Research at MPR

UM PIs: Chad Brummett, MD; Andrew Chang, MD; Jennifer Waljee, MD, MS, MPH; Daniel Clauw, MD

MCC2 Site PIs: Kumari Adams; Lara Zador; Todd Mulderink; Tanja Jovanovic

Funding: National Institutes of Health (NIH) - $11,040,608

Timeline: August 2020 - May 2026

Website:  https://a2cps.org/

Description: The A2CPS Study is a multisite project that collects data from patients for up to 6 months after surgery with baseline and 3-month collection of multiple psychosocial, imaging, “omics”, quantitative sensory testing (QST), physical function, and pain variables.The goal is to develop a set of biomarkers or “signatures” that can predict whether a patient will transition from acute to chronic pain or be resilient. This will allow researchers to develop more individualized treatments for patients and better understand the biological bases of pain. The University of Michigan is part of MCC2 (Multisite Clinical Center 2) along with Corewell Heath, Trinity Health, Henry Ford, and Wayne State University. 

Other sites included: 

• MCC1 (Multisite Clinical Center 1) includes Rush Medical Center, University of Chicago, University of Illinois – Chicago, and NorthShore Health System
• CCC (Clinical Coordinating Center) located at University of Iowa
• DIRC (Data Integration Resource Center) includes Johns Hopkins University, Texas Advanced Computing Center, and Dartmouth University.
• ODGC (Omics Data Generation Centers) includes University of California San Diego, Wake Forest University, and Pacific Northwest National Laboratory. 

PIs: Chad Brummett, MD; Andrew Chang, MD; Jennifer Waljee MD, MS, MPH

Funding: National Institutes of Health (NIH) - $580,395

Timeline: August 2022 - July 2025

Description: Increasing the racial/ethnic diversity of participants in clinical pain research and including diverse partners in the design and conduct of research are intertwined goals that are essential to increasing the acceptability, feasibility, rigor, and relevance of pain research. This proposed administrative supplement to the parent Multisite Clinical Center (MCC) for the Acute to Chronic Pain Signatures Program (A2CPS) at the University of Michigan will support a robust effort to enhance patient and other community engagement, particularly that of underrepresented minorities, and to implement a sustained outreach effort to under-resourced Black and Hispanic communities in and around Detroit, Michigan. 

We plan to do this by: 

1. Hiring a Community Research Facilitator (CRF),
2. Partnering with the Community Advisory Board (CAB) for Clinical Research in Chronic Pain,
3. Hiring additional research coordinators at our Detroit sites, and
4. Having staff with direct patient contact complete the Faster Together Coursera training course.

PI: Mark Bicket, MD, PhD

External PIs: Karim Ladha, MD

Funding: Patient-Centered Outcomes Research Institute (PCORI) - $4,003,429

Timeline: April 2022 - April 2028

Website: https://www.caresstudy.com/

Description:

The Comparing Analgesic Regimen Effectiveness and Safety for Surgery (CARES) is a pragmatic randomized clinical trial designed to compare the effectiveness at 6 months of two clinically-relevant analgesic prescribing strategies to treat acute pain after discharge from low-risk surgery. Rather than comparing simple uniform treatments, this study will compare two flexible prescribing regimens that can each be tailored to individual patient preferences and responses. 

Patients will be assigned to either 

1. NSAID, which emphasizes one NSAID taken with acetaminophen, or
2. OPIOID, which emphasizes the use of opioid analgesics taken with acetaminophen.CARES will randomize 900 adults undergoing one of three common low-risk surgical procedures, laparoscopic cholecystectomy, inguinal hernia repair, and breast lumpectomy, to either the NSAID or OPIOID arm. 

The intervention structure and data collection protocol will be the same for both arms; only the prescribing assignment will differ between them.

PI: Chad Brummett, MD

Funding: Precision Health 

Timeline: 2012 - Ongoing

Description:

The Michigan Genomics Initiative (MGI) is a collaborative research effort among physicians and researchers at the University of Michigan with the goal of harmonizing patient electronic medical records with genetic data to gain novel biomedical insights. Current participation involves filling out a short questionnaire and providing a small blood sample. Genetic material (DNA) is extracted from part of the aliquoted blood and sequenced. The rest of the blood sample is stored securely at the University of Michigan. Patients consent to be contacted in the future for any applicable study conducted through the University of Michigan’s Central Biorepository.

PI: Chad Brummett, MD

External PI: Frances Williams, PhD FRCP(E)

Funding: Investigator Initiated

Timeline: September 2022 - June 2025

Description: 

Participants enrolled in the Michigan Genomics Initiative or the Analgesic Outcome Study with lumbar MR imaging of the spine will be included. T2 weighted images will be used. Relevant phenotypes will be extracted using both a modified version of SpineNetV2, automated computer-vision software, and a study team-developed model for (i) detecting and labeling vertebrae in clinical spinal MRIs and (ii) radiologically grading intervertebral discs detected during the previous stage for a range of common radiological conditions. In addition to disc degeneration phenotypes outlined, the application of a radiomic phenotype currently being developed and validated on Northern Finland Birth Cohort and Twins UK data will be considered for further analysis. This "radiomic" phenotype will be based on shape, histogram, and texture (radiomic) imaging features extracted from sagittal T2-weighted MRI sequences.

This study will represent a significant advance in our understanding of the genetics of LDD, about which there are scant data at present. However, many additional opportunities should follow.

PI: Mark Bicket, MD, PhD

External PI: Lorraine Kelley-Quon, MD, MSHS

Funding: Patient-Centered Outcomes Research Institute (PCORI) - $7,027,353

Timeline: 4/1/2024-6/30/2029

Website: https://www.cares4kids.org/

Description:

CARES for Kids is a multicenter, patient-level, parallel group, pragmatic, comparative effectiveness, randomized trial evaluating the superiority of NSAIDs vs. opioids in adolescent and young adult patients undergoing very common surgical procedures that have low risk of major medical or surgical complications. We will be enrolling 900 patients aged 12 to 20 years undergoing one of three elective procedures, which include tonsil removal (tonsillectomy), gallbladder removal (laparoscopic cholecystectomy) and knee scope (arthroscopy). Patients will be assigned to either 1) NSAID, which emphasizes one NSAID taken with acetaminophen, or 2) OPIOID, which emphasizes the use of one opioid analgesic taken with acetaminophen and NSAIDs. The intervention structure and data collection protocol will be the same for both arms; only the prescribing strategy assignment will differ between the two groups.

PIs: Chad Brummett, MD; Kevin Boehnke, PhD

External PI: Joel Gagnier, PhD

Funding: National Institutes of Health - National Institute of Arthritis and Musculoskeletal and Skin Diseases

Timeline: September 2023-August 2028

Description:

Cannabidiol for postoperative Opioid Reduction in primary total Knee arthroplasty (The CORK trial) is a multi-center, randomized, 2x2 factorial, double-blind, placebo-controlled clinical trial of cannabidiol (CBD) in adult patients undergoing primary total knee arthroplasty. Eligible participants will be randomized with equivalent probability to (1) pre- and post-operative CBD, (2) pre-operative placebo + post-operative CBD, (3) pre-operative CBD + post-operative placebo, or (4) pre- and post-operative placebo.  Our overarching hypothesis is that CBD exerts opioid-sparing effects through anti-inflammatory, analgesic, and anxiolytic mechanisms.

PI: Chad Brummett, MD

Years of funding: 2012 - ongoing

Number of patients to be recruited: No target number

Study goals/aims: The Michigan Genomics Initiative (MGI) is a collaborative research effort among physicians and researchers at the University of Michigan with the goal of harmonizing patient electronic medical records with genetic data to gain novel biomedical insights. Current participation involves filling out a short questionnaire and giving a small blood sample. DNA is extracted from part of the aliquoted blood and genetically sequenced. The rest of the blood sample is stored securely at U-M. Patients consent to be contacted in the future for any applicable study conducted through U-M’s Central Biorepository.

Inclusion/Exclusion criteria: Currently, all patients 18 years of age or older undergoing surgery at the University of Michigan Health System are potentially eligible for participation in MGI.

PI: Chad Brummett, MD

Years of funding: 2010 – ongoing

Number of patients to be recruited: No target number.

Study goals/aims: AOS is a prospective, observational survey study of pain, mood, functional, and health outcomes.

Inclusion/Exclusion criteria: Currently, all patients 18 years of age or older undergoing ACL repair, ankle surgery, knee arthroscopy, shoulder surgery, total knee arthroplasty, total hip arthroplasty, distal arm and hand surgery, breast surgery, hysterectomy, inguinal hernia repair, myomectomy, prostatectomy, or thoracic surgery.

PI: Daniel Clauw, MD; Chad Brummett, MD

Years of funding: 5 years

Number of patients to be recruited: 800 participants: There will be 200 participants in each treatment (OA, RA, CTS) condition, 100 FM patients, 100 healthy controls.

Study goals/aims: To better understand factors that influence health and pain. This can ultimately lead to better recommendations for more effective treatments based on an individual’s unique characteristics.

Aim 1 - To demonstrate that the current 2011 FM Survey Criteria predict non-responsiveness to peripherally-directed therapies, including:

a) surgery intended to relieve pain (hip arthroplasty, carpal tunnel release),

b) administration of a biologic agent to treat an autoimmune disorder (RA), and

c) acute and sub-acute administration of opioids (given to relieve pain immediately following hip arthroplasty and carpal tunnel release). 

Aim 2 - To demonstrate that in all three cohorts, individuals with the highest FM Survey Criteria scores will have the most pronounced neurobiological findings associated with pain centralization, including abnormal QST findings and aberrant findings on functional, chemical and structural neuroimaging.

Aim 3 - To use the data from the above aims as well as other ongoing studies to develop and pilot test a more efficient and predictive self-report measure of centralization than the 2011 FM Survey Criteria, which we will refer to as the Centralized Pain Index (CPI). 

Aim 4 - To explore the clinical and mechanistic features of two important subsets of centralized pain: top-down activity-independent centralization (i.e. previously termed primary FM) vs. bottom-up activity-dependent pain centralization or central sensitization (i.e. previously termed secondary FM).

Inclusion/Exclusion criteria*:

The subjects will be drawn from patients over the age of 21, who are scheduled for one of three treatments: total hip arthroplasty, carpal tunnel release, or administration of a biologic for rheumatoid arthritis (RA).

Include:

• Ability to read and speak English to allow for written informed consent, phenotyping, and patient
  • reported outcomes measures;
• Willingness to participate in longitudinal follow-up (questionnaires and outcomes measures) for 6- months after their treatment (Osteoarthritis (OA), Rheumatoid arthritis (RA), and Carpal tunnel syndrome (CTS) cohorts only).

Exclude:

• Inability to provide written informed consent;
• Severe physical impairment (e.g., blindness, deafness, paraplegia);
• Co-morbid medical conditions that may significantly impair physical functional status (e.g., history of non-skin malignancy, or autoimmune disorder [except the RA cohort]) (and precludes operative treatment for CTS cohort);
• Illicit drug or unreported opioid use (unreported opioid use would be considered opioid misuse or abuse and thereby exclusionary);
• Medical or psychiatric conditions that in the judgment of study personnel would preclude participation in this study (e.g., malignancy, psychosis, suicidal ideation; note that stable anxiety and depression are NOT exclusions);
• Pregnant;
• Liver failure (and precludes operative treatment for CTS cohort);
• Self-reported liver cirrhosis (and precludes operative treatment for CTS cohort);
• Self-reported hepatitis (and precludes operative treatment for CTS cohort);
• Uncontrolled diabetes (and precludes operative treatment for CTS cohort);
• Severe Cardiovascular disease (examples: history of myocardial infarction, unstable angina, severe coronary artery disease, congestive heart failure, or severe valvular abnormalities) that is self-reported by patient or by medical record (and precludes operative treatment for CTS cohort);
• Average daily opioid dosing of >15 mg oral morphine equivalents preoperatively (e.g., > two 5 mg oxycodone tablets/day or > three 5 mg hydrocodone tablets/day). Conversions will be made based on well-accepted conversion tools we have used previously.^3,4

*There are additional Inclusion and Exclusion Criteria for different cohorts

PI: Daniel Clauw, MD; Chad Brummett, MD

Years of funding: 5 years

Number of patients to be recruited: 200 (60 will undergo additional phenotyping and imaging)

Study goals/aims: We propose to superimpose research staff onto the clinical setting to record pain scores and standardize opioid administration to determine if FMness leads to increased pain, decreased opioid responsiveness to the same amount of pain, or both.  We will also perform a prospective neuroimaging study on subsets of these individuals undergoing surgery to determine the degree to which fMRI and PET imaging studies described above can predict subsequent opioid responsiveness.

Aim 1 - Demonstrate that the baseline fibromyalgia survey score (FMness) predicts opioid responsiveness in the postoperative period in individuals with knee OA undergoing arthroplasty. 

Aim 2 - Perform fMRI and PET with a µ-opioid receptor ligand prior to knee arthroplasty in a subset of Aim 1 (n = 60) patients selected to span the entire continuum of FMness to: a) predict opioid responsiveness during surgery, and b) validate that self-report FMness is closely related to fMRI evidence of measures of centralized pain (connectivity changes and hyperalgesia) as well as endogenous opioid functional measures as measured with PET. 

Inclusion/Exclusion criteria:

Subjects will be drawn from patients over the age of 18 who are scheduled for primary unilateral total knee arthroplasty (TKA) at the University of Michigan. The inclusion criteria for Aims 1 and 2 will be similar, with additional exclusions for TKA (Aim 1) patients participating in the Aim 2 imaging studies.

Include - Non-Imaging (Aim 1)

• Total knee arthroplasty (TKA) patients enrolled in the Analgesic Outcome Study II (HUM#00106315)

Exclude – Non-Imaging (Aim 1)

• Taking opioids (narcotic pain medications, e.g. hydrocodone, Vicodin, Norco, morphine, methadone, fentanyl) chronically in the 3 months prior to the study visit, defined as daily use
• Any opioid (narcotic) use within 4 weeks of the first study visit
• Individuals receiving or applying for compensation or disability
• Inability to provide written informed consent
• Severe physical impairment (e.g. blindness, deafness, paraplegia)
• Co-morbid medical conditions that may significantly impair physical functional status (e.g., history of non-skin malignancy)
• Known lumbar spinal stenosis (challenges/risks in performing neuraxial anesthesia)
• Illicit drug or unreported opioid use
• Medical or psychiatric conditions that in the judgment of study personnel would preclude participation in this study
• Planned admission to an extended care facility or rehabilitation facility.

Include - Imaging (Aim 2)

• Total knee arthroplasty (TKA) patients enrolled in the Analgesic Outcome Study II (HUM#00106315)
• Patients over 18 but less than 76 years old (to mitigate against vascular disease leading to functional imaging abnormalities in elderly)
• Right handed
• Non-smokers (nicotine affects PET results)
• Not taking narcotic (opioid) pain medications for at least 4 weeks before the first scheduled study visit and have not taken them daily in the last 3 months  No contraindications to fMRI (e.g. metal implants) or PET (e.g. exceeding allowed radiation exposure from other procedures).
• Willingness to refrain from NSAIDs and acetaminophen pain medications for 12 hours prior to dense phenotyping
• Willingness to refrain from physical activity or exercise that would cause muscle and/or joint soreness for 48 hours prior to dense phenotyping (routine exercise or activity that does not lead to soreness is acceptable)
• Able to lie still on your back for 4-5 hours for PET scan.
• Fibromyalgia survey score- in order to address the underlying hypothesis, potential participants will complete the fibromyalgia survey criteria (1-page measure, approximately 2-3 min) after they discuss surgery.  The questionnaire will be administered by the treating surgeon and or study staff and collected by the research team.   We will recruit enough patients to satisfy the spectrum of fibromyalgia scores in four quartiles based on our previously existing data.  Once a quartile is filled (e.g. 15 patients enrolled), then we will not include more people from that quartile.

Exclude - Imaging (Aim 2)

• Taking opioids (narcotic pain medications, e.g. hydrocodone, Vicodin, Norco, morphine, methadone, fentanyl) chronically in the 3 months prior to your study visit, defined as daily use
• Any opioid (narcotic) use within 4 weeks of the first study visit
• Individuals receiving or applying for compensation or disability
• Inability to provide written informed consent
• Severe physical impairment (e.g. blindness, deafness, paraplegia)
• Co-morbid medical conditions that may significantly impair physical functional status (e.g., history of non-skin malignancy)
• Known lumbar spinal stenosis (challenges/risks in performing neuraxial anesthesia)
• Illicit drug or unreported opioid use
• Medical or psychiatric conditions that in the judgment of study personnel would preclude participation in this study
• Planned admission to an extended care facility or rehabilitation facility.
• Subjects will be excluded from undergoing an PET scan if they would receive a total of over 5 rad to a radiosensitive organ (bone marrow, gonads, lens of the eye) or 15 rad to any other organ or to the body as a whole during a 12 month period by participating in research studies, or who are receiving medications which interfere with the study radiopharmaceuticals.
• Liver failure
• Self-reported liver cirrhosis
• Self-reported hepatitis
• Severe Cardiovascular disease (examples: hx of myocardial infarction, unstable angina, severe coronary artery disease, congestive heart failure, or severe valvular abnormalities) that are self-reported by patient or by medical record.
• Positive urine drug screen for nicotine, opioids or cannabis. Participants who test positive at screening will be allowed to rescreen after washout.
• Positive pregnancy screen or nursing during recruitment
• Current, recent (within the last 6 months), or habitual use of artificial nails or nail enhancements
• Any impairment, activity or situation that in the judgement of the Principal Investigator would prevent satisfactory completion of the study
• Known severe peripheral vascular disease (self-reported)
• Known peripheral neuropathy (self-reported)
• For the visual stimulation portion of the protocol only: history of seizures or migraines.

PI: Sawsan As-Sanie, MD; Daniel Clauw, MD

Years of funding: 5 years (6/1/17-2/28/22)

Number of patients to be recruited: 500 women

Study goals/aims: Our long-term goal is to build a quantitative understanding of how peripheral and central nervous system factors independently contribute and interact to determine whether a woman will experience chronic pelvic pain (CPP), how severe that pain will be, and which women will respond to what treatments. This prospective observational study will recruit women who are scheduled to undergo hysterectomy.

Aim 1 - Demonstrate that preoperative markers of central sensitization independently predict a higher likelihood of persistent pelvic pain 12-months following hysterectomy. 

Aim 2 - Demonstrate that preoperative markers indicative of peripheral sensitization independently predict a lower likelihood of persistent pelvic pain following hysterectomy.

Aim 3 - Develop an exploratory predictive model using measures of central (Aim 1) and peripheral sensitization (Aim 2), as well as additional anatomic factors (e.g. severity of anatomic pathology including endometriosis, adhesions; surgical approach), and psychosocial factors (depression, anxiety, catastrophizing, social support) to estimate the likelihood of persistent pelvic pain 12-months following hysterectomy.

Inclusion/Exclusion criteria*^, **:

Include (for all subjects):

• Female scheduled for hysterectomy for benign (non-cancer) indication
• Over 21 and under 70 years of age
• Ability to read and speak English to allow for written informed consent, phenotyping, and patient reported outcome measurements

Exclude (for all subjects):

• Any chronic medical condition, psychiatric condition, or use of any medications that in the judgment of the PI would make the individual inappropriate for entry into this study or interfere with the interpretation of results. These will be considered positive if by self-report or in the medical record.  (Note: Healthy controls may not have a history of persistent or recurrent mood disorder.  However, CPP subjects with mood disorders such as depression or anxiety will not be excluded).
• Medical conditions that may significantly delay or interfere with postoperative recovery, or would make it unsafe for participants to take part in the study, including but not limited to: uncontrolled autoimmune/inflammatory diseases, cardiovascular or pulmonary disorders (e.g., angina, congestive heart failure, severe valvular abnormalities, COPD, chronic asthma), renal or liver disease, uncontrolled endocrine or allergic disorders (e.g., hypothyroidism, diabetes, allergic rhinitis), neurologic conditions (e.g., multiple sclerosis, prior stroke, neurological tumor, peripheral neuropathy), and malignancy (any malignancy except for localized cancers, such as treated thyroid cancer, dermatologic cancer).
• Additional major surgery which is known to significantly increase postoperative pain, morbidity, and/or recovery time planned at time of hysterectomy, such as bowel resection, orthopedic, or major breast procedure (e.g. mastectomy). Concurrent uterovaginal prolapse or incontinence procedures will be permit-ted.
• Concurrent participation in other therapeutic trials
• Pregnant and or lactating
• History of illegal drug use or substance abuse within past two years
• Any impairment, activity or situation that in the judgment of the Study Coordinator or Principal Investigator would prevent satisfactory completion of the study protocol.

*There are additional inclusion criteria for different cohorts

**Based on eligibility and interest in participation, each participant will be enrolled in either the “Survey-only” portion of the study, versus the “Full-study protocol”.

PI: Chad Brummett, MD

Years of funding:  3 years

Number of patients to be recruited: 1400 participants will be recruited from Michigan recruitment sites.

MCC2 (Multisite Clinical Center 2) includes University of Michigan, Henry Ford, St. Joseph Ann Arbor, Beaumont, Wayne State University, and Spectrum Health. These sites will recruit 1400 patients having thoracic surgery.

Other institutions involved:

CCC (Clinical Coordinating Center) located at University of Iowa

DIRC (Data Integration Resource Center) includes Johns Hopkins University, Texas Advanced Computing Center, and Dartmouth University.

ODGC (Omics Data Generation Centers) includes University of California San Diego, Wake Forrest University, and Pacific Northwest National Laboratory.

MCC1 (Multisite Clinical Center 1) includes Rush Medical Center, University of Chicago, University of Illinois – Chicago, and NorthShore Health System. These sites will recruit 1800 patients having knee replacement surgery 

Study goals/aims: A2CPS will collect data from patients for up to 6 months after surgery. The goal is to develop a set of biomarkers or “signatures” that can predict whether a patient will transition from acute to chronic pain or be resilient. This will allow researchers to develop more individualized treatments for patients and better understand the biological bases of pain.

Aim 1 – Will use a candidate approach to examine whether putative biomarkers across multiple domains (clinical, biospecimen, psychosocial, and brain structure/function) individually predict susceptibility or resilience to the development of chronic pain 6 months after surgery.

Aim 2 – Will develop biosignatures using primary biomarkers to determine if combinations of biomarkers improve the prediction from acute to chronic pain after surgery.

Aim 3 – Will use a discover-validation approach to define novel putative biomarkers and biosignatures across multiple domains (clinical, biospecimen, psychosocial, and brain structure/function) that predict the susceptibility and resilience to development of chronic pain at 6 months post-surgery.

Inclusion/Exclusion criteria

Knee replacement cohort:

Include:

• Provision of signed and dated informed consent
• Willing to comply with all study procedures and availability for the duration of the study
• Male or female aged 18 to <85
• Individuals diagnosed with knee osteoarthritis scheduled to undergo a single primary partial or total knee replacement, conversion of a partial knee replacement, or a revision of a total knee replacement. All surgical approaches will be included for the study including robotic controlled and muscle sparing techniques.

Exclude:

• Patients undergoing surgery for an inflammatory arthritic condition such a rheumatoid arthritis or osteonecrosis
• Patients undergoing revision surgery with an infectious diagnosis involving the joint to be replaced (this will be a 2-staged procedure)
• Patients undergoing bilateral knee replacements, planned staged bilateral knee replacements within 3 months of each other, or are within 3 months of a prior contralateral knee replacement
• Patients with known contra-indications to magnetic resonance imaging (MRI)

Thoracotomy cohort:

Include:

• Provision of signed and dated informed consent
• Willing to comply with all study procedures and availability for the duration of the study
• Male or female aged 18 to <85
• Individuals scheduled for surgery using a thoracic approach at any of the participating hospitals

Exclude:

• Patients with known contra-indications to magnetic resonance imaging (MRI)
• Patients who have undergone prior thoracic surgery within 3 months
• Patients undergoing a bilateral thoracic procedure
• Patients undergoing another planned major surgery within the 6-month follow-up period

PI: Mark Bicket, MD, PhD

Years of funding: NA

Number of patients to be recruited: 250 subjects between two standard of care groups – prescription group and over-the-counter group.

Study goals/aims: PROTECT is a quality improvement and survey project with the goal of evaluating the difference in self-reported consumption of acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) from prescribing vs. recommending over-the-counter medication use to treat pain over 14 days following discharge from elective outpatient surgery.

Inclusion/Exclusion criteria:

Include:

• Male and female patients 18 years of age and older
• Anticipated to be prescribed and use an opioid medication to treat acute pain after elective outpatient surgery

Exclude:

• Male and female patients younger than 18 years of age
• Contraindications to taking acetaminophen or NSAIDs
• No significant analgesic medication use before surgery
• Inability to receive emails or phone calls for follow up assessment