Use of patient-reported global assessment measures in clinical trials of chronic pain treatments: ACTTION systematic review and considerations.

ABSTRACT: Establishing clinically meaningful changes in pain experiences remains important for clinical trials of chronic pain treatments. Regulatory guidance and pain measurement initiatives have recommended including patient-reported global assessment measures (eg, Patient-Global Impression of Change [PGIC]) to aid interpretation of within-patient differences in domain-specific clinical trial outcomes (eg, pain intensity). The objectives of this systematic review were to determine the frequency of global assessment measures inclusion, types of measures, domains assessed, number and types of response options, and how measures were analyzed. Of 4172 abstracts screened across 6 pain specialty journals, we reviewed 96 clinical trials of chronic pain treatments. Fifty-two (54.2%) studies included a global assessment measure. The PGIC was most common (n = 28; 53.8%), with relatively infrequent use of other measures. The majority of studies that used a global assessment measure (n = 31; 59.6%) assessed change or improvement in an unspecified domain. Others assessed overall condition severity (n = 9; 17.3%), satisfaction (n = 8; 15.4%), or overall health status/recovery (n = 5; 9.6%). The number, range, and type of response options were variable and frequently not reported. Response options and reference periods even differed within the PGIC. Global assessment measures were most commonly analyzed as continuous variables (n = 24; 46.2%) or as dichotomous variables with positive categories combined to calculate the proportion of participants with a positive response to treatment (n = 18; 34.6%). This review highlights the substantial work necessary to clarify measurement and use of patient global assessment in chronic pain trials and provides short- and long-term considerations for measure selection, reporting and analysis, and measure development.

Evaluating the balance of benefits and harms in chronic pain clinical trials: prioritizing individual participants over individual outcomes.

BACKGROUND: Randomized clinical trials (RCTs) generally assess efficacy and safety separately, with the conclusion of whether a treatment is beneficial based solely on the efficacy endpoint. However, assessing and combining efficacy and safety domains, using a single composite outcome measure, can provide a more comprehensive assessment of the overall effect of a treatment. Furthermore, composite outcomes can incorporate information regarding the relationship between the individual outcomes. In fact, such outcomes have been suggested in the clinical trials literature for at least 15 years. OBJECTIVES: To (1) identify whether recent primary publications of chronic pain RCTs from major pain journals included a composite outcome measure of benefits and harms and (2) discuss the potential benefits of such outcomes in various stages of treatment development, including as outcome measures in RCTs, and to support decisions of Data and Safety Monitoring Boards and ordering of treatments in the context of treatment guidelines. EVIDENCE REVIEW: RCTs published in 6 major pain journals published between 2016 and 2021 that investigated interventions for chronic pain were reviewed. FINDINGS: Of 73 RCTs identified, only 2 included a composite outcome measure of benefits and harms. Both of these articles compared 2 active treatments. CONCLUSIONS: Composite outcomes of benefits and harms are underutilized in chronic pain RCTs. The advantages and challenges of using such outcomes are discussed.

Covariate Adjustment in Chronic Pain Trials: An Oft-Missed Opportunity.

Self-reported pain intensity, frequently used as an outcome in randomized clinical trials (RCTs) of chronic pain, is often highly variable and could be associated with multiple baseline factors. Thus, the assay sensitivity of pain trials (ie, the ability of the trial to detect a true treatment effect) could be improved by including prespecified baseline factors in the primary statistical model. The objective of this focus article was to characterize the baseline factors included in statistical analyses of chronic pain RCTs. Seventy-three RCTs published between 2016 and 2021 that investigated interventions for chronic pain were included. The majority of trials identified a single primary analysis (72.6%; n = 53). Of these, 60.4% (n = 32) included one or more covariates in the primary statistical model, most commonly baseline value of the primary outcome, study site, sex, and age. Only one of the trials reported information regarding associations between covariates and outcomes (ie, information that could inform prioritization of covariates for prespecification in future analyses). These findings demonstrate inconsistent use of covariates in the statistical models in chronic pain clinical trials. Prespecified adjustments for baseline covariates that could increase precision and assay sensitivity should be considered in future clinical trials of chronic pain treatments. PERSPECTIVE: This review demonstrates inconsistent inclusion and potential underutilization of covariate adjustment in analyses of chronic pain RCTs. This article highlights areas for possible improvement in design and reporting related to covariate adjustment to improve efficiency in future RCTs.

Association of the Effectiveness of Eye Drop Self-instillation and Glaucoma Progression.

PRCIS: Among patients with glaucoma or ocular hypertension, ineffective self-instillation of eye drops was associated with an increased long-term risk of progression or advancement of treatment to incisional surgery. PURPOSE: The purpose of this study was to evaluate the association between the efficacy of self-instillation of eye drops and long-term glaucoma outcomes. METHODS: In a previous study, video recordings of eye drop self-instillation by patients with glaucoma or ocular hypertension were graded as effective or ineffective depending on whether the patient successfully instilled at least 1 drop on the right ocular surface. Glaucomatous progression was then retrospectively defined as retinal nerve fiber layer thinning as measured by either optical coherence tomography, visual field progression, or need for incisional glaucoma surgery as determined by a glaucoma specialist unaware of patient performance in the eye drop instillation study. Subjects with at least 2 follow-up optical coherence tomography or visual field studies were included in the current study. RESULTS: The original study enrolled 119 patients. Sufficient follow-up data were available for 101 patients. Eighty-eight patients (87.1%) were effective in eye drop instillation at baseline. Mean follow-up was 5.1 years, during which time 73 patients (72.3%) had progression or underwent incisional surgery in either eye. A significantly higher proportion of patients in the ineffective group met the criteria for progression or underwent incisional surgery (effective: 68.2%; ineffective: 100%; N=101; P=0.017, Fisher exact test). Kaplan-Meier survival analyses showed a significantly faster time to reaching an endpoint in the ineffective group (N=101; P=0.012, log-rank test). There was no difference in age, baseline intraocular pressure, or baseline retinal nerve fiber layer thickness between the groups. CONCLUSION: Ineffective self-installation of eye drops was associated with an increased risk of glaucoma progression or treatment advancement to incisional surgery.

Mixing Studies in Patients With Prolonged Activated Partial Thromboplastin Time or Prothrombin Time.

BACKGROUND: Patients presenting for surgery may have isolated or combined prolonged activated partial thromboplastin time (aPTT) and/or prothrombin time (PT). In patients not receiving anticoagulants or with no identifiable cause for abnormal clot formation, a mixing study is performed. The index of circulating anticoagulant (ICA) has been used to predict the presence of an inhibitor, usually a lupus anticoagulant. METHODS: We retrospectively reviewed the results of mixing studies performed at Northwestern Memorial Hospital, between January 1, 2010 and February 29, 2012. We determined the number of samples that normalized or remained prolonged, the clotting factors associated with prolonged test results, and the presence of coagulation inhibitors. We calculated the ICA in the samples with prolonged aPTT and PT to determine its ability to predict a lupus anticoagulant. The primary comparison of interest was the diagnostic utility of the ICA at cutoff values of 11% for predicting the presence of lupus anticoagulant. RESULTS: There were 269 mixing studies performed: 131 samples with prolonged aPTT; 95 with prolonged PT; and 43 with both prolonged aPTT and prolonged PT. Of the samples with a prolonged aPTT, 55 of 131 (42%) normalized, 36 of 131 (27%) partially corrected, and 40 of 131 (31%) remained prolonged. Thirty-three of 95 samples (35%) with prolonged PT normalized, while 62 of 95 (65%) remained prolonged. Eight of 43 (19%) mixing studies of patients with prolonged PT and aPTT normalized; the aPTT normalized, but the PT remained prolonged in 17 of 43 (39%); the PT normalized, but the aPTT remained prolonged in 7 of 43 (16%); and both tests remained prolonged in 11 of 43 (26%) samples. Prolongations in the aPTT were primarily associated with low activities of CF XII, while the majority of the prolongations in PT were secondary to low activities in CF VII. Combined prolongations were secondary to deficiencies in both the intrinsic and extrinsic as well as the common pathways. An ICA >11% had 100% (95% CI, 59%-100%) sensitivity, 53% (95% CI, 35%-70%) specificity, and 77% (95% CI, 62%-92%) accuracy in predicting the presence of lupus anticoagulant in patients with prolonged aPTT. CONCLUSIONS: Normalization of the aPTT and PT in a mixing study was associated with low clotting factor activity. The ICA may be helpful in predicting the presence of a lupus anticoagulant. As anesthesiologists take ownership of the perioperative surgical home, we need to understand the clinical implications of the results of mixing studies.

Urgent Complex Intraoperative Reintubation in a Known Difficult Airway After Endotracheal Tube Damage: A Case Report.

Treacher Collins syndrome is an inherited disorder resulting in maldevelopment of the first and second branchial arches. Patients have complex orofacial anatomy often requiring airway interventions from birth. A 17-year-old boy with Treacher Collins syndrome and history of difficult ventilation and intubation presented for elective maxillofacial reconstruction. After uneventful awake nasal fiberoptic intubation, the nasotracheal tube was damaged intraoperatively. Due to the patient's unique anatomy, a fiberoptic bronchoscope and ventilating exchange catheter were utilized together to facilitate a nasotracheal tube exchange. This case demonstrates the utilization of a combination of advanced airway techniques in an urgent perioperative setting.

Inter-Rater Agreement in the Assessment of Video Recordings of Eye Drop Instillation by Glaucoma Patients.

PURPOSE: To create a standardized method for evaluating the video recordings of patients self-instilling eye drops and to determine the level of agreement of eye drop instillation efficacy, safety and efficiency ratings by three masked graders. DESIGN: Prospective cross-sectional study. PARTICIPANTS: 78 patients with open-angle glaucoma or ocular hypertension who had at least 6 months of experience with the use of eye drop medications. METHODS: Participants were video recorded while self-instilling artificial tears sequentially to both eyes. Three masked observers graded these video recordings on three criteria: efficacy (the determination of whether an eye drop was instilled on the ocular surface), safety (assessment of whether the tip of the medication bottle made contact with the ocular surface or eyelids), and efficiency (the number of eye drops expressed from the bottle). MAIN OUTCOME MEASURES: After grading the video recordings based on efficacy, safety, and efficiency, kappa statistics were used to estimate inter-rater agreement. RESULTS: The mean kappa level of agreement for efficacy, safety, and efficiency was 0.64 (95% confidence interval (CI), 0.42-0.87), 0.73 (95% CI, 0.58-0.88), and 0.62 (95% CI, 0.42-0.81), respectively. CONCLUSIONS: We demonstrated good inter-rater reproducibility of the masked analysis of video recordings of patients self-instilling eye drops based on three criteria: efficiency, safety, and efficacy.

Correlation Between Inter-Eye Difference in Average Retinal Nerve Fiber Layer Thickness and Afferent Pupillary Response as Measured by an Automated Pupillometer in Glaucoma.

PURPOSE: To assess the correlations between the relative afferent pupillary defect measured by a binocular, computerized, and commercially available pupillometer and the inter-eye differences in average retinal nerve fiber layer (RNFL) thickness measured by spectral-domain optical coherence tomography (SD-OCT) and visual field index (VFI) and mean deviation (MD) measured by automated static perimetry in patients with glaucoma. DESIGN: Cross-sectional study. PARTICIPANTS: Thirty four patients with open-angle glaucoma. METHODS: Pupillary constriction amplitudes were measured with an automated pupillometer. SD-OCT imaging of the circumpapillary RNFL and automated static perimetry were performed within 6 months of pupillometry. MAIN OUTCOME MEASURES: Main outcome measures included Spearman correlation coefficients between relative afferent pupillary defect as measured by pupillometry and inter-eye differences in average RNFL thickness, VFI, and MD. RESULTS: Correlation coefficients between relative afferent pupillary defect and inter-eye difference in average RNFL thickness, MD, and VFI were -0.81 (P<0.001), -0.73 (P<0.001), and -0.68 (P<0.001), respectively. CONCLUSIONS: The automated pupillometer quantifies asymmetry in afferent pupillary responses in proportion to structural and functional asymmetry as measured SD-OCT and automated static perimetry.