Contextual Effects on Inflammatory Biomarkers and Pain Relief After Spinal Joint Manipulation (CONTEXT-PAIN)

The Influence of Contextual Effects on Biochemical Parameters Associated With Inflammation and the Analgesic Efficacy of Spinal Joint Manipulation Therapy

The goal of this clinical trial is to learn whether contextual effects created by observational learning can change pain relief and inflammation-related biological responses after spinal joint manipulation in adults with chronic non-specific low back pain. The main questions it aims to answer are:

Does positive, neutral, or negative observational learning change pain after spinal joint manipulation? Does it change disability, lumbar range of motion, stress, fear of movement, empathy, and treatment expectations? Does it change pressure pain threshold, lumbar tissue temperature, and blood markers related to inflammation, including interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor alpha (TNF-α), and interleukin-10 (IL-10)?

The researchers will compare 3 groups: a positive expectation group, a neutral group, and a negative expectation group. Before the treatment, each participant will have a short interaction with a trained simulated patient. The simulated patient will present a positive, neutral, or negative experience with spinal manipulation, depending on group assignment. After this, all the participants will receive the same spinal joint manipulation procedure.

The participants will:

• be randomly assigned to 1 of 3 study groups,
• complete baseline questionnaires and clinical tests before treatment,
• take part in a brief observational learning session before manipulation,
• receive 1 spinal joint manipulation treatment,
• complete outcome measurements before treatment, about 60 minutes after treatment, and 24 hours after treatment,
• provide blood samples for analysis of inflammation-related biomarkers.

This study will include adults aged 18 to 65 years with chronic non-specific low back pain. The main outcome is pain intensity. Secondary outcomes include disability, stress, empathy, fear of movement, lumbar range of motion, tissue temperature, pressure pain threshold, and treatment expectations. Exploratory outcomes include blood biomarkers related to inflammation.

Study Overview

• Status: Recruiting
• Conditions: Low Back Pain
• Intervention / Treatment: Behavioral: Observational Learning; Procedure: Spinal Joint Manipulation

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 73
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Kamil Zaworski, PhD; Phone Number: +48506764250; Email: k.zaworski@dyd.akademiabialska.pl
• Study Contact Backup: Name: Joanna Baj-Korpak, PhD; Phone Number: +48833456208; Email: j.baj-korpak@dyd.akademiabialska.pl

Study Locations

• Poland
  • Lublin Voivodeship
    • Biała Podlaska, Lublin Voivodeship, Poland, 21-500
      • Recruiting
      • John Paul II University in Biała Podlaska
      • Contact: Kamil Zaworski, PhD; Phone Number: +48506764250; Email: k.zaworski@dyd.akademiabialska.pl
      • Contact: Joanna Baj-Korpak, PhD; Phone Number: +48833456208; Email: j.baj-korpak@dyd.akademiabialska.pl
    • Biała Podlaska, Lublin Voivodeship, Poland, 21-500
      • Recruiting
      • Laboratory of the John Paul II University in Biała Podlaska
      • Contact: Kamil Zaworski, PhD; Phone Number: +48506764250; Email: k.zaworski@dyd.akademiabialska.pl

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• people with low back pain lasting longer than 3 months, aged 18 to 65 years,
• highest reported pain intensity during the last 24 hours of at least 4 out of 10 on the 11-point Numeric Pain Rating Scale (NPRS-11), where 0 = no pain and 10 = worst imaginable pain,
• clinical diagnosis of chronic non-specific low back pain (NSCLBP) based on symptoms located in the lumbar spine region and not on imaging findings,
• no use of nonsteroidal anti-inflammatory drugs (NSAIDs) for at least 7 days before the study,
• no use of pain medication for at least 24 hours before the study,
• no use of corticosteroids,
• no previous spinal manipulation therapy,
• no alcohol, nicotine, or coffee consumption for at least 12 hours before the study,
• written informed consent to participate in the study.

Exclusion Criteria:

• physiotherapy students,
• presence of red flags, such as a history of cancer, constant or non-mechanical pain, progressive or radiating pain, sensory deficits in the trunk or - lower limbs, lower limb muscle weakness, or bladder/bowel dysfunction,
• body mass index (BMI) greater than 30,
• previous lumbar spine surgery,
• lumbar spine injury within 6 months before the study,
• diagnosed diabetes,
• diagnosed rheumatic diseases,
• affective disorders such as post-traumatic stress disorder (PTSD) or schizophrenia,
• spondylolisthesis or spondylolysis confirmed by imaging,
• diagnosed endometriosis,
• use of hormonal medications,
• sleep disorders,
• shift work,
• musculoskeletal injury within the last 14 days,
• active infection,
• pregnancy,
• endocrine disorders such as hyperthyroidism or hypothyroidism,
• use of opioid medications, including over-the-counter combination products such as codeine with paracetamol,
• current or recent use of antidepressants affecting serotonin or dopamine (including SSRIs, SNRIs, tricyclic antidepressants, MAO inhibitors, or ketamine),
• current diagnosis of major depressive disorder or bipolar disorder, as well as PTSD or schizophrenia,
• ongoing psychotherapy during the study period,
• cognitive impairment or significant hearing impairment that may interfere with understanding or processing the observational learning procedure.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Positive Observational Learning + Spinal Joint Manipulation; The participants are exposed to a standardized positive observational learning procedure before treatment. A simulated patient describes clear improvement in low back pain and lumbar mobility after spinal manipulation and demonstrates comfortable lumbar movement. After this interaction, the participants receive the same spinal joint manipulation procedure as in the other study arms.	Behavioral: Observational Learning; A standardized pre-treatment observational learning procedure delivered through an interaction with a simulated patient presenting positive, neutral, or negative treatment-related expectations and recovery behavior.; Procedure: Spinal Joint Manipulation; A standardized high-velocity, low-amplitude lumbar spinal manipulation applied after the observational learning procedure in all study arms.
Experimental: Neutral Observational Learning + Spinal Joint Manipulation; The participants are exposed to a standardized neutral observational learning procedure before treatment. A simulated patient has a brief neutral interaction and does not describe treatment effects or demonstrate functional improvement. After this interaction, the participants receive the same spinal joint manipulation procedure as in the other study arms.	Behavioral: Observational Learning; A standardized pre-treatment observational learning procedure delivered through an interaction with a simulated patient presenting positive, neutral, or negative treatment-related expectations and recovery behavior.; Procedure: Spinal Joint Manipulation; A standardized high-velocity, low-amplitude lumbar spinal manipulation applied after the observational learning procedure in all study arms.
Experimental: Negative Observational Learning + Spinal Joint Manipulation; The participants are exposed to a standardized negative observational learning procedure before treatment. A simulated patient reports little or no improvement in low back pain after spinal manipulation and demonstrates limited lumbar movement with visible discomfort. After this interaction, the participants receive the same spinal joint manipulation procedure as in the other study arms.	Behavioral: Observational Learning; A standardized pre-treatment observational learning procedure delivered through an interaction with a simulated patient presenting positive, neutral, or negative treatment-related expectations and recovery behavior.; Procedure: Spinal Joint Manipulation; A standardized high-velocity, low-amplitude lumbar spinal manipulation applied after the observational learning procedure in all study arms.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain intensity score on the 11-point Numeric Pain Rating Scale (NPRS-11)	Pain intensity will be assessed using the 11-point Numeric Pain Rating Scale (NPRS-11), where 0 indicates no pain and 10 indicates the worst imaginable pain. This is the primary outcome measure.	Baseline (pre-intervention), 60 minutes after spinal joint manipulation, and 24 hours after spinal joint manipulation.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lumbar range of motion	Lumbar range of motion will be assessed using standardized clinical measurement procedures. Higher values indicate greater lumbar mobility.	Baseline (pre-intervention), 60 minutes after spinal joint manipulation, and 24 hours after spinal joint manipulation.
Pressure pain threshold at lumbar levels L3-L5 measured by pressure algometry	Pressure pain threshold will be measured using a pressure algometer at lumbar levels L3, L4, and L5. Measurements will be taken over the spinous process and 2 cm laterally on both sides in the lumbar erector spinae region. Participants will indicate when pressure first becomes painful.	Baseline (pre-intervention), 60 minutes after spinal joint manipulation, and 24 hours after spinal joint manipulation.
Stress score on the 11-point Stress Numeric Rating Scale (SNRS-11)	Stress level will be assessed using the 11-point Stress Numeric Rating Scale (SNRS-11), where 0 indicates no stress and 10 indicates the highest stress level.	Baseline (pre-intervention), 60 minutes after spinal joint manipulation, and 24 hours after spinal joint manipulation.
Perceived stress score on the 10-item Perceived Stress Scale (PSS-10)	Perceived stress will be assessed using the 10-item Perceived Stress Scale (PSS-10), a licensed self-report questionnaire. Higher scores indicate greater perceived stress.	Baseline (pre-intervention), 60 minutes after spinal joint manipulation, and 24 hours after spinal joint manipulation.
Empathic concern score on the Interpersonal Reactivity Index	Empathy will be assessed using the Empathic Concern subscale of the Interpersonal Reactivity Index. Higher scores indicate greater empathic concern.	Baseline (pre-intervention)
Disability score related to low back pain on the Roland-Morris Disability Questionnaire	Disability related to low back pain will be assessed using a validated disability questionnaire for low back pain. Higher scores indicate greater disability.	Baseline (pre-intervention), 24 hours after spinal joint manipulation.
Kinesiophobia score on the Tampa Scale of Kinesiophobia	Kinesiophobia will be assessed using a validated self-report questionnaire evaluating fear of movement. Higher scores indicate greater fear of movement.	Baseline (pre-intervention), 24 hours after spinal joint manipulation.
Lumbar tissue temperature measured by infrared thermography	Lumbar tissue temperature will be assessed in the lumbar region using standardized measurement procedures.	Baseline (pre-intervention), 60 minutes after spinal joint manipulation, and 24 hours after spinal joint manipulation.
Lumbar flexion and extension range of motion measured by Medi-Mouse	Lumbar range of motion will be assessed using the Medi-Mouse device. Lumbar flexion and extension will be measured using standardized procedures. Higher values indicate greater lumbar mobility.	Baseline (pre-intervention), 60 minutes after spinal joint manipulation, and 24 hours after spinal joint manipulation.
Expected treatment benefit score on a 0-100 Visual Analog Scale (VAS)	Expected treatment benefit will be assessed using a self-report measure of the participants' expectations regarding the anticipated benefit of treatment. This measure will also be used to verify the immediate effect of the observational learning manipulation.	Baseline (pre-intervention) and immediately after the observational learning procedure, before spinal joint manipulation.
Fulfillment of treatment expectations score on a 0-100 Visual Analog Scale (VAS)	Fulfillment of treatment expectations will be assessed using a self-report measure evaluating the extent to which treatment outcomes match prior expectations.	60 minutes after spinal joint manipulation and 24 hours after spinal joint manipulation.
Attitude toward manual therapy score on a 0-100 Visual Analog Scale (VAS)	Attitude toward treatment with manual therapy will be assessed using a Visual Analog Scale (VAS) from 0 to 100, where 0 indicates a very negative attitude and 100 indicates a very positive attitude. The participants will answer the question: "What is your attitude toward treatment with manual therapy?"	Baseline (pre-intervention)
Patient satisfaction score on an 11-point numeric rating scale	Patient satisfaction with treatment will be assessed using an 11-point numeric rating scale from 0 to 10, where 0 indicates "not satisfied at all" and 10 indicates "completely satisfied". The participants will answer the question: "Are you satisfied with the treatment you received?" Higher scores indicate greater satisfaction.	24 hours after spinal joint manipulation.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Inflammation-related blood biomarkers	Blood biomarkers related to inflammation will be analyzed, including interleukin-6 (IL-6), high-sensitivity C-reactive protein (hs-CRP), tumor necrosis factor alpha (TNF-α), and interleukin-10 (IL-10).	Baseline (pre-intervention), 60 minutes after spinal joint manipulation, and 24 hours after spinal joint manipulation.

Collaborators and Investigators

• Sponsor: John Paul II University in Biała Podlaska
• Investigators: Study Chair: Kamil Zaworski, PhD, John Paul II University in Biała Podlaska

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2026
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): September 30, 2026

Study Registration Dates

• First Submitted: March 27, 2026
• First Submitted That Met QC Criteria: March 27, 2026
• First Posted (Actual): April 2, 2026

Study Record Updates

• Last Update Posted (Actual): June 3, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: low back pain; placebo; nocebo; spinal joint manipulation; observational learning; contextual effects
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Back Pain; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Low Back Pain
• Other Study ID Numbers: JohnPaul2U_KZ; SN.TJO-61.501.17.2025 (Other Grant/Funding Number: John Paul II University in Biała Podlaska)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

De-identified individual participant data collected in this study will be made available to other researchers upon reasonable request. Shared data may include demographic and baseline characteristics, group allocation, outcome measures, and analyzable datasets related to pain intensity, disability, range of motion, psychological variables, pressure pain threshold, thermographic measures, and inflammatory biomarkers, after removal of direct identifiers.

Access Criteria:

Access to de-identified data will be granted to qualified researchers upon reasonable request to the principal investigator, subject to applicable ethics committee requirements, institutional policies, and confirmation that the proposed use is consistent with participant consent. A data access agreement may be required.

• IPD Sharing Time Frame: Data will become available beginning 6 months after publication of the primary results and will remain available for 5 years thereafter.
• IPD Sharing Access Criteria: De-identified individual participant data and supporting documents will be made available to qualified researchers upon reasonable request to the principal investigator. Access will be granted for methodologically sound research purposes, subject to participant consent, ethics committee requirements, institutional policies, and, where applicable, a data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No