing principles of best evidence synthesis on a scale of 1 to 5. Data syntheses: 227 studies met inclusion criteria and were included in qualitative synthesis. RESULTS: Evidence synthesis based on randomized controlled trials (RCTs) and observational studies showed Level I and II evidence of PNS in chronic migraine headache; Level II evidence in cluster headache, postamputation pain, chronic pelvic pain, chronic low back and lower extremity pain; and Level IV evidence in peripheral neuropathic pain, and postsurgical pain. Peripheral field stimulation has Level II evidence in chronic low back pain, and Level IV evidence in cranial pain. LIMITATIONS: Lack of high-quality RCTs. Meta-analysis was not possible due to wide variations in experimental design, research protocol, and heterogeneity of study population. CONCLUSIONS: The findings of this systematic review suggest that PNS may be effective in managing chronic headaches, postamputation pain, chronic pelvic pain, and chronic low back and lower extremity pain, with variable levels of evidence in favor of this technique.

Experimental Hand and Knee Pain Cause Differential Effects on Corticomotor Excitability.

Acute pain elicits a well-known inhibitory effect on upper limb corticomotor excitability, whereas the temporal effects of lower-limb experimental pain and pain in a remote limb are less clear. The aim of this study was to compare the temporal corticomotor excitability changes in the upper and lower limbs in response to acute upper and lower limb pain. In a cross-over design, 13 participants (age 29 ± 9 years; 12 male) attended 2 sessions where experimental pain was induced by injecting hypertonic saline into either the first dorsal interosseous (FDI) muscle or infrapatellar fat pad at the knee, inducing a short-lasting pain experience scored on a numerical rating scale (NRS). Motor evoked potentials (MEPs) in response to transcranial magnetic stimulation were recorded in the FDI and vastus lateralis (VL) muscles before, during, and following pain. Hand and knee pain NRS scores were not significantly different. Hand pain elicited a short duration inhibition of the FDI MEPs (P < .0001) together with a facilitation of VL MEPs (P = .001) that outlasted the duration of pain. Knee pain elicited a short-duration facilitation of VL MEPs (P = .003) with no significant effect in the FDI MEPs (P = .46). The findings indicate a limb-specific corticomotor response to experimental pain that may be related to limb function. PERSPECTIVE: These data demonstrate the impact of acute, experimental pain on corticomotor excitability in the upper and lower limbs. This facilitates our understanding of the effect of pain on motor control of both local and distant muscles.

Risk Factors Associated With Transition From Acute to Chronic Low Back Pain in US Patients Seeking Primary Care.

Importance: Acute low back pain (LBP) is highly prevalent, with a presumed favorable prognosis; however, once chronic, LBP becomes a disabling and expensive condition. Acute to chronic LBP transition rates vary widely owing to absence of standardized operational definitions, and it is unknown whether a standardized prognostic tool (ie, Subgroups for Targeted Treatment Back tool [SBT]) can estimate this transition or whether early non-guideline concordant treatment is associated with the transition to chronic LBP. Objective: To assess the associations between the transition from acute to chronic LBP with SBT risk strata; demographic, clinical, and practice characteristics; and guideline nonconcordant processes of care. Design, Setting, and Participants: This inception cohort study was conducted alongside a multisite, pragmatic cluster randomized trial. Adult patients with acute LBP stratified by SBT risk were enrolled in 77 primary care practices in 4 regions across the United States between May 2016 and June 2018 and followed up for 6 months, with final follow-up completed by March 2019. Data analysis was conducted from January to March 2020. Exposures: SBT risk strata and early LBP guideline nonconcordant processes of care (eg, receipt of opioids, imaging, and subspecialty referral). Main Outcomes and Measures: Transition from acute to chronic LBP at 6 months using the National Institutes of Health Task Force on Research Standards consensus definition of chronic LBP. Patient demographic characteristics, clinical factors, and LBP process of care were obtained via electronic medical records. Results: Overall, 5233 patients with acute LBP (3029 [58%] women; 4353 [83%] White individuals; mean [SD] age 50.6 [16.9] years; 1788 [34%] low risk; 2152 [41%] medium risk; and 1293 [25%] high risk) were included. Overall transition rate to chronic LBP at six months was 32% (1666 patients). In a multivariable model, SBT risk stratum was positively associated with transition to chronic LBP (eg, high-risk vs low-risk groups: adjusted odds ratio [aOR], 2.45; 95% CI, 2.00-2.98; P < .001). Patient and clinical characteristics associated with transition to chronic LBP included obesity (aOR, 1.52; 95% CI, 1.28-1.80; P < .001); smoking (aOR, 1.56; 95% CI, 1.29-1.89; P < .001); severe and very severe baseline disability (aOR, 1.82; 95% CI, 1.48-2.24; P < .001 and aOR, 2.08; 95% CI, 1.60-2.68; P < .001, respectively) and diagnosed depression/anxiety (aOR, 1.66; 95% CI, 1.28-2.15; P < .001). After controlling for all other variables, patients exposed to 1, 2, or 3 nonconcordant processes of care within the first 21 days were 1.39 (95% CI, 1.21-2.32), 1.88 (95% CI, 1.53-2.32), and 2.16 (95% CI, 1.10-4.25) times more likely to develop chronic LBP compared with those with no exposure (P < .001). Conclusions and Relevance: In this cohort study, the transition rate to chronic LBP was substantial and increased correspondingly with SBT stratum and early exposure to guideline nonconcordant care.

Cellular Circuits in the Brain and Their Modulation in Acute and Chronic Pain.

Chronic, pathological pain remains a global health problem and a challenge to basic and clinical sciences. A major obstacle to preventing, treating, or reverting chronic pain has been that the nature of neural circuits underlying the diverse components of the complex, multidimensional experience of pain is not well understood. Moreover, chronic pain involves diverse maladaptive plasticity processes, which have not been decoded mechanistically in terms of involvement of specific circuits and cause-effect relationships. This review aims to discuss recent advances in our understanding of circuit connectivity in the mammalian brain at the level of regional contributions and specific cell types in acute and chronic pain. A major focus is placed on functional dissection of sub-neocortical brain circuits using optogenetics, chemogenetics, and imaging technological tools in rodent models with a view towards decoding sensory, affective, and motivational-cognitive dimensions of pain. The review summarizes recent breakthroughs and insights on structure-function properties in nociceptive circuits and higher order sub-neocortical modulatory circuits involved in aversion, learning, reward, and mood and their modulation by endogenous GABAergic inhibition, noradrenergic, cholinergic, dopaminergic, serotonergic, and peptidergic pathways. The knowledge of neural circuits and their dynamic regulation via functional and structural plasticity will be beneficial towards designing and improving targeted therapies.

Preoperative Chronic and Acute Pain Affects Postoperative Cognitive Function Mediated by Neurotransmitters.

The effective prevention of postoperative cognitive dysfunction (POCD) needs to be explored, and the effect of preoperative pain on POCD remains unclear. We established a chronic pain model induced by chronic constriction injury (CCI) and models of acute pain and anxiety without pain in mice that were subsequently subjected to partial hepatectomy surgery. Morris water maze (MWM) tests were performed to evaluate the learning and memory abilities of the mice. ELISA was used to measure IL-1ß, IL-6, and TNF-α in serum, and HPLC-MS was used to detect neurotransmitters in the prefrontal cortices and hippocampi of the mice. The results indicated that chronic pain induced by CCI might have significantly impaired the learning and memory abilities of mice, while acute pain and anxiety without pain only affected the memory abilities of mice. Perioperative acute pain increased the level of IL-1ß in serum, and CCI might have increased the level of IL-6. CCI and acute pain increased dopamine (DA) levels in the cortex, similar to anxiety. Like anxiety, CCI increased 5-hydroxytryptamine (5-HT) levels in the prefrontal cortex and hippocampus. Acute pain led to a decrease in the acetylcholine (ACH) level in the hippocampus. Our results suggest that acute pain and CCI-induced chronic pain might aggravate postoperative cognitive dysfunction via neurotransmitters and by changing the levels of inflammatory factors such as IL-1ß and IL-6.

Nocturnal peripheral vasoconstriction predicts the frequency of severe acute pain episodes in children with sickle cell disease.

The basic model of SCD physiology states that vaso-occlusion occurs when hemoglobin S-containing red blood cells (RBC) undergo sickling before they escape the capillary into a larger vessel. We have shown that mental stress, pain and cold, and events reported by patients to trigger SCD vaso-occlusive crisis (VOC), cause rapid and significant decrease in blood flow, reducing the likelihood that RBC could transit the microvasculature before sickling occurs. However, the critical link between decrease in microvascular blood flow and the incidence of future sickle VOC has never been established experimentally in humans. Using data from centrally adjudicated, overnight polysomnograms (PSG), previously collected in a prospective multi-center cohort sleep study, we analyzed the beat-to-beat amplitudes of vasoconstriction reported by the fingertip photoplethysmogram in 212 children and adolescents with SCD and developed an algorithm that detects vasoconstriction events and quantifies the magnitude (Mvasoc ), duration, and frequency of vasoconstriction that reflect the individual's inherent peripheral vasoreactivity. The propensity to vasoconstrict, quantified by median Mvasoc , predicted the incidence rate of post-PSG severe acute vaso-occlusive pain events (P = .006) after accounting for age and hemoglobin. Indices of sleep-disordered breathing contributed to median Mvasoc but did not predict future pain rate. Median Mvasoc was not associated with vaso-occlusive pain events that occurred prior to each PSG. These results show that SCD individuals with high inherent propensity to vasoconstrict have more frequent severe acute pain events. Our empirical findings are consistent with the fundamental SCD hypothesis that decreased microvascular flow promotes microvascular occlusion.

Management of Acute Pain From Non-Low Back, Musculoskeletal Injuries : A Systematic Review and Network Meta-analysis of Randomized Trials.

BACKGROUND: Patients and clinicians can choose from several treatment options to address acute pain from non-low back, musculoskeletal injuries. PURPOSE: To assess the comparative effectiveness of outpatient treatments for acute pain from non-low back, musculoskeletal injuries by performing a network meta-analysis of randomized clinical trials (RCTs). DATA SOURCES: MEDLINE, EMBASE, CINAHL, PEDro (Physiotherapy Evidence Database), and Cochrane Central Register of Controlled Trials to 2 January 2020. STUDY SELECTION: Pairs of reviewers independently identified interventional RCTs that enrolled patients presenting with pain of up to 4 weeks' duration from non-low back, musculoskeletal injuries. DATA EXTRACTION: Pairs of reviewers independently extracted data. Certainty of evidence was evaluated by using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. DATA SYNTHESIS: The 207 eligible studies included 32 959 participants and evaluated 45 therapies. Ninety-nine trials (48%) enrolled populations with diverse musculoskeletal injuries, 59 (29%) included patients with sprains, 13 (6%) with whiplash, and 11 (5%) with muscle strains; the remaining trials included various injuries ranging from nonsurgical fractures to contusions. Topical nonsteroidal anti-inflammatory agents (NSAIDs) proved to have the greatest net benefit, followed by oral NSAIDs and acetaminophen with or without diclofenac. Effects of these agents on pain were modest (around 1 cm on a 10-cm visual analogue scale, approximating the minimal important difference). Regarding opioids, compared with placebo, acetaminophen plus an opioid improved intermediate pain (1 to 7 days) but not immediate pain (≤2 hours), tramadol was ineffective, and opioids increased the risk for gastrointestinal and neurologic harms (all moderate-certainty evidence). LIMITATIONS: Only English-language studies were included. The number of head-to-head comparisons was limited. CONCLUSION: Topical NSAIDs, followed by oral NSAIDs and acetaminophen with or without diclofenac, showed the most convincing and attractive benefit-harm ratio for patients with acute pain from non-low back, musculoskeletal injuries. No opioid achieved benefit greater than that of NSAIDs, and opioids caused the most harms. PRIMARY FUNDING SOURCE: National Safety Council. (PROSPERO: CRD42018094412).