Imaging Pain Relief in Osteoarthritis

NCT02208778 | Completed Phase 4

• 1 other identifier: 13124
• Study Type: interventional
• Target: 77
• Locations: 1 country
• Sites: 1

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.

Conditions

Osteoarthritis; Chronic Pain

Keywords

Osteoarthritis; Chronic Pain; Pain relief

Outcome Measures

Primary Outcomes (4)

• Reduction in nociceptive brain response after duloxetine

  Baseline, week six

• Neural network change (resting condition) induced by duloxetine

  Baseline, week six

• Predicting response to duloxetine from baseline fMRI metrics using univariate and multivariate analysis

  Baseline, week six

• Differences in brain response and network change between responders and non-responders

  Baseline, week six

Secondary Outcomes (3)

• Identification of QST and questionnaire parameters that predict response to duloxetine

  Baseline, week six

• Correlation between baseline CPM and TS with brain activity and connectivity changes

  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

Other Outcomes (1)

• Determination of gene variations that can be linked with duloxetine treatment response

  Baseline, week six

Study Arms (4)

Duloxetine

EXPERIMENTAL

Duloxetine 30 mg a day (2 weeks), then 60 mg a day (4weeks), taken by mouth

Drug: Duloxetine

Placebo (for Duloxetine)

PLACEBO COMPARATOR

Sugar pill: 1 capsule a day (2 weeks), then 2 capsules a day (4 weeks) taken by mouth

Drug: Placebo (for Duloxetine)

Remifentanil

EXPERIMENTAL

Intravenous infusion with maximum estimated plasma target of 1.0 ng/ml, during less than 20 minutes

Drug: Remifentanil

Placebo (for Remifentanil)

PLACEBO COMPARATOR

Intravenous infusion of normal saline, during less than 20 min

Drug: Placebo (for Remifentanil)

Interventions

Duloxetine DRUG

54 participants will be allocated for duloxetine treatment

Also known as: Cymbalta

Duloxetine

Remifentanil DRUG

27 participants will be allocated to Remifentanil infusion

Also known as: Remifentanil hydrochloride

Remifentanil

Placebo (for Remifentanil) DRUG

Placebo comparator to Remifentanil treatment. 27 participants will be allocated to this arm

Also known as: Sodium chloride, Normal saline

Placebo (for Remifentanil)

Placebo (for Duloxetine) DRUG

Sugar pill manufactured to mimic Duloxetine 30mg. 27 participants will be allocated to this intervention

Also known as: Sugar pill

Placebo (for Duloxetine)

Eligibility Criteria

• Age: 35 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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;
• Persons that do not have the capacity to consent;
• Aged less than 35;
• Major medical, neurological and psychiatric co-morbidities;
• Other significant medical condition;
• Metallic agents embedded within the body (ie. Shrapnel, surgical pins);

Sponsors & Collaborators

• University of Nottingham: lead
• Arthritis Research UK: collaborator

Study Sites (1)

University of Nottingham - School of Medicine - Radiological Sciences

Nottingham, Nottinghamshire, NG7 2UH, United Kingdom

Location

Related Publications (1)

• Reckziegel D, Bailey H, Cottam WJ, Tench CR, Mahajan RP, Walsh DA, Knaggs RD, Auer DP. Imaging pain relief in osteoarthritis (IPRO): protocol of a double-blind randomised controlled mechanistic study assessing pain relief and prediction of duloxetine treatment outcome. BMJ Open. 2017 Jun 26;7(6):e014013. doi: 10.1136/bmjopen-2016-014013.

  PMID: 28652290 DERIVED

MeSH Terms

Conditions

Osteoarthritis; Chronic Pain

Interventions

Duloxetine Hydrochloride; Remifentanil; Sodium Chloride; Saline Solution; Sugars

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thiophenes; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Propionates; Acids, Acyclic; Carboxylic Acids; Piperidines; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations; Carbohydrates

Study Officials

• Dorothee P Auer, PhD

  University of Nottingham

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 4, 2014
• First Posted: August 5, 2014
• Study Start: December 1, 2014
• Primary Completion: June 1, 2016
• Study Completion: June 1, 2016
• Last Updated: November 27, 2017

Record last verified: 2017-05

Locations

GB (1)