Understanding Pain Mechanisms in Knee Osteoarthritis

Study Overview
=================
Brief Summary
-----------------
UP-KNEE study is a feasibility, double-blind, placebo-controlled randomised parallel study in participants with radiographically defined knee OA, and with self-reported chronic knee pain.

Detailed Description
-----------------
Osteoarthritis (OA) of the knee joint is a common cause of chronic pain, disability and impaired quality of life. Knee OA affects   1 in 5 adults over 45 years, with many requiring major knee surgery to alleviate pain and restore mobility. However, > 1 in 5 patients will continue to suffer from pain despite surgery. It remains largely unknown who will fail to respond, and why. Chronic postoperative pain may be linked to a particular type of pain, that is not only driven by the joint damage itself but by changes in the central nervous system (central pain). Several lines of evidence support this idea, but there is a need for a better understanding of the underlying mechanisms as well as a better tool to differentiate between peripherally- and centrally-augmented knee pain in order to identify who will benefit the most from knee surgery. To this end, the proposed research is a feasibility study aiming to provide proof of concept for a future main trial. The study combines the diagnostic power of non-invasive imaging with experimental approaches to investigate central pain by modelling the peripheral effects of knee surgery. This will provide novel insights into the contribution of peripheral and central pain mechanisms in knee OA which can pave the way for better treatment results. This study is expected to last for one year. It is funded by Versus Arthritis Pain Centre and forms part of a wider scientific project aiming at increasing knowledge and understanding of OA pain.

Official Title
-----------------
Is There a Difference in the Analgesic Response to Intra-articular Bupivacaine Injection in People With Knee Osteoarthritis Pain With or Without Central Sensitisation?: a Feasibility Randomised Controlled Trial

Conditions
-----------------
Osteoarthritis, Knee, Chronic Pain

Intervention / Treatment
-----------------
* Drug: Intra-articular injection of bupivacaine in the knee joint
* Drug: Intra-articular injection of placebo in the knee joint


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Radiographically defined OA knee changes (K/L > 2); Must have self-reported knee pain (measuring at least 30 mm to 80 mm on a 100 mm VAS for rest, use or night pain); Able to give informed consent; Aged 45 years and older; All genders; Able to perform the six-minute walk test. Exclusion Criteria: Aged less than 45 years; Breastfeeding or pregnancy; Not having the capacity to consent; Non-English speakers; Major medical, neurological and psychiatric co-morbidities; Hip OA (ipsilateral or contralateral); Fibromyalgia; Sensory dysfunctional illness; Chronic pain conditions other than OA; Presence of local or systemic infection or suspicion of infection in the knee joint, overlying soft tissue or elsewhere; History of septic arthritis in the knee to be injected; Acute haemarthrosis in the joint to be injected; Recent trauma within 72 hours; Prosthetic joint; Presence of broken skin or rash over the area to be injected; Severe coagulopathy (can take aspirin or anti-platelets inhibitors such as clopidogrel); Any anti-coagulant therapy (e.g. warfarin); Severe liver disease or severe kidney disease; Known hypersensitivity, allergy or intolerance to local anaesthetic / bupivacaine; Recently taken other medicines containing local anaesthetic / bupivacaine within 1 month; Surgery planned within 3 months of entry to study; Neuropathic pain medications such as opioid analgesics, antiepileptic drugs such as pregabalin / gabapentin, and tricyclic antidepressants such as amitriptyline when taken for neuropathic pain treatment; Current or recent intake centrally-active medication (e.g. have recently taken monoamine oxidase inhibitor (MAOI)); Complete heart block; The presence of any contraindication for MRI.

Ages Eligible for Study
-----------------
Minimum Age: 45 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intra-articular injection of bupivacaine<br>5 ml of bupivacaine (0.25% w/v) | Drug: Intra-articular injection of bupivacaine in the knee joint<br>* 25 participants will be allocated to the bupivacaine arm.<br>* Other names: Bupivacaine hydrochloride;|
| Placebo Comparator: Intra-articular injection of sodium chloride<br>5 ml of sodium chloride (9mg/ml, 0.9% solution for injection) | Drug: Intra-articular injection of placebo in the knee joint<br>* 25 participants will be allocated to the placebo arm.<br>* Other names: Sodium chloride;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change from baseline in pain score during the six-minute walk test | The change from baseline in pain score using the Visual Analogue Scale during the six-minute walk test. (visual analogue scale ranges from 0-100; 0 meaning no pain and 100 worst imaginable pain) | From baseline to approximately one hour after intra-articular injection with bupivacaine or placebo | 
| The change from baseline in pain score at rest | The change from baseline in pain score using the Visual Analogue Scale at rest. (visual analogue scale ranges from 0-100; 0 meaning no pain and 100 worst imaginable pain) | From baseline to approximately one hour after intra-articular injection with bupivacaine or placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quantitative sensory testing (QST) | Correlations between change of pain score and QST findings will be assessed. | Baseline and within 30 minutes after intra-articular injection with bupivacaine or placebo | 
| Brain functional magnetic resonance imaging (fMRI) | Correlations between the change of pain score and brain network activity using predefined seeds in the pain processing regions will be assessed. | Baseline and 1 hour after intra-articular injection with bupivacaine or placebo | 
| Magnetic Resonance Imaging Knee Osteoarthritis Score (MOAKS) | Correlations between the change of pain score and the level of joint damage quantified by MOAKS will be assessed. Higher MOAKS indicate worse outcome. | Baseline | 
| The number of eligible participants who are recruited and randomised to the study | To assess the feasibility of recruitment, the number of eligible participants who are recruited and randomised to the study will be measured. | Through study completion, an average of 6 months | 
| A study-specific checklist to assess the feasibility of the randomisation process | Evaluation of effective randomisation of participants to the study arms using a study-specific checklist and assessment of the randomisation protocol throughout the study. | Through study completion, an average of 6 months | 
| A study-specific questionnaire to assess the acceptability of the trial methods | A study-specific questionnaire will be administered to participants to assess the acceptability of the study design and research process. | Assessed immediately after the final intervention | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Knee osteoarthritis, Chronic pain