Chronic PainNCT05003323
Brain Biomarker of Endogenous Analgesia in Patients With Chronic Knee Pain
An observational study of Chronic Pain and Chronic Knee Pain, run by University of Pittsburgh at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 45 to 80 yearsHealthy volunteers can take part
- Conditions the study is for
- Chronic Pain, Chronic Knee Pain, Knee Osteoarthritis
- How many people
- 110 participants
- Where
- 1 siteUnited States
- Study dates
- 18 Nov 2021to 20 Oct 2023
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 45 to 80 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: Participants will be recruited from the Pitt+Me registry which comprises of any members of the local population who are registered in the program.
Who may be able to join
- 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.
Who cannot join
- 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
Show all 16Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
UPMC Pain Medicine at Centre Commons
Pittsburgh, Pennsylvania, 15206
About this study
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.
Read the detailed description
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.
- Conditions
- Chronic Pain, Chronic Knee Pain, Knee Osteoarthritis, Analgesia
- Medical subject headings
- Chronic Pain, Osteoarthritis, Knee, Agnosia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| High Knee Pain with Osteoarthritis | Adults 45-80 years old who have moderately severe knee osteoarthritis and rate their daily knee pain at >=6 on a 0-10 numeric rating scale | |
| Low Knee Pain with Osteoarthritis | Adults 45-80 who have moderately severe knee osteoarthritis and rate their daily knee pain at <=5 on a 0-10 numeric rating scale | |
| Healthy Controls | Age matched, BMI matched adults who do not have knee osteoarthritis or chronic pain |
What is being measured
The primary outcome is the main question the study is designed to answer.
Differences in offset analgesia
Pain intensity difference during offset and control heat stimuli
Measured: 15 minutes
Differences in brain region activation- QST
Difference in brain region activation (as measured by oxygenated hemoglobin, HbO) between CNS inhibition and control stimuli during QST procedures.
Measured: 2-3 hours
Differences in brain region activation- walking test
Change in brain region activation (HbO) between rest and ambulation during the 6 minute walking test test
Measured: 15 minutes
Differences in brain region activation- stair climbing
Change in brain region activation (HbO) between rest and ambulation during the stair climbing test
Measured: 15 minutes
Secondary outcomes (19)
Differences in resting fNIRS signaling
Differences in fNIRS resting state connectivity as measured by brain region activation
Measured: 5-10 minutes
QST battery responses
Differences in responses to QST to characterize threshold and tolerance to cutaneous thermal and mechanical stimuli
Measured: 2-3 hours
Pain intensity scores after stair climbing task
Verbal score from 0-100 on numeric rating scale (NRS) of pain following stair climbing task. Higher NRS scores indicate higher pain intensity.
Measured: 10 minutes
Pain intensity scores after walking test
Verbal score from 0-100 on NRS of pain following 6 minute walking task. Higher NRS scores indicate higher pain intensity.
Measured: 6 minutes
Duration of stair climbing task
Differences in time taken to complete stair climbing task
Measured: 10 minutes
Distance walked during 6 minute walking task
Differences in distance walked during 6 minute walking task
Measured: 6 minutes
Questionnaire score- PROMIS 29
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.
Measured: 1 hour
Questionnaire score- Knee Injury and Osteoarthritis Outcome Score (KOOS)
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.
Measured: 1 hour
Questionnaire score- State Trait Anxiety Inventory (STAI) Y1-2
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.
Measured: 1 hour
Questionnaire score- Pain Catastrophizing Scale (PCS)
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.
Measured: 1 hour
Questionnaire score- STAI Y1 post testing
Standardized survey score of state trait anxiety inventory Y1 assessing anxiety immediately after QST procedures. Higher scores indicate worse anxiety state.
Measured: 1 hour
Questionnaire score- Situational Pain Catastrophizing Scale post testing
Standardized survey score assessing pain perception immediately after QST procedures are completed.
Scores range from 0-24, with higher scores representing more pain catastrophizing.
Measured: 1 hour
Questionnaire score- Situational Pain Catastrophizing Scale post mobility tasks
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.
Measured: 1 hour
Questionnaire score- Beck Depression Inventory-II (BDI-II)
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.
Measured: 1 hour
Questionnaire score- Generalized Anxiety Disorder 2-item (GAD-2)
Standardized survey score of GAD-2 assessing anxiety. Scores range from 0-6. Higher scores indicate higher likelihood of having GAD.
Measured: 1 hour
Questionnaire score- Barratt Impulsiveness Scale-11
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.
Measured: 1 hour
Questionnaire score- Barratt Simplified Measure of Social Status
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.
Measured: 1 hour
Questionnaire score- Patient Health Questionnaire 2 (PHQ-2)
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.
Measured: 1 hour
Questionnaire score- Fibromyalgia Severity Scale
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.
Measured: 1 hour
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Aug 2021
- Study start18 Nov 2021
- Primary completion20 Oct 2023
- Study completion20 Oct 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Chronic PainStudies of the same condition, open and under way.
- More trials run by University of PittsburghThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 110 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Pittsburgh
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Benedict Alter, University of Pittsburgh
- Investigators
- Benedict Alter, MD, PhD, Principal investigator, University of Pittsburgh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05003323
- Sponsor's protocol ID
- STUDY20060254
- Status last verified
- Jan 2025
- First submitted
- 6 Aug 2021
- Last updated
- 13 Jan 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Alter BJ, Maurer M, O'Connell B, Sanchez AG, Kaynar AM, DiGioia AM, Huppert T, Wasan AD. Deficits in temporal pain inhibition are associated with greater pain and functional impairment in osteoarthritis. Pain. 2025 Nov 1;166(11):2490-2509. doi: 10.1097/j.pain.0000000000003648. Epub 2025 Jun 19.
PubMed 40539481
Study at a glance
From the registry record, last updated by the sponsor on 13 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Brain Biomarker of Endogenous Analgesia in Patients With Chronic Knee Pain
- ClinicalTrials.gov ID
- NCT05003323
- Acronym / sponsor ID
- STUDY20060254
- Conditions
- Chronic Pain, Chronic Knee Pain, Knee Osteoarthritis, Analgesia
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 110 participants (actual)
- Lead sponsor
- University of PittsburghUniversity, hospital or other
- Study start
- 18 Nov 2021 (actual)
- Primary completion
- 20 Oct 2023 (actual)
- Study completion
- 20 Oct 2023 (actual)
- First posted
- 12 Aug 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| High Knee Pain with Osteoarthritis | – | –Adults 45-80 years old who have moderately severe knee osteoarthritis and rate their daily knee pain at >=6 on a 0-10 numeric rating scale |
| Low Knee Pain with Osteoarthritis | – | –Adults 45-80 who have moderately severe knee osteoarthritis and rate their daily knee pain at <=5 on a 0-10 numeric rating scale |
| Healthy Controls | – | –Age matched, BMI matched adults who do not have knee osteoarthritis or chronic pain |
Who may qualify
- Ages
- 45 to 80 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- Participants will be recruited from the Pitt+Me registry which comprises of any members of the local population who are registered in the program.
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (16 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Differences in offset analgesia
Time frame: 15 minutes
Pain intensity difference during offset and control heat stimuli
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.
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
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
19 secondary outcomes
Differences in resting fNIRS signaling
Time frame: 5-10 minutes
QST battery responses
Time frame: 2-3 hours
Pain intensity scores after stair climbing task
Time frame: 10 minutes
Pain intensity scores after walking test
Time frame: 6 minutes
Duration of stair climbing task
Time frame: 10 minutes
Distance walked during 6 minute walking task
Time frame: 6 minutes
Questionnaire score- PROMIS 29
Time frame: 1 hour
Questionnaire score- Knee Injury and Osteoarthritis Outcome Score (KOOS)
Time frame: 1 hour
Questionnaire score- State Trait Anxiety Inventory (STAI) Y1-2
Time frame: 1 hour
Questionnaire score- Pain Catastrophizing Scale (PCS)
Time frame: 1 hour
Questionnaire score- STAI Y1 post testing
Time frame: 1 hour
Questionnaire score- Situational Pain Catastrophizing Scale post testing
Time frame: 1 hour
Questionnaire score- Situational Pain Catastrophizing Scale post mobility tasks
Time frame: 1 hour
Questionnaire score- Beck Depression Inventory-II (BDI-II)
Time frame: 1 hour
Questionnaire score- Generalized Anxiety Disorder 2-item (GAD-2)
Time frame: 1 hour
Questionnaire score- Barratt Impulsiveness Scale-11
Time frame: 1 hour
Questionnaire score- Barratt Simplified Measure of Social Status
Time frame: 1 hour
Questionnaire score- Patient Health Questionnaire 2 (PHQ-2)
Time frame: 1 hour
Questionnaire score- Fibromyalgia Severity Scale
Time frame: 1 hour
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jan 2025.
- Derived from this study: PubMed 40539481Alter BJ, Maurer M, O'Connell B, Sanchez AG, Kaynar AM, DiGioia AM, Huppert T, Wasan AD. Deficits in temporal pain inhibition are associated with greater pain and functional impairment in osteoarthritis. Pain. 2025 Nov 1;166(11):2490-2509. doi: 10.1097/j.pain.0000000000003648. Epub 2025 Jun 19.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Benedict Alter, MD, PhD principal investigator
University of Pittsburgh
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Chronic Pain and Chronic Knee Pain, run by University of Pittsburgh at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Differences in offset analgesia (time frame: 15 minutes). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05003323, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jan 2025.