Molecular Pathways Involved in Knee Pain

NCT04443452 | Completed Results

• 3 other identifiers: 1909822473275727
• Study Type: observational
• Target: 71
• Locations: 1 country
• Sites: 1

Brief Summary

Knee osteoarthritis (OA) is the most common form of arthritis and the most common cause of knee pain in the world. The rate of knee arthritis is as high as that of cardiac disease and is the most common problem in individuals over the age of 65. Central Sensitization (CS) is a marker of widespread pain sensitivity that can occur throughout the central nervous system distribution, leading to changes in the spinal cord as well as in the brain. The presence of CS increases the complexity of the clinical picture and can negatively affect treatment outcomes. CS is present in \>20% of patients suffering from knee OA indicating that in the majority of individuals suffering with painful knee OA, knee pain should be related to molecular changes in the joint. CS might be also associated with discrete synovial fluid proteomic signatures due to the generation by the joint of chemical mediators (e.g. nerve growth factor) that drive CS, or CS might moderate the relationship between synovial fluid proteomic signatures and symptoms due to alterations in pain processing. The aim of this study is to explore the potential molecular links between pain and structure on knee pain using synovial fluid proteomics. A secondary purpose is to explore the association of knee pain with biomarkers of stress, metabolism and dietary habits. In a single session, ultrasound-guided synovial fluid, blood urine and saliva extraction, clinical assessment, completion of a questionnaire booklet and knee x-rays will be conducted. The clinical assessment will measure three features of central sensitisation (sensitivity to blunt pressure on the most painful knee, changes in pain felt during repeated light pricking of the knee skin, and reduction in pain that accompanies inflation of a blood pressure cuff on the non-dominant arm), features of leg strength (dynamometer, time up-and-go test) and features of balance (sway). Participant involvement at each session is expected to last less than 3 hours. Individuals over 45 having complaints of knee pain for 3-6 months are eligible to participate. The clinical assessments, questionnaire completion and subsequent statistical analysis are expected to be completed within 18 months of study commencement. The findings can provide more insight into the traits of knee pain, allow the examination of possible correlations to each other, and highlight potential detrimental effects of them on knee joint health.

Conditions

Knee Osteoarthritis; Knee Pain Chronic

Outcome Measures

Primary Outcomes (3)

• Pain Sensitivity: Pressure Pain Detection Threshold (PPT)

  PPT is a non-invasive test during which the sensitivity of the nerves is assessed by recording the amount of pressure applied to the skin. Pressure is applied through a probe. The pressure probe used is mounted in a handheld device connected to a computer. Pressure applied to the skin is gradually increased until the participant indicates (by pressing a button) that the sensation has changed from pressure to pain. The probe will be used on the contralateral forearm (brachioradialis muscle) using a standardised protocol used in other studies within the Pain Centre. Each region will be tested one time with short rest periods between each. The participants will be familiarised with the test before it is administered so that they know what to expect and how to respond.

  At baseline

• Pain Sensitivity: Temporal Summation Pain (TS)

  TS is a non-invasive test during which repetitive mechanical stimulation is applied over a short period to get their augmented response. A 256mN weighted pinprick stimulator will be used and applied perpendicular to the skin of suprapatellar region of the painful knee (5cm proximal from the centre of patella). The participant will be asked to rate the pain or sharpness they experience from 0-10 where 0 indicates no pain or sharpness and 10 indicates the most intense pain or sharpness imaginable. The response of the participant will be recorded. The same stimulator at the same site will be applied ten times repeatedly at a rate of 1/second. At the end of the series of 10 pinpricks, the participant will be asked to rate the average pain or sharpness they experienced out of the 10 stimuli using the same scale. The TS value will be calculated as the difference between the two ratings (single stimulus minus the average of the 10 stimuli).

  At baseline

• Pain Sensitivity: Conditioned Pain Modulation (CPM)

  CPM is the application of PPT before and while a pressure cuff is inflated. A 7.5cm wide tourniquet cuff will be wrapped around the arm contra-laterally to the most painful knee. The lower rim of tourniquet cuff will be kept 3cm proximal to cubital fossa. The cuff will be inflated with the aim to reach above-systolic pressure with a maximum of 270mm/Hg. After target pressure is achieved, the participant will be asked to repeatedly make a handgrip or squeeze a foam ball until they develop ischemic pain ≥4 out of 10 on a 0-10 scale. Once NRS of 4/10 will be achieved, the probe of algometer will be applied in the same manner as during PPT testing. Once the participant presses the button, the probe will be withdrawn, and the cuff will be deflated released from the participants arm. The difference in PPT score (PPT with conditioning minus PPT without conditioning) will be considered the CPM value. A positive value indicates efficient CPM whereas a negative value indicates impaired CPM.

  At baseline

Secondary Outcomes (8)

• Central Aspects of Knee Pain (CAP-Knee)

  At baseline

• Anxiety

  At baseline

• Depression

  At baseline

• Cognitive Function

  At baseline

• Sleep Quality

  At baseline

Other Outcomes (12)

• Dietary Habits (OPTIONAL)

  At baseline

• Biosamples (Synovial Fluid A)

  At baseline

• Biosamples (Synovial Fluid B)

  At baseline

Study Arms (2)

Prevalent Central Sensitisation

Participants with sensitisation that significantly deviates from the normal mean as assessed by Quantitative Sensory Testing

Diagnostic Test: Quantitative Sensory Testing; Radiation: Radiographic Evaluation; Procedure: Ultrasound-guided Aspiration; Diagnostic Test: Muscle Strength Assessment; Diagnostic Test: Function Assessment (A); Diagnostic Test: Function Assessment (B); Diagnostic Test: Balance Assessment

Non-prevalent Central Sensitisation

All other participants with sensitisation that is not significantly deviating from the normal mean as assessed by Quantitative Sensory Testing

Diagnostic Test: Quantitative Sensory Testing; Radiation: Radiographic Evaluation; Procedure: Ultrasound-guided Aspiration; Diagnostic Test: Muscle Strength Assessment; Diagnostic Test: Function Assessment (A); Diagnostic Test: Function Assessment (B); Diagnostic Test: Balance Assessment

Interventions

Quantitative Sensory Testing DIAGNOSTIC_TEST

PPT: An electronic data collection unit will be used featuring an electronic algometer connected with a laptop where the amount of pressure will be displayed on the screen. When the pressure pain detection threshold is reached (the point where the pressure sensation starts to be experienced as pain), the individual will press a button at a handheld device, that will automatically store the pressure value in the system and serve as an indication, for the examiner, to stop the testing. TS: A pinprick stimulator (Weight: 256mNewton) will be used. The examiner will apply the pen that features a retractable blunt needle in a repetitive manner (once per second for ten seconds). The individual will be asked for the intensity of pain (NRS) at the first and at the last time and the given score will be noted. CPM: A manual blood pressure sphygmomanometer will be used in conjunction with the electronic algometer described above (PPT).

Also known as: Pressure Pain Detection Threshold (PPT), Temporal Summation (TS), Conditioned Pain Modulation (CPM)

Non-prevalent Central Sensitisation; Prevalent Central Sensitisation

Radiographic Evaluation RADIATION

Tibiofemoral and patellofemoral radiographs of the most painful knee will be taken using a standardised protocol (standing posterior-anterior (PA) and skyline views) and will be scored by a single experienced observer in order to generate data for correlation analyses with the primary and secondary outcomes. A Perspex Rosenberg template with lead beads is used for the standing PA view to standardising the degree of knee flexion, foot rotation and magnification. PA radiographs are taken with the participant facing the x-ray tube while standing on the Rosenberg jig and leaning forwards with their thighs touching the anterior aspect of the jig, the x-ray beams passing from the posterior aspect through to the anterior aspect of the knee. Variable jigs are used for the skyline view to obtaining 300 of knee flexion with the participant lying in a reclined supine position on a couch. Grading of radiographs for changes of OA will be based on the Kellgren and Lawrence (K/L) score.

Also known as: X-rays

Non-prevalent Central Sensitisation; Prevalent Central Sensitisation

Ultrasound-guided Aspiration PROCEDURE

Ultrasound scanning will be conducted on the most painful knee to identify synovial effusion. During the ultrasound scan, the supra-patellar pouch, medial and lateral recess of the knees will be assessed for synovial thickening, synovial fluid/effusion and for positive power Doppler. An ultrasonic probe will be used to direct ultrasonic waves onto the knee joint during sonography, and a computer converts the signals received so that they can be presented on the screen. During skin application, a sterile probe cover and sterile acoustic gel will be used. Once the best aspiration location is identified and the location of the needle insertion marked, the skin will be prepared with a cleansing agent such as iodine or chlorhexidine. The needle may be introduced into the skin either parallel to the probe or perpendicular to the probe. Once the aspiration is completed, the needle will be removed, the skin cleansed, and a bandage will be applied.

Also known as: Synovial Fluid Extraction

Non-prevalent Central Sensitisation; Prevalent Central Sensitisation

Muscle Strength Assessment DIAGNOSTIC_TEST

Isometric testing will be done at 30 and 60 degrees of flexion as done in the previous study and the participant will be in sitting position with hips and knees strapped to keep the position standardised.

Also known as: Isometric Dynamometer

Non-prevalent Central Sensitisation; Prevalent Central Sensitisation

Function Assessment (A) DIAGNOSTIC_TEST

The participant will start in a seated position. The participant will stand up upon therapist's command, walk 3 meters, turn around, walk back to the chair and sit down. The time will stop when the participant is seated. The subject can use an assistive device. If the assistive device is used, it will be documented. Important Note: A practice trial will be completed before the timed trial.

Also known as: Time Up-and-Go Test

Non-prevalent Central Sensitisation; Prevalent Central Sensitisation

Function Assessment (B) DIAGNOSTIC_TEST

The 30-Second Chair Test is administered using a chair. The participant is seated in the middle of the chair with arms crossed at the wrists and held against the chest. The participant will practice a repetition or 2 before completing the test. If a participant must use their arms to complete the test, they are scored 0. The participant is encouraged to complete as many full stands as possible within 30 seconds. The participant is instructed to fully sit between each stand. While monitoring the participant's performance to ensure proper form, the tester silently counts the completion of each correct stand. The score is the total number of stands within 30 seconds (more than halfway up at the end of 30 seconds counts as a full stand). Incorrectly executed stands are not counted. The 30-second chair stand involves recording the number of stands a person can complete in 30 seconds rather than the amount of time it takes to complete a pre-determined number of repetitions.

Also known as: 30 seconds Sit-to-Stand Test

Non-prevalent Central Sensitisation; Prevalent Central Sensitisation

Balance Assessment DIAGNOSTIC_TEST

Static balance and postural sway either in the medial-lateral or antero-posterior direction will be assessed using the RS Scan force plate. The participant will be asked to stand on the plate looking straight forward for 30 seconds in two conditions: first with their eyes open and then with eyes closed. Medial-lateral, antero-posterior and total sway will be recorded.

Also known as: Static Balance Test, Postural Sway Test

Non-prevalent Central Sensitisation; Prevalent Central Sensitisation

Eligibility Criteria

• Age: 45 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Adults equal or above the age of 45 with a history of knee pain of at least 3 months duration that may or may not have been radiographically and no-radiographically classified as having knee pain due to osteoarthritis.

You may qualify if:

• have the ability to give informed consent
• be 45 years or over
• have complaints of knee pain for 3-6 months with or without radiographically established OA (K/L scale score ≥ 1)
• have complaints of knee pain for 3-6 months with or without satisfying the non-radiographic American College of Rheumatology criteria for knee OA
• are willing to undertake knee synovial fluid aspiration
• be able to speak, read, and write in English as all instructions and questionnaires are designed in the English language

You may not qualify if:

• Inability to give informed consent due to cognitive impairment or otherwise - (capacity levels are already established under General Practitioner care)
• Inability to understand key aspects of the study due to cognitive impairment or otherwise
• Giving history of additional co-morbidities such as cancer, neurological conditions, inflammatory joint diseases including rheumatoid arthritis, diabetic neuropathies, fractures or other conditions causing greater disability than their knee pain
• Acute soft tissue injury to the knee within last 3 months before potential recruitment

Sponsors & Collaborators

• University of Nottingham: lead
• Versus Arthritis: collaborator

Study Sites (1)

The University of Nottingham, City Hospital Campus

Nottingham, Nottinghamshire, NG5 1PB, United Kingdom

Location

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Biospecimen

Retention: SAMPLES WITH DNA

Blood, Urine, Saliva, Synovial fluid from the most painful knee, Faeces (OPTIONAL)

MeSH Terms

Conditions

Osteoarthritis, Knee

Interventions

Postsynaptic Potential Summation; X-Rays; Endoscopic Ultrasound-Guided Fine Needle Aspiration

Condition Hierarchy (Ancestors)

Osteoarthritis; Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases

Intervention Hierarchy (Ancestors)

Synaptic Transmission; Signal Transduction; Biochemical Phenomena; Chemical Phenomena; Synaptic Potentials; Membrane Potentials; Cell Physiological Phenomena; Electrophysiological Phenomena; Physiological Phenomena; Nervous System Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena; Electromagnetic Radiation; Electromagnetic Phenomena; Magnetic Phenomena; Physical Phenomena; Radiation; Radiation, Ionizing; Biopsy, Fine-Needle; Biopsy, Needle; Biopsy; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Image-Guided Biopsy; Specimen Handling; Ultrasonography, Interventional; Ultrasonography; Diagnostic Imaging; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Minimally Invasive Surgical Procedures; Investigative Techniques

Results Point of Contact

• Title: Professor Ana Valdes
• Organization: University of Nottingham

ana.valdes@nottingham.ac.uk

0115823114

Study Officials

• Ana M Valdes, PhD

  University of Nottingham

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 5, 2020
• First Posted: June 23, 2020
• Study Start: November 6, 2020
• Primary Completion: December 1, 2023
• Study Completion: December 1, 2023
• Last Updated: August 13, 2025
• Results First Posted: August 13, 2025

Record last verified: 2025-04

Locations

GB (1)