Prediction of chronic postsurgical pain in adults: A protocol for multivariable prediciton model development

INTRODUCTION: Chronic postsurgical pain (CPSP) is a condition that affects an estimated 10%–50% of adults, depending on the surgical procedure. CPSP often interferes with activities of daily living and may have a negative impact on quality of life, emotional and physical well-being. Clinical prediction models can help clinicians target preventive strategies towards patients at high-risk of CPSP. Therefore, the objective of this study is to develop a clinically applicable and generalisable prediction model for CPSP in adults. METHODS AND ANALYSIS: This research will be a prospective single-centre observational cohort study in Denmark spanning approximately 1 year or until a predefined number of patients are recruited (n=1526). Adult patients aged 18 years and older scheduled to undergo surgery will be recruited at Aarhus University Hospital. The primary outcome is CPSP 3 months after surgery defined as average pain intensity at rest or on movement ≥3 on numerical rating scale (NRS) within the past week, and/or average pain interference ≥3 on NRS among any of seven short-form Brief Pain Inventory items in the past week (general activity, mood, walking ability, normal work (including housework), relations with other people, sleep and enjoyment of life). Logistic regression will be used to conduct multivariate analysis. Predictive model performance will be evaluated by discrimination, calibration and model classification. ETHICS AND DISSEMINATION: This research has been approved by Central Region Denmark and will be conducted in accordance with the Danish Data Protection Act and Declaration of Helsinki. Study findings will be disseminated through conference presentations and peer-reviewed publication. A CPSP risk calculator (CPSP-RC) will be developed based on predictors retained in the final models. The CPSP-RC will be made available online and as a mobile application to be easily accessible for clinical use and future research including validation and clinical impact assessments. TRIAL REGISTRATION NUMBER: NCT04866147

Factors associated with persistent postsurgical pain after total knee or hip joint replacement: A systematic review and meta-analysis

Studies have identified demographic, clinical, psychosocial, and perioperative variables associated with persistent pain after a variety of surgeries. This study aimed to perform a systematic review and meta-analysis of factors associated with persistent pain after total knee replacement (TKR) and total hip replacement (THR) surgeries. To meet the inclusion criteria, studies were required to assess variables before or at the time of surgery, include a persistent postsurgical pain (PPSP) outcome measure at least 2 months after a TKR or THR surgery, and include a statistical analysis of the effect of the risk factor(s) on the outcome measure. Outcomes from studies implementing univariate and multivariable statistical models were analyzed separately. Where possible, data from univariate analyses on the same factors were combined in a meta-analysis. Eighty-one studies involving 171,354 patients were included in the review. Because of the heterogeneity of assessment methods, only 44% of the studies allowed meaningful meta-analysis. In meta-analyses, state anxiety (but not trait anxiety) scores and higher depression scores on the Beck Depression Inventory were associated with an increased risk of PPSP after TKR. In the qualitative summary of multivariable analyses, higher preoperative pain scores were associated with PPSP after TKR or THR. This review systematically assessed factors associated with an increased risk of PPSP after TKR and THR and highlights current knowledge gaps that can be addressed by future research

Relief of chronic pain associated with increase in midline frontal theta power

INTRODUCTION: There is a need to identify objective cortical electrophysiological correlates for pain relief that could potentially contribute to a better pain management. However, the field of developing brain biomarkers for pain relief is still largely underexplored. OBJECTIVES: The objective of this study was to investigate cortical electrophysiological correlates associated with relief from chronic pain. Those features of pain relief could serve as potential targets for novel therapeutic interventions to treat pain. METHODS: In 12 patients with chronic pain in the upper or lower extremity undergoing a clinically indicated nerve block procedure, brain activity was recorded by means of electroencephalogram before and 30 minutes after the nerve block procedure. To determine the specific cortical electrophysiological correlates of relief from chronic pain, 12 healthy participants undergoing cold-pressor test to induce experimental acute pain were used as a control group. The data were analyzed to characterize power spectral density patterns of pain relief and identify their source generators at cortical level. RESULTS: Chronic pain relief was associated with significant delta, theta, and alpha power increase at the frontal area. However, only midfrontal theta power increase showed significant positive correlation with magnitude of reduction in pain intensity. The sources of theta power rebound were located in the left dorsolateral prefrontal cortex (DLPFC) and midline frontal cortex. Furthermore, theta power increase in the midline frontal cortex was significantly higher with chronic vs acute pain relief. CONCLUSION: These findings may provide basis for targeting chronic pain relief via modulation of the midline frontal theta oscillations

Cannabinoids, cannabis, and cannabis-based medicines for pain management: an overview of systematic reviews

Cannabinoids, cannabis, and cannabis-based medicines (CBM) are increasingly used to manage pain, with limited understanding of their efficacy and safety. We assessed methodological quality, scope, and results of systematic reviews of randomised controlled trials of these treatments. Several search strategies sought self-declared systematic reviews. Methodological quality was assessed using both AMSTAR-2 and techniques important for bias reduction in pain studies. Of the 106 articles read, 57 were self-declared systematic reviews, most published since 2010. They included any type of cannabinoid, cannabis, or CBM, at any dose, however administered, in a broad range of pain conditions. No review examined the effects of a particular cannabinoid, at a particular dose, using a particular route of administration, for a particular pain condition, reporting a particular analgesic outcome. Confidence in the results in the systematic reviews using AMSTAR-2 definitions was critically low (41), low (8), moderate (6), or high (2). Few used criteria important for bias reduction in pain. Cochrane reviews typically provided higher confidence; all industry-conflicted reviews provided critically low confidence. Meta-analyses typically pooled widely disparate studies, and, where assessable, were subject to potential publication bias. Systematic reviews with positive or negative recommendation for use of cannabinoids, cannabis, or CBM in pain typically rated critically low or low (24/25 [96%] positive; 10/12 [83%] negative). Current reviews are mostly lacking in quality and cannot provide a basis for decision-making. A new high-quality systematic review of randomised controlled trials is needed to critically assess the clinical evidence for cannabinoids, cannabis, or CBM in pain

Closed-loop acoustic stimulation during sedation with dexmedetomidine (CLASS-D): Protocol for a within-subject, crossover, controlled, interventional trial with healthy volunteers

Introduction: The relative power of slow-delta oscillations in the electroencephalogram (EEG), termed slow-wave activity (SWA), correlates with level of unconsciousness. Acoustic enhancement of SWA has been reported for sleep states, but it remains unknown if pharmacologically induced SWA can be enhanced using sound. Dexmedetomidine is a sedative whose EEG oscillations resemble those of natural sleep. This pilot study was designed to investigate whether SWA can be enhanced using closed-loop acoustic stimulation during sedation (CLASS) with dexmedetomidine. Methods: Closed-Loop Acoustic Stimulation during Sedation with Dexmedetomidine (CLASS-D) is a within-subject, crossover, controlled, interventional trial with healthy volunteers. Each participant will be sedated with a dexmedetomidine target-controlled infusion (TCI). Participants will undergo three CLASS conditions in a multiple crossover design: in-phase (phase-locked to slow-wave upslopes), anti-phase (phase-locked to slow-wave downslopes) and sham (silence). High-density EEG recordings will assess the effects of CLASS across the scalp. A volitional behavioral task and sequential thermal arousals will assess the anesthetic effects of CLASS. Ambulatory sleep studies will be performed on nights immediately preceding and following the sedation session. EEG effects of CLASS will be assessed using linear mixed-effects models. The impacts of CLASS on behavior and arousal thresholds will be assessed using logistic regression modeling. Parametric modeling will determine differences in sleepiness and measures of sleep homeostasis before and after sedation. Results: The primary outcome of this pilot study is the effect of CLASS on EEG slow waves. Secondary outcomes include the effects of CLASS on the following: performance of a volitional task, arousal thresholds, and subsequent sleep. Discussion: This investigation will elucidate 1) the potential of exogenous sensory stimulation to potentiate SWA during sedation; 2) the physiologic significance of this intervention; and 3) the connection between EEG slow-waves observed during sleep and sedation