Clinical trial NCT04870957: The Back Pain Consortium Research Program Study
Official title: University of Michigan Mechanistic Research Center -The Back Pain Consortium Research Program
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Chronic Low-back Pain
Keywords: Pain
Back Pain
Lead sponsor: University of Michigan
Sponsor class: OTHER
Collaborators: name: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
First posted: 2021-05-04
Enrollment: 494
Sex: ALL
Minimum age (years): 25
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Sequential, multiple assignment, randomized trial (SMART) design
Primary purpose: TREATMENT

Brief summary: This study is being completed to better understand who benefits from different chronic pain treatments and how these treatments work.

This study will include a four week run-in period for all cLBP participants. After completing the PainGuide (online or smart phone accessible website) run-in period, participants will be assessed using either the light or light plus deep phenotyping assessment battery and those who minimal or modest improvement in their pain (based on PGIC) will be randomized to one of four 8-week treatments (mindfulness-based stress reduction (MBSR), physical therapy (PT) and exercise, acupressure self-management, or duloxetine).

In addition, participants will complete study visits including physical exams, complete surveys, provide samples (blood,saliva, etc.), wear an electronic wrist device at certain times, and have Magnetic resonance imaging (MRIs) during the study.

Following one of the 4 treatments (8 weeks) if participants have a certain level of pain (that meets eligibility for more treatment) they will be then randomized to complete one of the 3 treatments that was not already assigned to them.

The study hypothesizes the following:

that this interventional response phenotyping can identify individuals with different underlying mechanisms for their pain who thus respond differentially to evidence-based interventions for chronic lower back pain (cLBP).

Detailed description: In addition, the following mechanistic hypothesis and Aims are included:

Mindfulness-Based Stress Reduction:

Aim 2: the study predicts that patients with chronic low back pain (cLBP) will preferentially respond to this therapy if PROs indicate higher levels of pain catastrophizing, as measured by the Pain Catastrophizing Scale, or lower scores on the Experiences Questionnaire.

Aim 3: the study hypothesizes that cLBP patients with decreased activation in response to pain in the subgenual anterior cingulate cortex (sgACC) and Prefrontal Cortex and increased activation in somatosensory cortex (S1) and thalamus will respond preferentially to MBSR.

Physical Therapy (PT) and Exercise

Aim 2: The primary hypothesis for the light phenotyping protocol is those individuals with the highest scores on the Fear Avoidance Beliefs Questionnaire and lowest scores for PROMIS Self-Efficacy for Managing Symptoms will be most likely to improve from PT/Exercise program.

Aim 3: the study hypothesis that low vagal tone and high basal inflammation will predict responsiveness to the PT/Exercise program.

Acupressure:

Aim 2: The study hypothesizes that females with cLBP will respond better to acupressure than men, as will those with higher scores on the 2011 Fibromyalgia Survey Questionnaire.

Aim 3: The study predicts that cLBP patients with higher posterior insula glutamate and/or greater insula - Default Mode Network (DMN) connectivity (as well as increased DMN-S1 connectivity

Duloxetine:

Aim 2: the study hypothesizes that it will replicate previous studies suggesting that participants with cLBP will preferentially respond to this therapy if patient reported outcomes indicate stronger elements of either neuropathic pain (indicated by a high PainDETECT score) or centralized/nociplastic pain (indicated by more widespread pain on the 2011 Fibromyalgia Survey Questionnaire).

Aim 3: the study anticipates then that deficient pain inhibition on quantitative sensory testing, decreased periaqueductal gray (PAG)-insula connectivity, and elevated stimulated inflammatory responses will be associated with a positive response to centrally-acting duloxetine.

Additionally, a subset of individuals (n=160) from these groups will be asked to participate in an expanded phenotyping study that will include structural and functional brain neuroimaging, quantitative sensory testing (QST), plasma measures of inflammation, and digital measurement of autonomic tone.

Eligibility criteria: Inclusion Criteria for Light Phenotyping (all participants):

* Definition of cLBP described in the NIH Task Force Report on Research Standards for Chronic Low Back Pain (for example (i.e.), low back pain present at least six months, and present more than half of those days.
* Individuals must have the eligible protocol pain interference score on PROMIS Pain Interference.
* Individuals must be willing to be randomized to receive any of the four proposed treatments.

Exclusion Criteria for Light Phenotyping (all participants):

* History of discitis osteomyelitis (spine infection) or spine tumor
* History of ankylosing spondylitis, rheumatoid arthritis, polymyalgia rheumatica, or psoriatic arthritis, lupus
* History of cauda equina syndrome or spinal radiculopathy with functional motor deficit (strength \<4/5 on manual motor testing)
* Diagnosis of any vertebral fracture in the last 6 months
* Osteoporosis requiring treatment other than vitamin D and calcium supplements
* Cancer (History of any bone-related cancer or cancer that metastasized to the bone, Currently in treatment for any cancer or plan to start cancer treatment in the next 12 months, History of any cancer treatment in the last 24 months)
* Life expectancy less than 2 years
* Unable to speak and write English
* Visual or hearing difficulties that would preclude participation
* Presence of any history that would preclude scanning in magnetic resonance imaging (MRI)
* Uncontrolled drug/alcohol addiction
* Individuals receiving disability or compensation within the past year, or involved in litigation
* Pregnancy or breastfeeding
* History of allergy to duloxetine
* Individuals on high doses of opioids (over 100 oral morphine equivalents (OME) per day)
* Scheduled back surgery, back surgery within the last year, or more than one back surgery in the past.
* Expecting to receive an injection of surgical procedure within the next year for their cLBP
* Current/planned (in the next 2 years) enrollment in another study of a device or investigational drug that would interfere with this study, this may include participation in a blinded trial.
* Any other diseases or conditions that would make a patient unsuitable for study participation as determined by the site principal investigators. This would include but not be limited to severe psychiatric disorders, active suicidal ideations or history of suicide attempts, and an uncontrolled drug and/or alcohol addiction

Contraindications to Study Intervention: duloxetine

* certain medications (per protocol)
* renal dysfunction (creatinine clearance \<30 milliliters per minute (mL/min) or End- Stage Renal Failure)
* Hepatic dysfunction: Liver function tests (LFTs) elevated times 1.5

Contraindications to Study Intervention: Acupressure

* Currently receiving acupressure or acupuncture through formal therapy

Contraindications to Study Intervention: MBSR

* Current participation in a structured MBSR program

Contraindications to Study Intervention: PT \& Exercise

* Currently receiving any type of structured manual therapy or exercise treatment for low-back pain.
* Contraindication for manual therapy and/or participation in an exercise program

Inclusion Criteria for Deep Phenotyping (subset 160 participants):

* Right hand dominant (such as the hand used when writing or throwing/catching a ball)
* Normal visual acuity or correctable (with corrective lenses- glasses or contacts) to at least 20/40 for reading instructions in the MRI and visual sensitivity testing
* No contraindications to MRI (i.e., metal implants)
* Willingness to refrain from taking any "as needed" medications, including pain medications such as Nonsteroidal anti-inflammatory drugs (i.e., Motrin, Advil, Aleve), acetaminophen, and opioids, for 8 hours before undergoing neuroimaging and 10.1 Quantitative Sensory Testing (QST)
* Willingness to refrain from alcohol and nicotine on the day of QST and neuroimaging (alcohol and nicotine consumption is allowed after testing is completed)
* Willingness to refrain from any unusual physical activity or exercise that would cause muscle and/or joint soreness for 48 hours prior to testing (routine exercise or activity that does not lead to soreness is acceptable)
* Able to lie still on back for 2 hours during MRI

Exclusion Criteria for Deep Phenotyping (subset 160 participants):

* Severe claustrophobia precluding MRI and evoked pain testing during scanning
* Diagnosed peripheral neuropathy
* Current, recent (within the last 6 months), or habitual use of artificial nails or nail enhancements. (Artificial nails can influence pressure pain sensitivity at the thumbnail)
* Body Mass Index greater than 45 or unable to comfortably fit in the bore of the MRI magnet

Primary outcomes:
measure: Change in Patient-Reported Outcomes Measurement Information System (PROMIS) pain interference 4a between week 6 to week 15
timeFrame: week 6 (T2), week 15 (T3)
Secondary outcomes:
measure: Change in the Pain, Enjoyment, and General Activity Scale (PEG) from week 6 to week 15
timeFrame: week 6 (T2), week 15 (T3)
measure: Change in Patient Global Impression of Change (PGIC) from week 6 to week 15
timeFrame: week 6 (T2), week 15 (T3)
Other outcomes:
Locations:
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
Study officials:
affiliation: University of Michigan
name: Afton Hassett, PsyD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Michigan
name: Daniel Clauw, MD
role: PRINCIPAL_INVESTIGATOR
References: