Trial Outcomes & Findings for Molecular Pathways Involved in Knee Pain (NCT NCT04443452)

Race and Ethnicity were not collected from any participant.

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.

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).

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.

Central augmented pain assessed on a 8-item CAP-Knee questionnaire, where items 1-7 are scored from 0-3, 0 indicating "never" and 3 indicating "often" or "always". Item 8 (pain distribution manikin) was allocated a score of 0 if at most 1 knee is shades, and no other regions below the waist, or a score of 3 if both knees were shaded, or one knee plus any additional shaded areas below the waist. A total sum score (minimum score of "0", maximum score of "24") will be calculated for analysis. The higher the value the higher the levels of central augmented pain.

Anxiety will be assessed with the Anxiety part of the Hospital Anxiety and Depression Scale (HADS) where patients are asked to indicate their levels of emotion frequency with a 4-level scale (0-3: 0 indicates never and 3 all the time) at 7 questions. A sum of all responses is calculated (minimum score of "0", maximum score of "21") for analysis. The higher the value the higher the levels of anxiety.

Depression will be assessed with the Depression part of the Hospital Anxiety and Depression Scale (HADS) where patients are asked to indicate their levels of emotion frequency with a 4-level scale (0-3: 0 indicates all the time and 3 never) at 7 questions. A sum of all responses is calculated (minimum score of "0", maximum score of "21") for analysis. The higher the value the higher the levels of depression.

Cognitive function will be assessed with the Cognitive Failures Questionnaire (CFQ) where participants are asked to indicate symptom frequency with a 0-4 scale (0 indicates never and 4 very often) on 25 statements. A sum of all responses is calculated (minimum score of "0", maximum score of "100") for analysis. The higher the value the more impaired cognitive function is.

Sleep quality will be assessed with the Pittsburgh Sleep Quality Index (PSQI) where participants are asked to respond to 18 statements indicating their: 1) sleep duration in minutes/hours on 4 questions, 2) symptom frequency with 4 possible answers spreading from 'not during the past month' to 'three or more times a week' on 12 statements, 3) symptom severity with 4 possible answers spreading from 'no problem at all' to 'very big problem' on 1 statement and 4) sleep quality with 4 possible answers spreading from 'very good' to 'very bad' on 1 statement. Responses are coded from 0-4 (0 indicating no sleeping issues and 4 frequent and severe sleeping problems). A sum of all 18 responses is calculated (minimum score of "0", maximum score of "72" being the maximum) for analysis. The higher the value the less sleep quality there is.

Knee pain, stiffness and physical functioning will be assessed with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) where participants are asked to rate their symptom severity with a 0-4 scale (0 indicates never and 4 extreme) five items for pain (score range 0-20), two for stiffness (score range 0-8), and 17 for functional limitation (score range 0-68). The higher the value in each domain the more pain, stiffness and physical dysfunction there is.

General health will be assessed with the Musculoskeletal Health Questionnaire (MSK-HQ) where participants are asked to indicate symptom frequency with a 0-4 scale (0 indicates very severe and 4 not at all severe) on 14 statements. A sum of all responses is calculated (minimum score of "0", maximum score of "56") for analysis. The lower the value the more reduced general musculoskeletal health is.

Frailty will be measured with a modified questionnaire where participants will be asked to respond to 8 Yes/No questions (Yes is marked with 1 and No with 0) about inability to walk, using aids, weight loss, co-morbidities and levels of physical activity. A total out of all responses (minimum score of "0", maximum score of "8") is calculated for analysis. The higher the score, the higher the levels of frailty

Dietary habits will be assessed with the Food Frequency Questionnaire (FFQ) where participants are asked to indicate the consumption frequency of different types of food materials with a 0-9 scale (0 indicates 'never or less than once a month' and 9 'more than 6 times per day') on 150 distinct foods divided into dairy, fruits, vegetables, meat and fish, soups, bread, sweets, potatoes, and beverages. A total score is calculated for each category with the maximum depending on the amount of items in each category. The larger the total value the more frequent the consumption of a food category per day is.

Concentration of inflammatory markers (cytokines) identified in extracted synovial fluid.

Concentration of proteomic concentrations (fibronectin) identified in extracted synovial fluid.

Concentration of gene expression molecules (RNA polymerase II) identified in extracted synovial fluid.

Concentration of stress markers (cortisol) identified in participants' blood samples.

Concentration of insulin resistance markers (fasting blood glucose) identified in participants' blood samples.

Concentration of metabolic rate markers (triglycerides) identified in participants' blood samples.

Concentration of metabolic rate markers (UTXII collagen degradation marker) identified in participants' urine samples.

Concentration of inflammatory regulator markers (maresins) identified in participants' urine samples.

Concentration of stress markers (cortisol) in participants' saliva samples.

Concentration of metabolic rate markers (glucosamine) in participants' faecal samples.

Concentration of metabolic rate markers (chondroitin sulfate) in participants' faecal samples.