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NCT Number: NCT05003323

Brain Biomarker of Endogenous Analgesia in Patients With Chronic Knee Pain

This case-control study in patients with knee osteoarthritis and pain-free control individuals aims to develop a brain biomarker of endogenous analgesia that may be used in subsequent clinical trials. Deficits in central nervous system (CNS) pain inhibition may contribute to chronic pain intensity, but quantitative sensory testing (QST) methods are limited. Incorporating brain imaging to assessments of CNS pain inhibition, by examining activity in relevant brain networks, would allow for an objective, physiologic measure of CNS pain inhibition. Preliminary data in pain-free volunteers implicate cortical activity measured with functional near-infrared spectroscopy (fNIRS) during CNS pain inhibition. Broadly, the investigators hypothesize that variability in CNS pain inhibition contributes to variability in clinical pain intensity.

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Key information

Conditions

Chronic Pain Agnosia Analgesia Arthritis Chronic Knee Pain Joint Diseases Knee Osteoarthritis Musculoskeletal Diseases Nervous System Diseases Neurobehavioral Manifestations Neurologic Manifestations Osteoarthritis Osteoarthritis, Knee Pain Pathological Conditions, Signs and Symptoms Perceptual Disorders Rheumatic Diseases Signs and Symptoms

Age range

45 year–80 year

Sex eligibility

All sexes

Study type

Observational

Primary location

UPMC Pain Medicine at Centre Commons

Pittsburgh, Pennsylvania, 15206, United States

About this study

The objective of this study is to identify the neural correlates of central nervous system (CNS) pain inhibition in patients with knee osteoarthritis (OA) and determine how the correlates relate to clinical chronic (i.e., greater than 6 months) knee pain. To attain this objective, the investigators will test the following working hypotheses: (H1) in knee OA patients with moderate osteoarthritis but severe knee pain, cortical correlates of CNS pain inhibition are diminished compared to patients with less knee pain and (H2) provocation of clinical knee pain with ambulation produces greater pain-related cortical activation in patients with greater clinical knee pain at baseline. The study will also compare patients with knee OA to a control group to test the hypothesis (H3) that CNS pain inhibition behavioral and functional near-infrared spectroscopy (fNIRS) brain imaging measures are diminished in knee OA. Finally, in exploratory analysis, the investigators hypothesize that cortical functional connectivity is altered in patients with greater knee pain.

The study approach is to measure brain activity in patients with knee osteoarthritis, divided into high pain intensity and low pain intensity groups, and in pain-free controls with fNIRS scanning during rest, quantitative sensory testing (QST) measures of CNS pain inhibition (conditioned pain modulation and offset analgesia), and walking and stair climbing tasks. The rationale is that successful completion of this study will determine whether fNIRS measures relate to QST measures of CNS pain inhibition and clinical pain intensity both at rest and during activity. This fundamental knowledge, in combination with prior studies of conditioned pain modulation (CPM), will be important to understanding how CNS pain inhibition may contribute to a range of chronic pain syndromes.

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • For the knee arthritis groups: Chronic knee pain with evidence of knee osteoarthritis - radiographically grades 2-4
  • Age: 45-80 years old
  • Gender: Males and females will be recruited.
  • Language: only English-speaking subjects will be included.

Exclusion criteria

  • Inflammatory arthritis (e.g. rheumatoid arthritis)
  • Inability to walk and climb stairs unassisted
  • History of knee replacement or open knee surgery
  • History of arthroscopic knee surgery within the last 3 months (>3 months does not exclude participant)
  • History of knee radiofrequency nerve ablation or ligation
  • Current opioid use
  • Current use of antidepressants that are not in the serotonin-selective reuptake inhibitor (SSRI) class. Patients who are currently using an SSRI are allowed to take part in the study
  • Cognitive impairment affecting the ability to provide informed consent, understand directions, and participate in study procedures
  • Uncontrolled or unstable medical disorder preventing participation in study procedures
  • History of brain surgery
  • Tattoos on forearm or knee
  • Pregnancy
  • Patients with chronic pain conditions that are more severe than their knee arthritis pain (e.g., CRPS, fibromyalgia)
  • Patients whose most painful knee is excluded for another reason (e.g., recent surgery on most painful knee)
  • For the pain-free control group: a history of chronic pain
  • History of intra-articular steroid injections, platelet enriched or hyaluronic acid injections in the last 1 month

Treatment and study plan

Primary outcomes

  1. Differences in offset analgesia

    Time frame: 15 minutes

    Pain intensity difference during offset and control heat stimuli

  2. Differences in brain region activation- QST

    Time frame: 2-3 hours

    Difference in brain region activation (as measured by oxygenated hemoglobin, HbO) between CNS inhibition and control stimuli during QST procedures.

  3. Differences in brain region activation- walking test

    Time frame: 15 minutes

    Change in brain region activation (HbO) between rest and ambulation during the 6 minute walking test test

  4. Differences in brain region activation- stair climbing

    Time frame: 15 minutes

    Change in brain region activation (HbO) between rest and ambulation during the stair climbing test

Secondary outcomes

  1. Differences in resting fNIRS signaling

    Time frame: 5-10 minutes

    Differences in fNIRS resting state connectivity as measured by brain region activation

  2. QST battery responses

    Time frame: 2-3 hours

    Differences in responses to QST to characterize threshold and tolerance to cutaneous thermal and mechanical stimuli

  3. Pain intensity scores after stair climbing task

    Time frame: 10 minutes

    Verbal score from 0-100 on numeric rating scale (NRS) of pain following stair climbing task. Higher NRS scores indicate higher pain intensity.

  4. Pain intensity scores after walking test

    Time frame: 6 minutes

    Verbal score from 0-100 on NRS of pain following 6 minute walking task. Higher NRS scores indicate higher pain intensity.

  5. Duration of stair climbing task

    Time frame: 10 minutes

    Differences in time taken to complete stair climbing task

  6. Distance walked during 6 minute walking task

    Time frame: 6 minutes

    Differences in distance walked during 6 minute walking task

  7. Questionnaire score- PROMIS 29

    Time frame: 1 hour

    Standardized survey score of PROMIS-29 assessing physical and mental health. Physical Function Score ranges from 4-20. Anxiety Score ranges from 4-20. Depression Score ranges from 4-20. Fatigue Score ranges from 4-20. Sleep Disturbance Score ranges from 4-20. Social Roles Score ranges from 4-20. Pain Interference Score ranges from 4-20. Pain Intensity Score ranges from 0-10. Higher scores indicate worse mental and physical health.

  8. Questionnaire score- Knee Injury and Osteoarthritis Outcome Score (KOOS)

    Time frame: 1 hour

    Standardized survey called Knee Injury and Osteoarthritis Outcome Score assessing knee pain. Scores range from 0 to 100 with a score of 0 indicating the worst possible knee symptoms and 100 indicating no knee symptoms.

  9. Questionnaire score- State Trait Anxiety Inventory (STAI) Y1-2

    Time frame: 1 hour

    Standardized survey score of state trait anxiety inventory Y1 and Y2 assessing anxiety before QST procedures.

    State Anxiety Score ranges from 20-80. Trait Anxiety Score ranges from 20-80. Higher scores indicate worse anxiety state and trait symptoms.

  10. Questionnaire score- Pain Catastrophizing Scale (PCS)

    Time frame: 1 hour

    Standardized survey score assessing pain perception before QST procedures. Rumination subscale score ranges from 0-16. Magnification subscale score ranges 0-12. Helplessness subscale score ranges from 0-24. Total score can be calculated by summing subscales. Total score ranges from 0-52, with higher scores indicating more pain catastrophizing.

  11. Questionnaire score- STAI Y1 post testing

    Time frame: 1 hour

    Standardized survey score of state trait anxiety inventory Y1 assessing anxiety immediately after QST procedures. Higher scores indicate worse anxiety state.

  12. Questionnaire score- Situational Pain Catastrophizing Scale post testing

    Time frame: 1 hour

    Standardized survey score assessing pain perception immediately after QST procedures are completed.

    Scores range from 0-24, with higher scores representing more pain catastrophizing.

  13. Questionnaire score- Situational Pain Catastrophizing Scale post mobility tasks

    Time frame: 1 hour

    Standardized survey score assessing pain perception immediately after walking and stair climbing tasks are completed.

    Scores range from 0-24, with higher scores representing more pain catastrophizing.

  14. Questionnaire score- Beck Depression Inventory-II (BDI-II)

    Time frame: 1 hour

    Standardized survey assessing depression. Scores range from 0-63. Total score of 0-13 is considered minimal range of depression, 14-19 is mild, 20-28 is moderate, and 29-63 is severe depression.

  15. Questionnaire score- Generalized Anxiety Disorder 2-item (GAD-2)

    Time frame: 1 hour

    Standardized survey score of GAD-2 assessing anxiety. Scores range from 0-6. Higher scores indicate higher likelihood of having GAD.

  16. Questionnaire score- Barratt Impulsiveness Scale-11

    Time frame: 1 hour

    Standardized survey score of Barratt Impulsiveness Scale-11 assessing the personality/behavioral construct of impulsiveness.

    Attention Impulsiveness Score ranges from 8-32. Motor Impulsiveness Score ranges from 11-44. Non-planning Impulsiveness Score ranges from 11-44. Subscale scores can be summed for a total score. Higher scores indicate greater levels of impulsivity.

  17. Questionnaire score- Barratt Simplified Measure of Social Status

    Time frame: 1 hour

    Standardized survey score of Barratt Simplified Measure of Social Status that measures social status based on marital status, employment status, educational attainment, and occupational prestige. Total Education Score ranges from 3-21. Total Occupation Score ranges from 5-45. Total score of education and occupation can be calculated by summing the subscales with a range 8-66. Higher scores indicate a higher social status.

  18. Questionnaire score- Patient Health Questionnaire 2 (PHQ-2)

    Time frame: 1 hour

    The PHQ-2 inquires about the frequency of depressed mood and anhedonia over the past two weeks. The PHQ-2 includes the first two items of the PHQ-9. A PHQ-2 score ranges from 0-6. The authors identified a score of 3 as the optimal cutpoint when using the PHQ-2 to screen for depression.

    If the score is 3 or greater, major depressive disorder is likely.

  19. Questionnaire score- Fibromyalgia Severity Scale

    Time frame: 1 hour

    This questionnaire tests if patients meet the 2016 criteria for fibromyalgia. The symptom severity score ranges from 0-12, with higher scores indicating a higher likelihood of fibromyalgia. Three symptom question items range from 0-3, and these are summed up for the final score (totaling 0-9). Three additional symptom questions have yes or no options. If the patient answers yes, 1 point is added to the final scale.

Sponsors and collaborators

Lead sponsor

University of Pittsburgh

Other

Registry information

Important dates

Study start
2021
Primary completion
2023
Study completion
2023
First posted
Aug 12, 2021
Registry last updated
Jan 13, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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