Functional Brain Imaging to Understand the Mechanisms of Pain Relief in Knee Osteoarthritis
Overview
- Phase
- Phase 4
- Intervention
- Duloxetine
- Conditions
- Osteoarthritis
- Sponsor
- University of Nottingham
- Enrollment
- 77
- Locations
- 1
- Primary Endpoint
- Reduction in nociceptive brain response after duloxetine
- Status
- Completed
- Last Updated
- 8 years ago
Overview
Brief Summary
Osteoarthritis (OA) is a degenerative joint disease and is the most common form of arthritis. Pain reduction and functional recovery are the key elements of the clinical management of OA. Current treatment guidelines recommend a combination of pharmacological and non-pharmacological treatments. However, these are not always effective, with nearly 20% of patients not responding to any standard therapy, including joint replacement.
The mechanisms of pain relief are not well understood and are complicated by the remarkably large placebo effect, and inter-individual variation. There is no objective criteria for predicting whether a patient will respond to a given treatment
Duloxetine, an antidepressant drug, has proven effectiveness in various chronic pain syndromes including knee OA. The effect is however limited and only clinically relevant in around half of the trial patients. Importantly, it is currently unclear how and in whom duloxetine alleviates chronic pain.
Advanced MRI techniques use strong magnetic fields and radio frequency signals to generate metabolic, anatomical and functional brain images (fMRI).
Remifentanil is a potent analgesic agent whose analgesic effect has been well characterised in healthy volunteers, including fMRI studies showing modulation of activation of regions in the brain related to pain processing. Nevertheless, the neural correlates of remifentanil effects have not yet been investigated in chronic pain patients.
The aim of this research is to use a combination of multimodal MRI, genetic and psychometric assessments to identify the mechanisms of pain relief in knee OA patients, following treatments with duloxetine and remifentanil, in a placebo controlled condition. With this we also aim to identify genetic, anatomical and brain activity predictors of treatment outcomes.
The main hypotheses are:
- Analgesic response to duloxetine treatment can be predicted using a range of baseline brain imaging markers and QST.
- Analgesic response to duloxetine is mediated by modulation of neural networks underpinning emotional control.
- Duloxetine-induced changes in brain activation differ between responders and non-responders.
This study is expected to last for two years. It is funded by Arthritis Research United Kingdom and forms part of a wider scientific investigation, using translational methodologies, to enhance the understanding of arthritis pain and to improve its treatment.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Radiographically defined OA knee changes with knee pain
- •Must have self-reported knee pain
- •Able to give informed consent
- •Over 35 years old
- •Male or female
- •Females not pregnant or lactating and using effective contraception
Exclusion Criteria
- •People with any known contraindication to MRI like
- •Intraocular metallic foreign bodies;
- •Intracranial aneurysm clips;
- •Cardiac pacemakers and defibrillators;
- •Cochlear implants;
- •People with a significant head tremor;
- •People with potential metal foreign bodies due to previous accidents;
- •Breastfeeding or pregnancy, confirmed by pregnancy test;
- •People that are felt to be unfit for the MRI scan according to the judgement of medically qualified personnel, either on the research team, or the patient's clinical team. (eg. due to back pain, claustrophobia, acute sickness etc.) This includes patients with signs of impaired temperature regulation such as an extremely high fever;
- •Patients with large tattoos, specifically in the head, neck or shoulder region;
Arms & Interventions
Duloxetine
Duloxetine 30 mg a day (2 weeks), then 60 mg a day (4weeks), taken by mouth
Intervention: Duloxetine
Placebo (for Duloxetine)
Sugar pill: 1 capsule a day (2 weeks), then 2 capsules a day (4 weeks) taken by mouth
Intervention: Placebo (for Duloxetine)
Remifentanil
Intravenous infusion with maximum estimated plasma target of 1.0 ng/ml, during less than 20 minutes
Intervention: Remifentanil
Placebo (for Remifentanil)
Intravenous infusion of normal saline, during less than 20 min
Intervention: Placebo (for Remifentanil)
Outcomes
Primary Outcomes
Reduction in nociceptive brain response after duloxetine
Time Frame: Baseline, week six
Neural network change (resting condition) induced by duloxetine
Time Frame: Baseline, week six
Predicting response to duloxetine from baseline fMRI metrics using univariate and multivariate analysis
Time Frame: Baseline, week six
Differences in brain response and network change between responders and non-responders
Time Frame: Baseline, week six
Secondary Outcomes
- Correlation between baseline CPM and TS with brain activity and connectivity changes(Baseline, week six)
- Identification of QST and questionnaire parameters that predict response to duloxetine(Baseline, week six)
- Group differences in brain activity and structure in pain processing, limbic and modulatory pathways changes following duloxetine treatment in comparison to placebo(Baseline, week six)