Skin-resident dendritic cells mediate postoperative pain via CCR4 on sensory neurons.

Inflammatory pain, such as hypersensitivity resulting from surgical tissue injury, occurs as a result of interactions between the immune and nervous systems with the orchestrated recruitment and activation of tissue-resident and circulating immune cells to the site of injury. Our previous studies identified a central role for Ly6Clow myeloid cells in the pathogenesis of postoperative pain. We now show that the chemokines CCL17 and CCL22, with their cognate receptor CCR4, are key mediators of this response. Both chemokines are up-regulated early after tissue injury by skin-resident dendritic and Langerhans cells to act on peripheral sensory neurons that express CCR4. CCL22, and to a lesser extent CCL17, elicit acute mechanical and thermal hypersensitivity when administered subcutaneously; this response abrogated by pharmacological blockade or genetic silencing of CCR4. Electrophysiological assessment of dissociated sensory neurons from naïve and postoperative mice showed that CCL22 was able to directly activate neurons and enhance their excitability after injury. These responses were blocked using C 021 and small interfering RNA (siRNA)-targeting CCR4. Finally, our data show that acute postoperative pain is significantly reduced in mice lacking CCR4, wild-type animals treated with CCR4 antagonist/siRNA, as well as transgenic mice depleted of dendritic cells. Together, these results suggest an essential role for the peripheral CCL17/22:CCR4 axis in the genesis of inflammatory pain via direct communication between skin-resident dendritic cells and sensory neurons, opening therapeutic avenues for its control.

Movement-evoked Pain versus Pain at Rest in Postsurgical Clinical Trials and in Meta-analyses: An Updated Systematic Review.

BACKGROUND: Given the widespread recognition that postsurgical movement-evoked pain is generally more intense, and more functionally relevant, than pain at rest, the authors conducted an update to a previous 2011 review to re-evaluate the assessment of pain at rest and movement-evoked pain in more recent postsurgical analgesic clinical trials. METHODS: The authors searched MEDLINE and Embase for postsurgical pain randomized controlled trials and meta-analyses published between 2014 and 2023 in the setting of thoracotomy, knee arthroplasty, and hysterectomy using methods consistent with the original 2011 review. Included trials and meta-analyses were characterized according to whether they acknowledged the distinction between pain at rest and movement-evoked pain and whether they included pain at rest and/or movement-evoked pain as a pain outcome. For trials measuring movement-evoked pain, pain-evoking maneuvers used to assess movement-evoked pain were tabulated. RESULTS: Among the 944 included trials, 504 (53%) did not measure movement-evoked pain (vs. 61% in 2011), and 428 (45%) did not distinguish between pain at rest and movement-evoked pain when defining the pain outcome (vs. 52% in 2011). Among the 439 trials that measured movement-evoked pain, selection of pain-evoking maneuver was highly variable and, notably, was not even described in 139 (32%) trials (vs. 38% in 2011). Among the 186 included meta-analyses, 94 (51%) did not distinguish between pain at rest and movement-evoked pain (vs. 71% in 2011). CONCLUSIONS: This updated review demonstrates a persistent limited proportion of trials including movement-evoked pain as a pain outcome, a substantial proportion of trials failing to distinguish between pain at rest and movement-evoked pain, and a lack of consistency in the use of pain-evoking maneuvers for movement-evoked pain assessment. Future postsurgical trials need to (1) use common terminology surrounding pain at rest and movement-evoked pain, (2) assess movement-evoked pain in virtually every trial if not contraindicated, and (3) standardize movement-evoked pain assessment with common, procedure-specific pain-evoking maneuvers. More widespread knowledge translation and mobilization are required in order to disseminate this message to current and future investigators.

Intraoperative pharmacologic opioid minimisation strategies and patient-centred outcomes after surgery: a scoping review.

BACKGROUND: Postoperative patient-centred outcome measures are essential to capture the patient's experience after surgery. Although a large number of pharmacologic opioid minimisation strategies (i.e. opioid alternatives) are used for patients undergoing surgery, it remains unclear which strategies are most promising in terms of patient-centred outcome improvements. This scoping review had two main objectives: (1) to map and describe evidence from clinical trials assessing the patient-centred effectiveness of pharmacologic intraoperative opioid minimisation strategies in adult surgical patients, and (2) to identify promising pharmacologic opioid minimisation strategies. METHODS: We searched MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL databases from inception to February 2023. We included trials investigating the use of opioid minimisation strategies in adult surgical patients and reporting at least one patient-centred outcome. Study screening and data extraction were conducted independently by at least two reviewers. RESULTS: Of 24,842 citations screened for eligibility, 2803 trials assessed the effectiveness of intraoperative opioid minimisation strategies. Of these, 457 trials (67,060 participants) met eligibility criteria, reporting at least one patient-centred outcome. In the 107 trials that included a patient-centred primary outcome, patient wellbeing was the most frequently used domain (55 trials). Based on aggregate findings, dexmedetomidine, systemic lidocaine, and COX-2 inhibitors were promising strategies, while paracetamol, ketamine, and gabapentinoids were less promising. Almost half of the trials (253 trials) did not report a protocol or registration number. CONCLUSIONS: Researchers should prioritise and include patient-centred outcomes in the assessment of opioid minimisation strategy effectiveness. We identified three potentially promising pharmacologic intraoperative opioid minimisation strategies that should be further assessed through systematic reviews and multicentre trials. Findings from our scoping review may be influenced by selective outcome reporting bias. STUDY REGISTRATION: OSF - https://osf.io/7kea3.

Postdischarge opioid use after lumbar spine surgery among older adults in Ontario: a population-based cohort study.

BACKGROUND: Prescription opioid use places a considerable economic burden on health care systems. Older patients undergoing surgical procedures for painful conditions commonly receive opioids pre- and postoperatively, and are susceptible to adverse reactions. This study explores predictors of prolonged postoperative opioid use among older patients after lumbar spine surgery and the consequences in terms of health care utilization and costs. METHODS: We conducted a retrospective population-based cohort study using Ontario administrative data from older adults undergoing spine surgery between 2006 and 2017. Data were analyzed from 90 days preoperatively to 1 year after hospital discharge, with last postoperative opioid prescriptions stratified into 90-day increments. We used multivariable ordinal logistic regression to identify predictors of long-term opioid use and generalized linear modelling to examine resource utilization and health care costs (2021 Canadian dollars). RESULTS: Of 15 109 patients included, 40.8% received preoperative opioid prescriptions. Preoperative opioid use strongly predicted prolonged postoperative use (odds ratio [OR] 4.47, 95% confidence interval [CI] 4.16-4.79), with 48.3% of patients who received preoperative opioids continuing to use opioids for longer than 9 months, relative to 12.7% of those without preoperative use. Several other risk factors for prolonged use were identified. Patients receiving long-term postoperative opioids incurred greater health care costs relative to those with opioids prescribed for fewer than 90 days (OR 1.49, 95% CI 1.44-1.54). CONCLUSION: Among older adults undergoing spine surgery, preoperative opioid use was a strong predictor of prolonged postoperative use, which was associated with increased health care costs. These results form an important baseline for future studies evaluating strategies to reduce opioid use targeting older surgical populations.

A Scoping Review of the Diurnal Variation in the Intensity of Neuropathic Pain.

BACKGROUND: Recent studies have suggested that neuropathic pain exhibits a daily diurnal pattern, with peak levels usually occurring in the late afternoon to evening and the trough in the morning hours, although literature on this topic has been sparse. This scoping review examines current evidence on the chronobiology of neuropathic pain both in animal models and in humans with neuropathic pain. METHODS: A literature search was conducted in major medical databases for relevant articles on the chronobiology of neuropathic pain both in animal models and in humans with neuropathic pain. Data extracted included details of specific animal models or specific neuropathic pain conditions in humans, methods and timing of assessing pain severity, and specific findings of diurnal variation in pain intensity or its surrogate markers. RESULTS: Thirteen animal and eight human studies published between 1976 and 2020 were included in the analysis. Seven of the 13 animal studies reported specific diurnal variation in pain intensity, with five of the seven studies reporting a trend toward increased sensitivity to mechanical allodynia or thermal hyperalgesia in the late light to dark phase. All eight studies in human subjects reported a diurnal variation in the intensity of neuropathic pain, where there was an increase in pain intensity through the day with peaks in the late evening and early night hours. CONCLUSIONS: Studies included in this review demonstrated a diurnal variation in the pattern of neuropathic pain that is distinct from the pattern for nociceptive pain. These findings have implications for potential therapeutic strategies for neuropathic pain.

Chronic opioid use after joint replacement surgery in seniors is associated with increased healthcare utilization and costs: a historical cohort study.

PURPOSE: Postoperative opioid use may be associated with increased healthcare utilization and costs. We sought to examine the relationship between duration of postoperative opioid prescriptions and healthcare costs and resource utilization in senior patients following hip and knee replacement. METHODS: We conducted a historical cohort study evaluating postoperative opioid use and healthcare costs in patients over the age of 65 yr undergoing primary total hip or knee arthroplasty over a ten-year period from 1 April 2006 to 31 March 2016. The last follow-up date was 31 March 2017. We identified preoperative and postoperative opioid prescriptions, patient characteristics, and healthcare costs using deidentified Ontario administrative databases (Institute of Clinical Evaluative Sciences). Duration of postoperative opioid use was divided into four categories: short-term (1-90 days), prolonged (91-180 days), chronic (181-365 days), and undocumented. RESULTS: The study included 49,638 hip and 85,558 knee replacement patients. Although the initial hospitalization accounted for the greatest cost in all patients, over the following year patients in the short-term opioid use group incurred the lowest average costs, and those in the chronic group incurred the highest (hip, CAD 17,528 vs CAD 26,736; knee, CAD 16,043 vs CAD 23,007), driven by increased healthcare resource utilization. CONCLUSION: Chronic opioid use after arthroplasty was associated with higher resource utilization and healthcare costs during the year following surgery. These results can be used to develop predictors of longer opioid use and higher costs. Further research is planned to determine whether recently implemented opioid reduction strategies can reduce healthcare resource utilization.

RéSUMé: OBJECTIF: L'utilisation postopératoire d'opioïdes peut être associée à une augmentation de l'utilisation et des coûts des soins de santé. Nous avons cherché à examiner la relation entre la durée des ordonnances d'opioïdes postopératoires, les coûts des soins de santé et l'utilisation des ressources chez les patients âgés après une arthroplastie de la hanche et du genou. MéTHODE: Nous avons réalisé une étude de cohorte historique évaluant la consommation postopératoire d'opioïdes et les coûts des soins de santé chez les patients de plus de 65 ans subissant une arthroplastie totale primaire de la hanche ou du genou sur une période de dix ans allant du 1er avril 2006 au 31 mars 2016. La dernière date de suivi était le 31 mars 2017. Nous avons identifié les ordonnances pré- et postopératoires d'opioïdes, les caractéristiques des patients et les coûts des soins de santé à l'aide de bases de données administratives de l'Ontario désidentifiées (ICES). La durée de la consommation d'opioïdes postopératoires était divisée en quatre catégories : à court terme (1 à 90 jours), prolongée (91 à 180 jours), chronique (181 à 365 jours) et non documentée. RéSULTATS: L'étude a porté sur 49 638 patients ayant subi une arthroplastie de la hanche et 85 558 patients une arthroplastie du genou. Bien que l'hospitalisation initiale ait représenté le coût le plus élevé chez tous les patients, au cours de l'année suivante, les patients du groupe de consommation d'opioïdes à court terme ont encouru les coûts moyens les plus bas et ceux du groupe chronique les coûts les plus élevés (hanche, 17 528 CAD vs 26 736 CAD; genou, 16 043 CAD vs 23 007 CAD) en raison de l'utilisation accrue des ressources de soins de santé. CONCLUSION: La consommation chronique d'opioïdes après une arthroplastie a été associée à une augmentation de l'utilisation des ressources et des coûts des soins de santé au cours de l'année suivant la chirurgie. Ces résultats peuvent être utilisés pour développer des modèles de prédiction d'une consommation prolongée d'opioïdes et de coûts plus élevés. D'autres recherches sont prévues pour déterminer si les stratégies de réduction de la consommation d'opioïdes récemment mises en œuvre pourront réduire l'utilisation des ressources en soins de santé.

Long-term opioid use in seniors following hip and knee arthroplasty in Ontario: a historical cohort study.

PURPOSE: Canadian seniors who undergo hip and knee arthroplasty often experience significant postoperative pain, which could result in persistent opioid use. We aimed to document the impact of preoperative opioid use and other characteristics on postoperative opioid prescriptions in elderly patients following hip and knee replacement before widespread dissemination of opioid reduction strategies. METHODS: We conducted a historical cohort study to evaluate postoperative opioid use in patients over 65 yr undergoing primary total hip and knee replacement over a ten-year period from 1 April 2006 to 31 March 2016, using linked de-identified Ontario administrative data. We determined the use of preoperative opioids and the duration of postoperative opioid prescriptions (short-term [1-90 days], prolonged [91-180 days], chronic [181-365 days], or undocumented). RESULTS: The study included 49,638 hip and 85,558 knee replacement patients. Eighteen percent of hip and 21% of knee replacement patients received an opioid prescription within 90 days before surgery. Postoperatively, 51% of patients filled opioid prescriptions for 1-90 days, while 24% of hip and 29% of knee replacement patients filled prescriptions between 6 and 12 months, with no impact of preoperative opioid use. Residence in long-term care was a significant predictor of chronic opioid use (hip: odds ratio [OR], 2.64; 95% confidence interval [CI], 1.93 to 3.59; knee: OR, 2.46; 95% CI, 1.75 to 3.45); other risk factors included female sex and increased comorbidities. CONCLUSION: Despite a main goal of joint arthroplasty being relief of pain, seniors commonly remained on postoperative opioids, even if not receiving opioids before surgery. Opioid reduction strategies need to be implemented at the surgical, primary physician, long-term care, and patient levels. These findings form a basis for future investigations following implementation of opioid reduction approaches.

RéSUMé: OBJECTIF: Les aînés canadiens subissant une arthroplastie de la hanche ou du genou éprouvent souvent une douleur postopératoire importante, ce qui pourrait entraîner la consommation persistante d'opioïdes. Nous avons cherché à documenter l'impact d'une utilisation préopératoire d'opioïdes et d'autres caractéristiques sur les prescriptions postopératoires d'opioïdes chez les patients âgés suivant un remplacement de hanche ou de genou avant l'utilisation répandue de stratégies de réduction d'opioïdes. MéTHODE: Nous avons réalisé une étude de cohorte historique pour évaluer la consommation postopératoire d'opioïdes chez les patients de plus de 65 ans subissant une arthroplastie totale primaire de la hanche ou du genou sur une période de dix ans du 1er avril 2006 au 31 mars 2016, à l'aide de données administratives dépersonnalisées et codées de l'Ontario. Nous avons déterminé la durée des ordonnances préopératoires et postopératoires d'opioïdes (à court terme [1-90 jours], prolongées [91-180 jours], chroniques [181-365 jours] ou non documentées). RéSULTATS: L'étude a porté sur 49 638 patients ayant subi une arthroplastie de la hanche et 85 558 patients une arthroplastie du genou. Dix-huit pour cent des patients ayant subi une arthroplastie de la hanche et 21 % des patients ayant subi une arthroplastie du genou ont reçu une ordonnance d'opioïdes dans les 90 jours précédant leur chirurgie. En période postopératoire, 51 % des patients ont utilisé leurs ordonnances d'opioïdes pendant 1 à 90 jours, tandis que 24 % des patients d'arthroplastie de la hanche et 29 % des patients d'arthroplastie du genou ont utilisé leurs ordonnances entre six et 12 mois. Le fait d'habiter dans un établissement de soins de longue durée était un prédicteur important de consommation chronique d'opioïdes (hanche : rapport de cotes [RC], 2,64; intervalle de confiance [IC] à 95 %, 1,93 à 3,59; genou : RC, 2,46; IC 95 %, 1,75 à 3,45); le sexe féminin et l'augmentation des comorbidités constituaient d'autres facteurs de risque. CONCLUSION: Bien que l'un des principaux objectifs de l'arthroplastie articulaire soit le soulagement de la douleur, les personnes âgées continuent généralement à consommer des opioïdes en période postopératoire, même si elles ne prenaient pas d'opioïdes avant leur chirurgie. Il est nécessaire de mettre en œuvre des stratégies de réduction des opioïdes qui s'adressent aux chirurgiens, aux médecins traitants, aux soins de longue durée et aux patients. Ces constatations constituent la base d'études futures réalisées à la suite de la mise en œuvre d'approches de réduction des opioïdes.

Frequency and characteristics of patient exclusion criteria in Canadian multidisciplinary pain treatment facilities: a cross-sectional study.

PURPOSE: A multidisciplinary approach is recommended for patients with complex chronic pain (CP). Many multidisciplinary pain treatment facilities (MTPFs) use patient exclusion criteria but little is known about their characteristics. The objective of this study was to describe the frequency and characteristics of exclusion criteria in public Canadian MTPFs. METHODS: We conducted a cross-sectional study in which we defined an MPTF as a clinic staffed with professionals from three disciplines or more (including at least one medical specialty) and whose services were integrated within the facility. We disseminated a web-based questionnaire in 2017-2018 to the administrative leads of MPTFs across the country. They were invited to complete the questionnaire about the characteristics of their facilities. Data were analyzed using descriptive statistics and correlation measures. RESULTS: A total of 87 MTPFs were included in the analyses. Half of them (52%) reported using three exclusion criteria or more. There was no significant association between the number of exclusion criteria and wait time for a first appointment or number of new consultations in the past year. Fibromyalgia and migraine were the most frequently excluded pain syndromes (10% and 7% of MPTFs, respectively). More than one MPTF out of four excluded patients with mental health disorders (30%) and/or substance use disorders (29%), including MPTFs with specialists in their staff. CONCLUSIONS: Multidisciplinary pain treatment facility exclusion criteria are most likely to affect CP patients living with complex pain issues and psychosocial vulnerabilities. Policy efforts are needed to support Canadian MPTFs in contributing to equitable access to pain management.

RéSUMé: OBJECTIF: Une approche multidisciplinaire est recommandée pour les patients souffrant de douleur chronique (DC) complexe. De nombreux centres multidisciplinaires de traitement de la douleur (CMTD) utilisent des critères d'exclusion des patients, mais on ne sait que peu de choses sur leurs caractéristiques. L'objectif de cette étude était de décrire la fréquence et les caractéristiques des critères d'exclusion dans les CMTD publics canadiens. MéTHODE: Nous avons mené une étude transversale dans laquelle nous avons défini un CMTD comme une clinique composée de professionnels de trois disciplines ou plus (y compris au moins une spécialité médicale) et dont les services étaient intégrés à l'établissement. En 2017-2018, nous avons fait parvenir un questionnaire en ligne aux responsables administratifs des CMTD partout au pays. Ils ont été invités à remplir le questionnaire sur les caractéristiques de leurs établissements. Les données ont été analysées à l'aide de statistiques descriptives et de mesures de corrélation. RéSULTATS: Au total, 87 CMTD ont été inclus dans les analyses. La moitié d'entre eux (52 %) ont déclaré utiliser trois critères d'exclusion ou plus. Il n'y avait pas d'association significative entre le nombre de critères d'exclusion et le temps d'attente pour un premier rendez-vous ou le nombre de nouvelles consultations au cours de la dernière année. La fibromyalgie et la migraine étaient les syndromes douloureux les plus fréquemment exclus (10 % et 7 % des CMTD, respectivement). Plus d'un CMTD sur quatre excluait les patients atteints de troubles de santé mentale (30 %) et/ou de troubles liés à l'utilisation de substances (29 %), y compris les CMTD comptant des spécialistes dans leur personnel. CONCLUSION: Les critères d'exclusion des centres multidisciplinaires de traitement de la douleur sont plus susceptibles d'affecter les patients atteints de douleur chronique vivant avec des problèmes de douleur complexes et des vulnérabilités psychosociales. Des efforts au niveau des politiques sont nécessaires pour aider les CMTD canadiens à favoriser un accès équitable à la prise en charge de la douleur.

Pharmacotherapy for the Prevention of Chronic Pain after Surgery in Adults: An Updated Systematic Review and Meta-analysis.

BACKGROUND: Chronic postsurgical pain can severely impair patient health and quality of life. This systematic review update evaluated the effectiveness of systemic drugs to prevent chronic postsurgical pain. METHODS: The authors included double-blind, placebo-controlled, randomized controlled trials including adults that evaluated perioperative systemic drugs. Studies that evaluated same drug(s) administered similarly were pooled. The primary outcome was the proportion reporting any pain at 3 or more months postsurgery. RESULTS: The authors identified 70 new studies and 40 from 2013. Most evaluated ketamine, pregabalin, gabapentin, IV lidocaine, nonsteroidal anti-inflammatory drugs, and corticosteroids. Some meta-analyses showed statistically significant-but of unclear clinical relevance-reductions in chronic postsurgical pain prevalence after treatment with pregabalin, IV lidocaine, and nonsteroidal anti-inflammatory drugs. Meta-analyses with more than three studies and more than 500 participants showed no effect of ketamine on prevalence of any pain at 6 months when administered for 24 h or less (risk ratio, 0.62 [95% CI, 0.36 to 1.07]; prevalence, 0 to 88% ketamine; 0 to 94% placebo) or more than 24 h (risk ratio, 0.91 [95% CI, 0.74 to 1.12]; 6 to 71% ketamine; 5 to 78% placebo), no effect of pregabalin on prevalence of any pain at 3 months (risk ratio, 0.88 [95% CI, 0.70 to 1.10]; 4 to 88% pregabalin; 3 to 80% placebo) or 6 months (risk ratio, 0.78 [95% CI, 0.47 to 1.28]; 6 to 68% pregabalin; 4 to 69% placebo) when administered more than 24 h, and an effect of pregabalin on prevalence of moderate/severe pain at 3 months when administered more than 24 h (risk ratio, 0.47 [95% CI, 0.33 to 0.68]; 0 to 20% pregabalin; 4 to 34% placebo). However, the results should be interpreted with caution given small study sizes, variable surgical types, dosages, timing and method of outcome measurements in relation to the acute pain trajectory in question, and preoperative pain status. CONCLUSIONS: Despite agreement that chronic postsurgical pain is an important topic, extremely little progress has been made since 2013, likely due to study designs being insufficient to address the complexities of this multifactorial problem.

Persistent Incisional Pain after Noncardiac Surgery: An International Prospective Cohort Study.

BACKGROUND: The purpose of this study was to determine the incidence, characteristics, impact, and risk factors associated with persistent incisional pain. The hypothesis was that patient demographics and perioperative interventions are associated with persistent pain. METHODS: This was a secondary analysis of an international prospective cohort study from 2012 to 2014. This study included patients who were 45 yr of age or older who underwent major inpatient noncardiac surgery. Data were collected perioperatively and at 1 yr after surgery to assess for the development of persistent incisional pain (pain present around incision at 1 yr after surgery). RESULTS: Among 14,831 patients, 495 (3.3%; 95% CI, 3.1 to 3.6) reported persistent incisional pain at 1 yr, with an average pain intensity of 3.6 ± 2.5 (0 to 10 numeric rating scale), with 35% and 14% reporting moderate and severe pain intensities, respectively. More than half of patients with persistent pain reported needing analgesic medications, and 85% reported interference with daily activities (denominator = 495 in the above proportions). Risk factors for persistent pain included female sex (P = 0.007), Asian ethnicity (P < 0.001), surgery for fracture (P < 0.001), history of chronic pain (P < 0.001), coronary artery disease (P < 0.001), history of tobacco use (P = 0.048), postoperative patient-controlled analgesia (P < 0.001), postoperative continuous nerve block (P = 0.010), insulin initiation within 24 h of surgery (P < 0.001), and withholding nonsteroidal anti-inflammatory medication or cyclooxygenase-2 inhibitors on the day of surgery (P = 0.029 and P < 0.001, respectively). Older age (P < 0.001), endoscopic surgery (P = 0.005), and South Asian (P < 0.001), Native American/Australian (P = 0.004), and Latin/Hispanic ethnicities (P < 0.001) were associated with a lower risk of persistent pain. CONCLUSIONS: Persistent incisional pain is a common complication of inpatient noncardiac surgery, occurring in approximately 1 in 30 adults. It results in significant morbidity, interferes with daily living, and is associated with persistent analgesic consumption. Certain demographics, ethnicities, and perioperative practices are associated with increased risk of persistent pain.

Efficacy and Safety of N-Acetylcysteine for the Management of Chronic Pain in Adults: A Systematic Review and Meta-Analysis.

OBJECTIVE: To assess the efficacy and safety of N-acetylcysteine in the treatment of chronic pain. METHODS: A systematic search was carried out until April 2020 for clinical studies of N-acetylcysteine in the management of any persistent or recurrent chronic pain condition for adults ≥ 18 years old. Risk of bias was assessed using the validated risk of bias tools. When appropriate, a meta-analysis using a random-effects model was performed, with a fixed-effect model for sensitivity analysis. RESULTS: Nine studies (n = 863) were included (five randomized controlled trials [RCTs], two open-label non-comparative studies and two comparative studies), that evaluated patients with sickle cell disease (3), complex regional pain syndrome (1), pelvic pain/endometriosis (2), rheumatoid arthritis (1), diabetic neuropathy (1), and chronic neuropathic pain (1). In the pooled analysis of three RCTs, N-acetylcysteine did not reduce pain intensities (SMD -0.21, 95% confidence interval [CI]: -0.33 to 0.75, random-effects), improve functional outcomes (SMD 0.21, 95% CI -0.33 to 0.75) or quality of life (SMD 0.60, 95% CI: -4.44 to 5.64); however, sensitivity analysis with a fixed effect model demonstrated an effect for pain intensities and function. Due to adverse events being inconsistently reported, no conclusion could be made regarding safety of N-acetylcysteine in chronic pain. CONCLUSIONS: While there is some evidence to indicate N-acetylcysteine may provide analgesic efficacy for certain pain conditions, there is insufficient evidence to provide definitive evidence on NAC in chronic pain management. Larger-size RCTs spanning a variety of chronic pain conditions are needed to determine N-acetylcysteine's role, if any, in pain medicine.

Chronic mechanical hypersensitivity in experimental autoimmune encephalomyelitis is regulated by disease severity and neuroinflammation.

Chronic pain severely affects quality of life in more than half of people living with multiple sclerosis (MS). A commonly-used model of MS, experimental autoimmune encephalomyelitis (EAE), typically presents with hindlimb paralysis, neuroinflammation and neurodegeneration. However, this paralysis may hinder the use of pain behavior tests, with no apparent hypersensitivity observed post-peak disease. We sought to adapt the classic actively-induced EAE model to optimize its pain phenotype. EAE was induced with MOG35-55/CFA and 100-600 ng pertussis toxin (PTX), and mice were assessed for mechanical, cold and thermal sensitivity over a 28-day period. Spinal cord tissue was collected at 14 and 28 days post-injection to assess demyelination and neuroinflammation. Only mice treated with 100 ng PTX exhibited mechanical hypersensitivity. Hallmarks of disease pathology, including demyelination, immune cell recruitment, cytokine expression, glial activation, and neuronal damage were higher in EAE mice induced with moderate (200 ng) doses of pertussis toxin, compared to those treated with low (100 ng) levels. Immunostaining demonstrated activated astrocytes and myeloid/microglial cells in both EAE groups. These results indicate that a lower severity of EAE disease may allow for the study of pain behaviors while still presenting with disease pathology. By using this modified model, researchers may better study the mechanisms underlying pain.

One-year Results of a Factorial Randomized Trial of Aspirin versus Placebo and Clonidine versus Placebo in Patients Having Noncardiac Surgery.

BACKGROUND: The authors previously reported that perioperative aspirin and/or clonidine does not prevent a composite of death or myocardial infarction 30 days after noncardiac surgery. Moreover, aspirin increased the risk of major bleeding and clonidine caused hypotension and bradycardia. Whether these complications produce harm at 1 yr remains unknown. METHODS: The authors randomized 10,010 patients with or at risk of atherosclerosis and scheduled for noncardiac surgery in a 1:1:1:1 ratio to clonidine/aspirin, clonidine/aspirin placebo, clonidine placebo/aspirin, or clonidine placebo/aspirin placebo. Patients started taking aspirin or placebo just before surgery; those not previously taking aspirin continued daily for 30 days, and those taking aspirin previously continued for 7 days. Patients were also randomly assigned to receive clonidine or placebo just before surgery, with the study drug continued for 72 h. RESULTS: Neither aspirin nor clonidine had a significant effect on the primary 1-yr outcome, a composite of death or nonfatal myocardial infarction, with a 1-yr hazard ratio for aspirin of 1.00 (95% CI, 0.89 to 1.12; P = 0.948; 586 patients [11.8%] vs. 589 patients [11.8%]) and a hazard ratio for clonidine of 1.07 (95% CI, 0.96 to 1.20; P = 0.218; 608 patients [12.1%] vs. 567 patients [11.3%]), with effect on death or nonfatal infarction. Reduction in death and nonfatal myocardial infarction from aspirin in patients who previously had percutaneous coronary intervention at 30 days persisted at 1 yr. Specifically, the hazard ratio was 0.58 (95% CI, 0.35 to 0.95) in those with previous percutaneous coronary intervention and 1.03 (95% CI, 0.91to 1.16) in those without (interaction P = 0.033). There was no significant effect of either drug on death, cardiovascular complications, cancer, or chronic incisional pain at 1 yr (all P > 0.1). CONCLUSIONS: Neither perioperative aspirin nor clonidine have significant long-term effects after noncardiac surgery. Perioperative aspirin in patients with previous percutaneous coronary intervention showed persistent benefit at 1 yr, a plausible sub-group effect.

Efficacy and Safety of Magnesium for the Management of Chronic Pain in Adults: A Systematic Review.

Chronic pain is a highly prevalent and complex health problem that is associated with a heavy symptom burden, substantial economic and social impact, and also, very few highly effective treatments. This review examines evidence for the efficacy and safety of magnesium in chronic pain. The previously published protocol for this review was registered in International Prospective Register of Systematic Reviews (PROSPERO), MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched until September 2018. We included randomized controlled trials (RCTs) comparing magnesium (at any dose, frequency, or route of administration) with placebo using participant-reported pain measures. A total of 9 RCTs containing 418 participants were included. Three studies examined neuropathic pain (62 participants), 3 examined migraines (190 participants), 2 examined complex regional pain syndrome (86 participants), and 1 examined low back pain with a neuropathic component (80 participants). Heterogeneity of included studies precluded any meta-analyses. No judgment could be made about safety because adverse events were inconsistently reported in the included studies. Evidence of analgesic efficacy from included studies was equivocal. However, reported efficacy signals in some of the included trials provide a rationale for more definitive studies. Future, larger-sized trials with good assay sensitivity and better safety assessment and reporting, as well as careful attention to formulations with optimal bioavailability, will serve to better define the role of magnesium in the management of chronic pain.

AAAPT Diagnostic Criteria for Acute Knee Arthroplasty Pain.

OBJECTIVE: The relationship between preexisting osteoarthritic pain and subsequent post-total knee arthroplasty (TKA) pain is not well defined. This knowledge gap makes diagnosis of post-TKA pain and development of management plans difficult and may impair future investigations on personalized care. Therefore, a set of diagnostic criteria for identification of acute post-TKA pain would inform standardized management and facilitate future research. METHODS: The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration (FDA), the American Pain Society (APS), and the American Academy of Pain Medicine (AAPM) formed the ACTTION-APS-AAPM Pain Taxonomy (AAAPT) initiative to address this goal. A multidisciplinary work group of pain experts was invited to conceive diagnostic criteria and dimensions of acute post-TKA pain. RESULTS: The working group used contemporary literature combined with expert opinion to generate a five-dimensional taxonomical structure based upon the AAAPT framework (i.e., core diagnostic criteria, common features, modulating factors, impact/functional consequences, and putative mechanisms) that characterizes acute post-TKA pain. CONCLUSIONS: The diagnostic criteria created are proposed to define the nature of acute pain observed in patients following TKA.

Pharmacological interventions for the prevention of acute postoperative pain in adults following brain surgery.

BACKGROUND: Pain following brain surgery can compromise recovery. Several pharmacological interventions have been used to prevent pain after craniotomy; however, there is currently a lack of evidence regarding which interventions are most effective. OBJECTIVES: The objectives are to assess the effectiveness of pharmacological interventions for prevention of acute postoperative pain in adults undergoing brain surgery; compare them in terms of additional analgesic requirements, incidence of chronic headache, sedative effects, length of hospital stay and adverse events; and determine whether these characteristics are different for certain subgroups. SEARCH METHODS: We searched MEDLINE, Embase, CINAHL, CENTRAL, Web of Science and two trial registries together with reference checking and citation searching on 28th of November 2018. SELECTION CRITERIA: We included blinded and non-blinded, randomized controlled trials evaluating pharmacological interventions for the prevention of acute postoperative pain in adults undergoing neurosurgery, which had at least one validated pain score outcome measure. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. We calculated mean differences for the primary outcome of pain intensity; any pain scores reported on a 0 to 100 scale were converted to a 0 to 10 scale. MAIN RESULTS: We included 42 completed studies (3548 participants) and identified one ongoing study. Nonsteroidal anti-inflammatories (NSAIDs) Nonsteroidal anti-inflammatories (NSAIDs) reduce pain up to 24 hours (0 to 6 hours, MD -1.16, 95% CI -1.57 to -0.76; 12 hours, MD -0.62, 95% CI -1.11 to -0.14; 24 hours, MD -0.66, 95% CI -1.18 to -0.13; 6 studies, 742 participants; all high-quality evidence). Results for other outcomes were imprecise (additional analgesic requirements: MD 1.29 mg, 95% CI -5.0 to 2.46, 4 studies, 265 participants; nausea and vomiting RR 1.34, 95% CI 0.30 to 5.94, 2 studies, 345 participants; both low-quality evidence). Dexmedetomidine reduces pain up to 12 hours (0 to 6 hours, MD -0.89, 95% CI -1.27 to -0.51, moderate-quality evidence; 12 hours, MD -0.81, 95% CI -1.21 to -0.42, low-quality evidence). It did not show efficacy at 24 hours (MD -0.08, 95% CI -0.32 to 0.16; 2 studies, 128 participants; low-quality evidence). Dexmedetomidine may decrease additional analgesic requirements (MD -21.36 mg, 95% CI -34.63 to -8.1 mg, 2 studies, 128 participants, low-quality evidence). Results for other outcomes were imprecise (nausea and vomiting RR -0.43, 95% CI 0.06 to 3.08, 3 studies, 261 participants; hypotension RR 0.5, 95% CI 0.05 to 5.28, 3 studies, 184 participants; both low-quality evidence). Scalp blocks may reduce pain up to 48 hours (0 to 6 hours, MD -0.98, 95% CI -1.66 to -0.3, 10 studies, 414 participants; 12 hours, MD -0.95, 95% CI -1.53 to -0.37, 8 studies, 294 participants; 24 hours, MD -0.78, 95% CI -1.52 to -0.05, 9 studies, 433 participants, all low-quality evidence; 48 hours, MD -1.34, 95% CI -2.57 to -0.11, 4 studies, 135 participants, very low-quality evidence. When studies with high risk of bias were excluded, significance remained at 12 hours only. Scalp blocks may decrease additional analgesia requirements (SMD -1.11, 95% CI -1.97 to -0.25, 7 studies, 314 participants). Results for other outcomes were imprecise (nausea and vomiting RR 0.66, 95% CI 0.33 to 1.32, 4 studies, 165 participants, very low-quality evidence). Scalp Infiltration may reduce pain postoperatively but efficacy was inconsistent, with a significant effect at 12 and 48 hours only (12 hours, MD -0.71, 95% CI -1.34 to -0.08, 7 studies, 309 participants, low-quality evidence; 48 hours, MD - 1.09, 95% CI -2.13 to - 0.06, 3 studies, 128 participants, moderate-quality evidence). No benefit was observed at other times (0 to 6 hours, MD -0.64, 95% CI -1.28 to -0.00, 9 studies, 475 participants, moderate-quality evidence; 24 hours, MD -0.39, 95% CI -1.06 to 0.27,6 studies, 260 participants, low-quality evidence. Scalp infiltration may reduce additional analgesia requirements MD -9.56 mg, 95% CI -15.64 to -3.49, 6 studies, 345 participants, very low-quality evidence). When studies with high risk of bias were excluded, scalp infiltration lost the pain benefit at 12 hours and effects on additional analgesia requirements, but retained the pain-reducing benefit at 48 hours (MD -0.56, 95% CI -1.20 to -0.32, 2 studies, 100 participants, very low-quality evidence). Results for other outcomes were imprecise (nausea and vomiting, RR 0.74, 95% CI 0.48 to 1.41, 4 studies, 318 participants, low-quality evidence). Pregabalin or gabapentin may reduce pain up to 6 hours (2 studies, 202 participants), MD -1.15,95% CI -1.66 to -0.6, 2 studies, 202 participants, low-quality evidence). One study examined analgesic efficacy at 12 hours showing significant benefit. No analgesia efficacy was shown at later times (24 hours, MD -0.29, 95% CI -0.78 to -0.19; 48 hours, MD - 0.06, 95% CI -0.86 to 0.77, 2 studies, 202 participants, low-quality evidence). Additional analgesia requirements were not significantly less (MD -0.37 (95% CI -1.10 to 0.35, 3 studies, 234 participants, low-quality evidence). Risk of nausea and vomiting was significantly reduced (RR 0.51, 95% CI 0.29 to 0.89, 3 studies, 273 participants, low-quality evidence). Results for other outcomes were imprecise (additional analgesia requirements: MD -0.37, 95% CI -1.10 to 0.35, 3 studies, 234 participants, low-quality evidence). Acetaminophen did not show analgesic benefit (0 to 6 hours, MD -0.35, 95% CI -1.00 to 0.30; 12 hours, MD -0.51, 95% CI -1.04 to 0.03, 3 studies, 332 participants, moderate-quality evidence; 24 hours, MD -0.34, 95% CI -1.20 to 0.52, 4 studies, 439 participants, high-quality evidence). Results for other outcomes remained imprecise (additional analgesia requirements, MD 0.07, 95% CI -0.86 to 0.99, 4 studies, 459 participants, high-quality evidence; length of hospitalizations, MD -3.71, 95% CI -14.12 to 6.7, 2 studies, 335 participants, moderate-quality evidence). AUTHORS' CONCLUSIONS: There is high-quality evidence that NSAIDs reduce pain up to 24 hours postoperatively. The evidence for reductions in pain with dexmedetomidine, pregabalin or gabapentin, scalp blocks, and scalp infiltration is less certain and of very low to moderate quality. There is low-quality evidence that scalp blocks and dexmedetomidine may reduce additional analgesics requirements. There is low-quality evidence that gabapentin or pregabalin may decrease nausea and vomiting, with the caveat that the total number of events for this comparison was low.

Circadian control of pain and neuroinflammation.

The importance of a neuroinflammatory response to the development and maintenance of inflammatory and neuropathic pain have been highlighted in recent years. Inflammatory cells contributing to this response include circulating immune cells such as monocytes, T and B lymphocytes, and neutrophils, as well as microglia in the central nervous system. Pain signals are transmitted via sensory neurons in the peripheral nervous system, which express various receptors and channels that respond to mediators secreted from these inflammatory cells. Chronobiological rhythms, which include the 24-hr circadian cycle, have recently been shown to regulate both nervous and immune cell activity and function. This review examines the current literature on chronobiological control of neuroinflammatory processes, with a focus on inflammatory and neuropathic pain states. While the majority of this work has stemmed from observational studies in humans, recent advances in using animal models have highlighted distinct mechanisms underlying these interactions. Better understanding interactions between the circadian and neuroimmune systems can help guide the development of new treatments and provide improved care for patients suffering from acute and chronic pain.

Bias in Before-After Studies: Narrative Overview for Anesthesiologists.

Before-after study designs are effective research tools and in some cases, have changed practice. These designs, however, are inherently susceptible to bias (ie, systematic errors) that are sometimes subtle but can invalidate their conclusions. This overview provides examples of before-after studies relevant to anesthesiologists to illustrate potential sources of bias, including selection/assignment, history, regression to the mean, test-retest, maturation, observer, retrospective, Hawthorne, instrumentation, attrition, and reporting/publication bias. Mitigating strategies include using a control group, blinding, matching before and after cohorts, minimizing the time lag between cohorts, using prospective data collection with consistent measuring/reporting criteria, time series data collection, and/or alternative study designs, when possible. Improved reporting with enforcement of the Enhancing Quality and Transparency of Health Research (EQUATOR) checklists will serve to increase transparency and aid in interpretation. By highlighting the potential types of bias and strategies to improve transparency and mitigate flaws, this overview aims to better equip anesthesiologists in designing and/or critically appraising before-after studies.

Combination pharmacotherapy for the treatment of fibromyalgia in adults.

BACKGROUND: Fibromyalgia is a chronic widespread pain condition affecting millions of people worldwide. Current pharmacotherapies are often ineffective and poorly tolerated. Combining different agents could provide superior pain relief and possibly also fewer side effects. OBJECTIVES: To assess the efficacy, safety, and tolerability of combination pharmacotherapy compared to monotherapy or placebo, or both, for the treatment of fibromyalgia pain in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase to September 2017. We also searched reference lists of other reviews and trials registries. SELECTION CRITERIA: Double-blind, randomised controlled trials comparing combinations of two or more drugs to placebo or other comparators, or both, for the treatment of fibromyalgia pain. DATA COLLECTION AND ANALYSIS: From all studies, we extracted data on: participant-reported pain relief of 30% or 50% or greater; patient global impression of clinical change (PGIC) much or very much improved or very much improved; any other pain-related outcome of improvement; withdrawals (lack of efficacy, adverse events), participants experiencing any adverse event, serious adverse events, and specific adverse events (e.g. somnolence and dizziness). The primary comparison was between combination and one or all single-agent comparators. We also assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: We identified 16 studies with 1474 participants. Three studies combined a non-steroidal anti-inflammatory drug (NSAID) with a benzodiazepine (306 participants); two combined amitriptyline with fluoxetine (89 participants); two combined amitriptyline with a different agent (92 participants); two combined melatonin with an antidepressant (164 participants); one combined carisoprodol, paracetamol (acetaminophen), and caffeine (58 participants); one combined tramadol and paracetamol (acetaminophen) (315 participants); one combined malic acid and magnesium (24 participants); one combined a monoamine oxidase inhibitor with 5-hydroxytryptophan (200 participants); and one combined pregabalin with duloxetine (41 participants). Six studies compared the combination of multiple agents with each component alone and with inactive placebo; three studies compared combination pharmacotherapy with each individual component but did not include an inactive placebo group; two studies compared the combination of two agents with only one of the agents alone; and three studies compared the combination of two or more agents only with inactive placebo.Heterogeneity among studies in terms of class of agents evaluated, specific combinations used, outcomes reported, and doses given prevented any meta-analysis. None of the combinations of drugs found provided sufficient data for analysis compared with placebo or other comparators for our preferred outcomes. We therefore provide a narrative description of results. There was no or inadequate evidence in any comparison for primary and secondary outcomes. Two studies only reported any primary outcomes of interest (patient-reported pain relief of 30%, or 50%, or greater). For each 'Risk of bias' item, only half or fewer of studies had unequivocal low risk of bias. Small size and selective reporting were common as high risk of bias.Our GRADE assessment was therefore very low for primary outcomes of pain relief of 30% or 50% or greater, PGIC much or very much improved or very much improved, any pain-related outcome, participants experiencing any adverse event, any serious adverse event, or withdrawing because of an adverse event.Three studies found some evidence that combination pharmacotherapy reduced pain compared to monotherapy; these trials tested three different combinations: melatonin and amitriptyline, fluoxetine and amitriptyline, and pregabalin and duloxetine. Adverse events experienced by participants were not serious, and where they were reported (in 12 out of 16 studies), all participants experienced them, regardless of treatment. Common adverse events were nausea, dizziness, somnolence, and headache. AUTHORS' CONCLUSIONS: There are few, large, high-quality trials comparing combination pharmacotherapy with monotherapy for fibromyalgia, consequently limiting evidence to support or refute the use of combination pharmacotherapy for fibromyalgia.