Secondary Exploratory Analysis of Directional Conditioned Pain Modulation Changes Following Spinal Mobilization and Associations with 4-Week Outcomes in Chronic Neck Pain

This secondary, exploratory project analyzes data from a prospective cohort study investigating whether subgrouping adults with mild chronic neck pain by the direction of conditioned pain modulation (CPM) changes immediately after spinal mobilization (SM) reveals meaningful differences in recovery trajectories over four weeks. Hypotheses: We hypothesize that participants exhibiting a negative CPM change following spinal mobilization will demonstrate superior recovery trajectories—especially improvements in function—over four weeks compared to those showing a positive CPM change. This mechanism-based subgrouping aims to predict clinically relevant outcomes beyond baseline CPM measures. Methods: Data were collected from 31 adults with mild, chronic non-specific neck pain enrolled in a rigorously conducted prospective cohort study. Each participant received a single 10-minute cervical spinal mobilization session. CPM was assessed shortly before and immediately after mobilization. Clinical outcomes—including pain intensity (Numeric Pain Rating Scale), function (Neck Disability Index), and global perceived recovery—were measured at baseline, 2 days, 2 weeks, and 4 weeks post-treatment. The original study was approved by institutional review boards at two universities, which also approved this secondary analysis with exempt status. The study was retrospectively registered on ClinicalTrials.gov (pending approval), as at the time the specific registration requirements for cohort studies with intervention were not fully known to us. Notably, two prior randomized controlled trials under our group were prospectively registered, demonstrating adherence to preregistration best practices where applicable. The research was funded by a NIOSH subcontract with progress and final reports submitted, and completed as part of a PhD dissertation that was successfully defended under customary academic oversight; this dissertation is publicly available through NYU ProQuest (Dissertation Publication ID #30569880). Analysis: Secondary exploratory analyses were performed by a biostatistician using mixed-effects linear models with fixed effects for CPM change subgroup (positive vs. negative), time, and their interaction, adjusting for relevant covariates. Random intercepts accounted for within-subject variation. The subgroup-by-time interaction tested differences in recovery trajectories over follow-up. This OSF registration prospectively documents the finalized analytic plan and interpretive framework prior to manuscript submission and public dissemination, despite data collection and analyses already completed. This approach ensures transparency and helps mitigate selective reporting, hindsight bias, and other analytic biases in this exploratory mechanistic investigation. Subgroup allocation was performed after data collection and completion of the original study, and participants, clinicians, and assessors were blinded to subgroup assignment throughout the study to minimize bias. Due to the exploratory nature, these hypothesis-generating, post-hoc secondary analyses require prospective validation. Novelty and Impact: While prior literature and systematic reviews mainly examine baseline CPM as a predictive biomarker, few studies investigate post-intervention CPM dynamics, and none known to us apply mechanistic subgrouping by direction of CPM change combined with longitudinal mixed-effects modeling including subgroup-by-time interactions. To our knowledge, this is the first such mechanistic-exploratory application in rehabilitation medicine and related clinical fields. The findings offer foundational insight toward personalized rehabilitation and hold promise for broader application in pain medicine, neurology, and pharmacology. By openly retrospectively (hybrid) registering hypotheses, methods, and analyses, we promote replication, validation, and clinical translation—potentially advancing precision rehabilitation and pain management paradigms.