脊椎関節マニピュレーション後の炎症性バイオマーカーと疼痛緩和に対する文脈的影響 (CONTEXT-PAIN)

Chronic non-specific low back pain is a common and disabling condition. Spinal joint manipulation is frequently used in its management, but the mechanisms underlying its effects are not fully understood. Increasing attention has been given to contextual factors, including treatment expectations, which may influence pain-related outcomes through psychological and neurophysiological pathways. One potentially important mechanism is observational learning, in which expectations are shaped by observing another person's experience with treatment. This mechanism has been studied in experimental pain settings, but it has been investigated only rarely in clinical populations and has not been adequately tested in the context of spinal manipulation for chronic non-specific low back pain.

The purpose of this study is to evaluate whether observational learning before treatment can modify the effects of spinal joint manipulation in adults with chronic non-specific low back pain. The trial is designed to examine whether a brief peer-modeling interaction presented before treatment can influence clinical outcomes, psychological responses, and selected mechanistic measures, including inflammatory biomarkers. The study will compare positive, neutral, and negative observational learning conditions to determine whether expectation-related contextual effects alter response to the same manual therapy procedure.

This study is a prospective, parallel-group, three-arm randomized controlled trial with follow-up assessment. The participants will be randomly assigned in a 1:1:1 ratio to one of three groups: positive observational learning, neutral observational learning, or negative observational learning. The target analyzed sample is 66 participants, and the recruitment target has been increased to 73 participants to account for possible dropout. Allocation concealment will be ensured using opaque, sequentially numbered envelopes prepared by an independent researcher. The participants, treating physiotherapists, outcome assessors, and statisticians will remain blinded to group allocation and study hypotheses throughout the trial.

The participants will be adults aged 18 to 65 years with chronic non-specific low back pain lasting more than 3 months and pain intensity of at least 4 out of 10 during the previous 24 hours. Eligibility will be based on clinical criteria for chronic non-specific low back pain. Key exclusion criteria include prior spinal manipulation, major spinal red flags, recent lumbar trauma or surgery, selected systemic or psychiatric conditions, pregnancy, active infection, relevant medication use that could affect pain or inflammatory responses, and factors that could interfere with understanding the observational learning procedure. A screening log will be maintained to document exclusions and reasons for non-enrollment.

All the participants will undergo the same spinal manipulation intervention. The manipulation will be delivered as a high-velocity, low-amplitude lumbar technique. The procedure will be applied on the symptomatic side identified by the participant; if the participant cannot identify the more symptomatic side, the physiotherapist will decide. If cavitation is not obtained, the physiotherapist may attempt the procedure on the opposite side. A maximum of two attempts per side will be allowed. This approach is intended to standardize the specific treatment component across all study groups.

The contextual manipulation will be delivered before the spinal manipulation through a one-time observational learning procedure. After completion of baseline assessments, each participant will take part in a brief standardized consultation in a waiting-room setting. The main researcher will provide neutral information about the spinal manipulation program and then briefly leave the room. A trained simulated patient will then enter and deliver a scripted interaction corresponding to the assigned study group. In the positive observational learning group, the simulated patient will describe clear improvement in low back pain and mobility after spinal manipulation and will reinforce this message by demonstrating comfortable lumbar movement. In the neutral group, the simulated patient will not comment on treatment effects and will only have a brief neutral interaction. In the negative observational learning group, the simulated patient will report little or no improvement and will reinforce this message by demonstrating limited lumbar movement with visible discomfort. Simulated patients will be trained to standardize tone of voice, body language, facial expression, and timing of the interaction. The female participants will interact with the female simulated patients, and the male participants will interact with the male simulated patients.

Data will be collected at baseline before treatment (T0), approximately 60 minutes after spinal manipulation (T1), and 24 hours after spinal manipulation (T2). Expected benefit will be assessed both at baseline and immediately after the observational learning interaction in order to evaluate whether the contextual manipulation changed treatment expectations. Fulfillment of expectations will be assessed after treatment and again at 24 hours. The primary endpoint is pain intensity. Secondary measures include pressure pain threshold, perceived stress, empathy, kinesiophobia, disability, lumbar range of motion, lumbar tissue temperature, expected benefit, fulfillment of expectations, attitude toward manual therapy, and treatment satisfaction. Exploratory outcomes include blood biomarkers related to inflammation.

Blood samples will be collected by qualified personnel under standardized conditions. To reduce variability, blood draws will be scheduled in the morning after fasting, and participants will receive instructions regarding restrictions on intense physical activity, caffeine, alcohol, nicotine, and analgesic or anti-inflammatory medication before sampling. Samples will be processed according to standard laboratory procedures, aliquoted, and stored at minus 80 degrees Celsius until analysis. Laboratory analyses will include interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor alpha (TNF-α), and interleukin-10 (IL-10). When feasible, assays will be performed using electrochemiluminescence multiplex methods; if this is not available, enzyme-linked immunosorbent assay methods will be used. Samples will be analyzed in duplicate with plate controls to monitor assay variability.

The study is intended to provide an integrated evaluation of how expectation-related contextual effects may influence response to spinal joint manipulation. By combining clinical, psychological, and biological outcomes, the trial seeks to clarify whether observational learning is a modifiable mechanism that can enhance or reduce treatment response in people with chronic non-specific low back pain. The underlying hypothesis is that positive observational learning will lead to more favorable outcomes than neutral or negative observational learning.

Statistical analyses will follow the intention-to-treat principle, with a per-protocol analysis conducted as a sensitivity analysis. Repeated measurements over time will be analyzed using mixed models with study group and time as factors, including the group-by-time interaction and baseline value as a covariate when appropriate. Prespecified contrasts will compare positive versus neutral, negative versus neutral, and positive versus negative conditions. Secondary outcomes will be analyzed with adjustment for multiplicity within comparison families. Exploratory biomarker analyses will emphasize effect estimates and confidence intervals. Missing data will be described, and mixed-model estimation will use all available observations under a missing-at-random assumption.

Participation in the study is voluntary and requires written informed consent. Ethics approval will be obtained from the Bioethics Committee at the John Paul II University in Biała Podlaska before recruitment begins. Because the study includes an expectation-based procedure using a simulated patient, full disclosure of the specific study aims and hypotheses will be provided to participants after completion of the study, in accordance with the ethical approach described in the protocol.