Biopsychosocial Influence on Shoulder Pain (BISP)

Biopsychosocial Influence on Shoulder Pain: a Randomized, Pre-clinical Trial

Chronic shoulder pain is a common, costly, and disabling problem for society. The identification of factors predictive of the development of chronic shoulder pain is necessary to develop innovative and effective treatments to reduce the societal impact of shoulder disorders. In previous work the investigators identified a genetic and psychological subgroup that robustly predicted heightened shoulder pain responses in a pre-clinical cohort and poor 12 month shoulder pain recovery rates in a clinical surgical cohort. In this follow-up study the investigator proposes to test how interventions tailored to the high risk subgroup affect pain responses in a pre-clinical cohort.

The optimal theorized match for the identified high-risk subgroup is a combination of personalized pharmaceutical and education interventions. This combined personalized intervention versus a placebo pharmaceutical and general education intervention group is the primary comparison of interest. Also, an evaluation of the individual effect of personalized pharmaceutical and educational interventions will be part of the study. Such comparisons will provide important information on what the active portion of the combined personalized intervention may be.

Study Overview

• Status: Completed
• Conditions: Shoulder Pain
• Intervention / Treatment: Drug: Propranolol LA (60 mg); Behavioral: Pain Processing Education; Drug: Placebo; Behavioral: Shoulder Anatomy Education

Detailed Description

Potential subjects will be screened and those meeting the high-risk criteria based on COMT genotype for high pain sensitivity and pain catastrophizing questionnaire score will be eligible for randomization into intervention groups (stratified by sex). Exercise induced shoulder injury will serve as the pain generating mechanism on Day 1 and participants will receive pharmaceutical and education interventions over Days 1-4, and Days 2-4 respectively. Statistical analysis will determine whether the combined personalized intervention group experienced shorter shoulder pain duration, lower peak pain intensity, or decreased upper-extremity disability and determine which molecular, psychological, and pain sensitivity regulation mechanisms are associated with pain relief. A preliminary analysis is planned after the first 300 subjects are equally randomized to the 4 intervention groups. The comparison of interest for the preliminary analysis is the combined personalized intervention group with the placebo and general education group for the primary outcome. Depending on the results of this preliminary analysis the randomization pattern may change, with details of these changes available in the protocol paper.

• Study Type: Interventional
• Enrollment (Actual): 264
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida Clinical and Translational Science Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 64 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• English speaking

Exclusion Criteria:

• chronic pain (> 3 months) in any area,
• currently experiencing neck or shoulder pain,
• previous history of neck or shoulder pain (operationally defined as experiencing neck or shoulder pain for longer than 48 hours or seeking medical treatment for neck or shoulder pain),
• neurological impairment of the in the upper-extremity (determined by loss of sensation, muscle weakness, and reflex changes),
• regular participation in upper-extremity weight training,
• currently or regular use of pain medication, and
• previous history of upper-extremity surgery.

Additional exclusion criteria for propranolol administration are reported history of or presence of any of the following cardiovascular conditions:

• clinically significant abnormal 12-lead ECG,
• sinus bradycardia (resting heart rate below 55 beats per minute),
• greater than first degree heart block,
• cardiac failure,
• coronary artery disease,
• uncontrolled hypertension (resting systolic blood pressure above 140 mm Hg), or hypotension (resting systolic blood pressure below 90 mm Hg),
• Wolff-Parkinson-White syndrome.

Non-cardiovascular reasons for study exclusion include:

• bronchial asthma,
• nonallergic bronchospasm,
• history of recent major surgery requiring general anesthesia,
• diabetes,
• pregnancy,
• major depression.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Personalized Pharmaceutical and Education; This group will have propranolol (Propranolol LA) 60 mg administered orally and receive the pain processing education modules as the combined intervention for this arm.	Drug: Propranolol LA (60 mg); Long-acting propranolol (Propranolol LA) 60 mg to be administered orally daily for Days 1 (before exercise induced muscle injury) and Days 2-4 following exercise induced muscle injury.; Other Names: Personalized Pharmaceutical; Behavioral: Pain Processing Education; Pain processing education modules will be administered Days 2-4 (after exercised induced muscle injury) following exercise enhance injury with the goal of better understanding of pain processing and psycho-education. This information will encourage shoulder activation by: a) reducing the threat of muscle injury; b) encouraging normal use of the shoulder and arm; and c) addressing specific concerns expressed by the subject (e.g. pain with shoulder motion is a sign of re-injury). This education component will be devoid of detailed information on shoulder anatomy, movement, and injury that characterizes the Shoulder Anatomy Education modules. These education modules will be scripted and structured so they are provided in a standardized manner for all subjects.; Other Names: Personalized Education
Placebo Comparator: Placebo Pharmaceutical, General Education; This group will have the placebo pharmaceutical administered orally and receive general shoulder anatomy education modules as the interventions for this arm.	Drug: Placebo; Placebo capsules will be prepared by the University of Florida Investigational Drug Service to be visually indistinguishable from the active medication and delivered orally. Placebo administration will be done in the same fashion as propranolol - administered on Days 1 (before exercise induced muscle injury) and the Days 2-4 after the exercise induced muscle injury.; Other Names: Placebo Pharmaceutical; Behavioral: Shoulder Anatomy Education; Shoulder anatomy education modules will be administered Days 2-4 (after exercised induced muscle injury) following exercise enhance injury with the goal of participant understanding shoulder anatomy and injury while reviewing: a) structure and arthrokinematics of the shoulder joint; b) muscle anatomy of the shoulder with emphasis on the rotator cuff; and c) potential shoulder pain generators from the exercise-induced injury. This education component will be devoid of information related to pain signaling and cognitive restructuring that characterizes Pain Processing Education modules. These education modules will be scripted and structured so they are provided in a standardized manner for all subjects.; Other Names: General Education
Active Comparator: Placebo Pharmaceutical, Personalized Education; This group will have the placebo pharmaceutical administered orally and receive the pain processing education modules as the combined intervention for this arm.	Behavioral: Pain Processing Education; Pain processing education modules will be administered Days 2-4 (after exercised induced muscle injury) following exercise enhance injury with the goal of better understanding of pain processing and psycho-education. This information will encourage shoulder activation by: a) reducing the threat of muscle injury; b) encouraging normal use of the shoulder and arm; and c) addressing specific concerns expressed by the subject (e.g. pain with shoulder motion is a sign of re-injury). This education component will be devoid of detailed information on shoulder anatomy, movement, and injury that characterizes the Shoulder Anatomy Education modules. These education modules will be scripted and structured so they are provided in a standardized manner for all subjects.; Other Names: Personalized Education; Drug: Placebo; Placebo capsules will be prepared by the University of Florida Investigational Drug Service to be visually indistinguishable from the active medication and delivered orally. Placebo administration will be done in the same fashion as propranolol - administered on Days 1 (before exercise induced muscle injury) and the Days 2-4 after the exercise induced muscle injury.; Other Names: Placebo Pharmaceutical
Active Comparator: Personalized Pharmaceutical, General Education; This group will have propranolol (Propranolol LA) 60 mg administered orally and receive general shoulder anatomy education modules as the interventions for this arm.	Drug: Propranolol LA (60 mg); Long-acting propranolol (Propranolol LA) 60 mg to be administered orally daily for Days 1 (before exercise induced muscle injury) and Days 2-4 following exercise induced muscle injury.; Other Names: Personalized Pharmaceutical; Behavioral: Shoulder Anatomy Education; Shoulder anatomy education modules will be administered Days 2-4 (after exercised induced muscle injury) following exercise enhance injury with the goal of participant understanding shoulder anatomy and injury while reviewing: a) structure and arthrokinematics of the shoulder joint; b) muscle anatomy of the shoulder with emphasis on the rotator cuff; and c) potential shoulder pain generators from the exercise-induced injury. This education component will be devoid of information related to pain signaling and cognitive restructuring that characterizes Pain Processing Education modules. These education modules will be scripted and structured so they are provided in a standardized manner for all subjects.; Other Names: General Education

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Met the Recovery Criterion for Shoulder Pain Intensity	The outcome has a range between 0 and 1, the higher scores mean a better outcome. Successful recovery was determined based on meeting the recovery criterion for shoulder pain intensity by at least 6 days. Specifically, recovery (Yes or No) was defined using Brief Pain Inventory (BPI) ratings as a current pain intensity rating of 0/10 and a worst pain intensity rating of less than 2/10.	Approximately 6 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disabilities of the Arm, Shoulder, and Hand Questionnaire (DASH)	The abridged version of the DASH (the QuickDASH) which consists of 11 functional items, with total scores ranging from 0 (not disability) to 100 (complete disability) will be used to assess upper-extremity disability. The primary outcome will be the highest DASH score recorded during the pain intensity recovery period.	Daily until recovery criterion met, approximately 5-15 days
Brief Pain Inventory (BPI) for Pain Duration	The Brief Pain Inventory (BPI) consists of rating pain intensity on an 11-point numerical rating scale ranging from 0 (no pain) to 10 (worst pain intensity imaginable). BPI will be recorded daily and the recovery criterion used for this study will be a BPI rating of current pain 0/10 and worst pain rating of less than 2/10. The pain duration is number of days from the date of induced pain to date of recovery. The longer the duration means a worse outcome.	Daily until recovery criterion met, approximately 5-15 days
Brief Pain Inventory (BPI) for Worst Shoulder Pain Intensity (Highest Daily Pain Intensity Rating) Recorded During Recovery.	The Brief Pain Inventory (BPI) which consists of rating pain intensity on an 11-point numerical rating scale ranging from 0 (no pain) to 10 (worst pain intensity imaginable). Participants will rate their current, best, and worst pain intensity on the BPI. This measure will be recorded daily through study completion, an average of 5 days. The worst pain intensity rating at Day 2 (when participants usually had the Peak Shoulder Pain Intensity) is reported.	Day 2 value of the worst pain intensity is reported

Collaborators and Investigators

• Sponsor: Duke University
• Collaborators: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Mark Bishop, PhD, University of Florida

Publications and helpful links

General Publications

• George SZ, Staud R, Borsa PA, Wu SS, Wallace MR, Greenfield WH, Mackie LN, Fillingim RB. Biopsychosocial influence on shoulder pain: Rationale and protocol for a pre-clinical trial. Contemp Clin Trials. 2017 May;56:9-17. doi: 10.1016/j.cct.2017.03.005. Epub 2017 Mar 14.
• Borsa PA, Parr JJ, Wallace MR, Wu SS, Dai Y, Fillingim RB, George SZ. Genetic and psychological factors interact to predict physical impairment phenotypes following exercise-induced shoulder injury. J Pain Res. 2018 Oct 23;11:2497-2508. doi: 10.2147/JPR.S171498. eCollection 2018.
• Butera KA, George SZ, Borsa PA, Dover GC. Prolonged Reduction in Shoulder Strength after Transcutaneous Electrical Nerve Stimulation Treatment of Exercise-Induced Acute Muscle Pain. Pain Pract. 2018 Nov;18(8):954-968. doi: 10.1111/papr.12690. Epub 2018 Apr 6.
• George SZ, Bishop MD, Wu SS, Staud R, Borsa PA, Wallace MR, Greenfield WH 3rd, Dai Y, Fillingim RB. Biopsychosocial influence on shoulder pain: results from a randomized preclinical trial of exercise-induced muscle injury. Pain. 2022 May 23. doi: 10.1097/j.pain.0000000000002700. Online ahead of print.

Helpful Links

• Abstract for citation and access to paper

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2016
• Primary Completion (Actual): November 5, 2021
• Study Completion (Actual): November 5, 2021

Study Registration Dates

• First Submitted: November 13, 2015
• First Submitted That Met QC Criteria: November 30, 2015
• First Posted (Estimate): December 3, 2015

Study Record Updates

• Last Update Posted (Estimate): January 13, 2023
• Last Update Submitted That Met QC Criteria: December 20, 2022
• Last Verified: December 1, 2022

More Information

Terms related to this study

• Keywords: Personalized Pharmaceutical; Personalized Education
• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Joint Diseases; Musculoskeletal Diseases; Arthralgia; Shoulder Pain; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Propranolol
• Other Study ID Numbers: Pro00078287; 2R01AR055899 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No