Effect of Opioid Taper on Pain Responses in Patients With Chronic Pain
Conditions: Chronic Pain
Sponsor: University of Pennsylvania

 
 
Official Title: Effect of Opioid Taper on Pain Responses in Patients with Chronic Pain 
NCT#: 03912298 
Date: September 25, 2018 

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Protocol Details
Basic Info
Confirmation Number:
chdehdci
Protocol Number:
831447
Created By:
PENA, JUAN S
Principal Investigator:
COMPTON, MARGARET A
Protocol Title:
Effect of Opioid Taper on Pain Responses in Patients with Chronic Pain
Short Title:
Opioid Taper in Chronic Pain
Protocol Description:
The purpose of this study is to determine the effect of opioid taper on pain sensitivity in patients 
with chronic pain. In a well-characterized sample of men and women with chronic neuropathic 
pain on high-dose opioid therapy, experimental pain responses (cold-pressor, quantitative sensory 
testing) will be serially described over the course of and following an individualized opioid taper. 
In addition, functional improvements and subject-level predictors of response will be described.
Submission Type:
Biomedical Research
Application Type:
EXPEDITED Category 4
Resubmission*
Yes
Study Personnel
Principal Investigator
Name:
COMPTON, MARGARET A
Dept / School / Div:
603 - Family and Community Health
Campus Address
Mail Code
4217
Address:
CLAIRE M. FAGAN NURSING 
418 CURIE BLVD, room 412
City State Zip:
PHILADELPHIA PA 19104-4217
Phone:
215-898-6679
Fax:
215-746-3374
Pager:
Email:
pcompton@nursing.upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
02/21/2020
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA

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Study Contacts
Name:
PENA, JUAN S
Dept / School / Div:
305 - LPS Administration
Campus Address
Mail Code
3309
Address:
4040 PRESIDENTIAL BLVD 
APT 2107 
City State Zip:
PHILADELPHIA PA 19131-0000
Phone:
215-746-0428
Fax:
3309
Pager:
Email:
juan.pena@pennmedicine.upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
11/08/2020
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA
Other Investigator
Name:
BADIOLA, IGNACIO J
Dept / School / Div:
4202 - AN-Anesthesia
Campus Address
Mail Code
4283
Address:
HUP 
3400 SPRUCE ST 
City State Zip:
PHILADELPHIA PA 19104-4283
Phone:
800-789-7366
Fax:
-
Pager:
Email:
Ignacio.Badiola@uphs.upenn.edu
HS Training Completed:
Yes
Training Expiration Date:
11/05/2020
Name of course completed :
CITI Protection of Human Subjects Research Training - ORA
Responsible Org (Department/School/Division):
603 - Family and Community Health
Key Study Personnel
Name:
HANLON, ALEXANDRA L
Department/School/Division:
RO-Radiation Oncology
HS Training Completed:
Yes
Training Expiration Date:
09/21/2020
Name of course completed:
CITI Protection of Human Subjects Research Training - ORA
Disclosure of Significant Financial Interests*
Does any person who is responsible for the design, conduct, or reporting of this research protocol have 
a FINANCIAL INTEREST?
No

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Penn Intellectual Property*
To the best of the Principal Investigator's knowledge, does this protocol involve the testing, 
development or evaluation of a drug, device, product, or other type of intellectual property (IP) that is 
owned by or assigned to the University of Pennsylvania?
No
Certification
I have reviewed the Financial Disclosure and Presumptively Prohibited Conflicts for Faculty 
Participating in Clinical Trials and the Financial Disclosure Policy for Research and Sponsored 
Projects  with all persons who are responsible for the design, conduct, or reporting of this research; and 
all required Disclosures have been attached to this application.
Yes
Biomedical Research
Clinical Trial*
Is this a clinical trial?
No
Investigator Initiated Trial*
Is this an investigator initiated trial?
Yes
If Yes, please be aware that the investigator may be required to create and manage a record of this trial 
in https://clinicaltrials.gov.
Drugs or Devices*
Does this research study involve Drugs or Devices?
No
IND Exemption
For studies that fall under an IND exemption, please provide the number below
For studies including IND or IDE's, please provide the number(s) below
IDE Review*
NOTE: For research involving investigational devices, you are required to review the guidance on 
Managing Research Device Inventory. Consult the Penn Manual for Clinical Research: https://
www.med.upenn.edu/pennmanual/secure/investigational-product-management-at-sites-not-using-
investigational-drug-services-(ids).html Please check the box Yes if you have reviewed the guidance.
Yes
Research Device Management*
Please indicate how research device(s) will be managed.
Not Applicable (no investigational devices)
Drug, Herbal Product or Other Chemical Element Management *
Please indicate how drugs, herbal products or other chemical entities will be managed.
Not Applicable (no drugs, herbal products or other chemical entities)
Radiation Exposure*
Are research subjects receiving any radiation exposure (e.g. X-rays, CT, Fluoroscopy, DEXA, pQCT, 
FDG, Tc-99m, etc.) that they would not receive if they were not enrolled in this protocol?
No

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Gene Transfer*
Does this research involve gene transfer (including all vectors) to human subjects?
No
Human Source Material*
Does this research include collection or use of human source material (i.e., human blood, blood 
products, tissues or body fluids)?
Yes
CACTIS and CT Studies*
Does the research involve Center for Advanced Computed Tomography Imaging Services (CACTIS) 
and CT studies that research subjects would not receive if they were not part of this protocol?
No
CAMRIS and MRI Studies*
Does the research involve Center for Advanced Magnetic Resonance Imaging and Spectroscopy 
(CAMRIS) and MRI studies that research subjects would not receive if they were not part of this 
protocol?
No
Investigational Agent or Device within the Operating Room*
Does the research project involve the use of an investigational agent or device within the Operating 
Room?
No
Cancer Related research not being conducted by an NCI cooperative group*
Does this protocol involve cancer-related studies in any of the following categories?
No
Processing of Materials*
Will the research involve processing (such as over encapsulating, or compounding)?
No
In-House Manufacturing of Materials*
Will the research involve processing (such as over encapsulating, or compounding)?
No
Medical Information Disclosure*
Does the research proposal involve the use and disclosure of research subject's medical information for 
research purposes?
Yes
If the answer is YES, indicate which items is is provided with this submission:
Modified research informed consent document that incorporates HIPAA requirements
CTRC Resources*
Does the research involve CTRC resources?
No
Pathology and Laboratory Medicine Resources*
Will samples be collected by hospital phlebotomy and/or processed or analyzed by any of the clinical 
laboratories of the University of Pennsylvania Health System?
No
Research Involves Apheresis, Cell Collection, and/or Blood Product Collection*
Does this research involve collection of blood products in the Penn Donor Center and/or the use of 
apheresis for treatment or collection of cells or other blood components?
No
Research involving blood transfusion or drug infusions*
Will your research involve blood transfusion or infusion of study drug in 3 Ravdin Apheresis Unit for 

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research purposes?
No
Trial in Radiation Oncology
Is this research a prospective trial being done in Radiation Oncology, and if so, has this protocol been 
approved by the Radiation Oncology Protocol committee?
N/A
Study in Radiation Oncology
Is this research a retrospective study being done in Radiation Oncology, and if so, has this project been 
reviewed by the Radiation Oncology Clinical Research Group?
N/A
Use of UPHS services*
Does your study require the use of University of Pennsylvania Health System (UPHS) services, tests or 
procedures*, whether considered routine care or strictly for research purposes?
No
Primary Focus*
Sociobehavioral (i.e. observational or interventional)
Protocol Interventions
Sociobehavioral (i.e. cognitive or behavioral therapy)
Drug
Device - therapeutic
Device - diagnostic (assessing a device for sensitivity or specificity in disease diagnosis)
Surgical
x Diagnostic test/procedure (research-related diagnostic test or procedure)
Obtaining human tissue for basic research or biospecimen bank
x Survey instrument
None of the above
The following documents are currently attached to this item:
There are no documents attached for this item.
Sponsors
Business Administrator
Name:
SCALA, DENISE S
Dept / School / Div:
631 - Office of Nursing Research
Phone:
215-898-0902
Fax:
215-898-3056
Pager:
Email:
scala@nursing.upenn.edu
Department budget code
000 - 000 - 0 - 000000 - 0000 - 0000 - 0000

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Funding Sponsors
Name:
NATIONAL INSTITUTE ON DRUG ABUSE/NIH/DHHS
Type:
UPENN Federal
Funding sponsors billing address
If you have selected a commercial or industry sponsor, please provide the appropriate address and 
contact information for the Sponsor for the purposes of billing for IRB review fees (initial review, 
continuing review and convened modification fees apply here). If the Sponsor is not industry/
commercial, this information is not necessary to provide with your application.
Funding sponsors gift
Is this research being funded by a philanthropic gift?
No
Regulatory Sponsor
IND Sponsor
none
000 - 000 - 0 - 000000 - 0000 - 0000 - 0000
Industry Sponsor
None
Project Funding*
Is this project funded by or associated with a grant or contract?
Pending
Sponsor Funding
Is this study funded by an industry sponsor?
No
Status of contract
The following documents are currently attached to this item:
Grant Application (comptonr21_egrant.pdf)
Multi-Site Research
Other Sites
No other sites
Management of Information for Multi-Center Research
The following documents are currently attached to this item:
There are no documents attached for this item.

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Protocol
Abstract
The US is in the midst of an epidemic of prescription drug abuse. According to the CDC, of the 52,404 
opioid overdose deaths that occurred in 2015, almost 25% involved a prescription opioid, a number that 
has quadrupled since 1999. This public health crisis was fueled by well-intended efforts to better treat 
chronic pain, however, the use of opioids for ongoing pain is not an evidence-based intervention. In 
fact, outcomes are often poorer for patients on opioids, with counterintuitive improvements appreciated 
when opioids are tapered. An oft-cited but untested explanation for this finding is opioid-induced 
hyperalgesia (OIH), or increased pain sensitivity secondary to ongoing opioid use. Unknown is the 
degree to which OIH contributes to the pain experience or how opioid taper might improve pain 
sensitivity. Proposed is an observational pilot designed to measure the effect of opioid taper on pain 
perception in patients with chronic pain. In a well-characterized sample of pain patients on high-dose 
opioid therapy, we will examine responses to experimental pain (cold-pressor, quantitative sensory) 
during a prescribed opioid taper. Responses will be measured at weekly intervals over the course of the 
taper, followed by monthly intervals up to 12months. In addition to characterizing pain perception over 
time, functional outcomes and variables related to the patient, chronic pain condition, and opioid 
therapy will be evaluated. It is anticipated that study findings will explicate the role opioid therapy plays 
in the pain experience of chronic pain patients, thereby providing evidence-based guidance for 
treatment.
Objectives
Overall objectives
The overall Specific Aim of this proposal is to determine the effect of opioid taper on pain sensitivity in 
patients with chronic pain. Specifically, in a well-characterized sample of men and women with chronic 
neuropathic pain and receiving high-dose opioid therapy (200mg morphine equivalents/day [MED]), 
experimental pain responses will be serially described over the course of an individualized opioid taper 
to a safer dose of 90mg MED for up to 12 months. Changes will be inspected within-subject over time, 
and pain perception will be measured with two valid and reliable experimental pain induction 
techniques commonly used to measure OIH (cold-pressor, quantitative sensory testing); in addition, 
related functional improvements and subject-level predictors of response will be described.  Hypothesis 
1. Subjects undergoing opioid taper will have improved pain responses over time compared to within-
subject baseline as measured by cold-pressor and quantitative sensory pain testing.  Hypothesis 2. 
Improvements in experimental pain responses will be positively related to improved functional 
outcomes compared to within-subject baseline as measured by the PROMIS physical, mental and social 
health measures.  Hypothesis 3. Degree of improvement in experimental pain responses related to 
opioid taper will be predicted by demographic, pain, and opioid use history characteristics of the 
subject.  Data showing that pain perception improves as opioids are withdrawn would provide an 
evidence-based, mechanistic rationale for opioid taper in patients with chronic pain and have the 
potential to support a sea-change in opioid prescription practices. In that ongoing opioid therapy brings 
with it significant health risks for the patient and the community, it is critical that empirical evidence of 
its efficacy be demonstrated to balance the benefits with the risks of adverse events, potential misuse 
and abuse, and patient safety.
Primary outcome variable(s)
The primary dependent variable, pain perception, will be measured using two highly reliable and valid 
pain induction techniques, the cold-pressor test (CPT) and quantitative sensory testing (QST), 
employing procedures consistent with those described in the literature. Order of pain testing will vary, 
and three aspects of the pain response will be captured at each study session: evoked pain; temporal 
summation; and conditioned pain modulation, which map on to the hypothesized peripheral, spinal and 
supra-spinal mechanisms of OIH.
Secondary outcome variable(s)
Concurrent with pain testing, the presence of opioid withdrawal symptoms using the well-validated 
clinical opiate withdrawal scale (COWS) will be assessed. Although prescribed analgesics will not be 
introduced during the taper, the concurrent use of over-the-counter (OTC) analgesics will be recorded. 
In addition, urine toxicology is collected to ensure that subjects are taking only their prescribed opioid 
at each pain data collection session. To account for the effects of disease progression and increased 
physical activity on pain responses, the study physician will evaluate subjects monthly for evidence of 

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disease progression, and each will be asked to complete a weekly Stanford Physical Activity Scale. To 
evaluate if opioid taper improves functional outcomes vis-a-vis improved pain responses, the PROMIS 
(Patient-Reported Outcomes Measurement Information System) person-centered measures will be 
utilized (http://www.healthmeasures.net/explore-measurement-systems/promis). Specifically, functional 
and quality of life indicators from the physical health (pain intensity, pain interference, physical 
function), mental health (life satisfaction), and social health (ability to participate in social roles and 
activities) PROMIS domains will be collected on a monthly basis and inspected for change in 
relationship to changes in experimental pain assay performance. Completion of monthly PROMIS 
measures is standard-of-care at the Penn Pain Medicine Center, so presents no additional burden to 
study participation.
Background
Prescription Opioid Abuse Epidemic The United States is in the midst of a growing and dangerous 
epidemic of prescription drug abuse. Of the 1 in 3 Americans who used a prescription opioid in 2015, 
11.3 million reported misusing the medication(37) with 1.9 million meeting diagnostic criteria for 
opioid use disorder (OUD).(38) The Centers for Disease Control and Prevention (CDC)(39) reported 
that 44 people in the U.S. die from overdose of prescription opioids daily, a number which has nearly 
quadrupled since 1999.(40) Further, the rapid rise of heroin and illicit fentanyl overdose in US has been 
tied to prescription opioid abuse; 45% of people who use heroin were also addicted to prescription 
opioid analgesics.(40,41) This public health crisis has been fueled in part by the large supply of opioids 
being prescribed in our communities. The quantity of prescription opioid analgesics sold to pharmacies, 
hospitals, and doctors offices was 4 times greater in 2010 than in 1999(39), and in 2016, clinicians 
wrote an estimated 215 million prescriptions for opioid analgesics.(42) Critical to addressing 
problematic prescribing practices is the development of safe and evidence-based practice guidelines for 
the use of opioids in the treatment of chronic pain. Need for Evidence-based Opioid Prescribing  In 
2016, the CDC released the Guideline for Prescribing Opioids for Chronic Pain(32), which targeted 
opioid analgesic prescribing practices as an important means to reduce prescription opioid abuse, OUD, 
and overdose deaths. Although the guideline included strategies to decrease risk, evidence to support 
the efficacy of the CDC recommendations is lacking.(20) It reflects concern at the federal level that 
healthcare providers are overprescribing these medications, particularly for chronic pain. In fact, it is 
currently estimated that between 5-8 million Americans use opioids on a daily basis for chronic pain 
relief(20), with a recent analysis showing that over half of all opioid prescriptions written in the VA 
system are for veterans with chronic pain.(43) Yet, opioid therapy for chronic pain is not an evidence-
based intervention. In a recent review, Von Korff(44) argues that outcomes are actually poorer for 
chronic pain patients on opioid therapy in comparison to those not taking opioids on multiple indicators 
including functional status, quality of life, return to work, and self-reported disability.(45-47) Recent 
NIH reviews conclude that evidence for long-term benefits with daily opioid use is limited.(33,48,49) 
These analyses have prompted renewed calls for tapering patients off opioid therapy(36,50,51), citing 
reports of decreased pain, improved function and better quality of life.(21,22,51-58) Potential Benefit of 
Opioid Taper Reduction of Opioid-induced Hyperalgesia (OIH)? There are multiple mechanisms by 
which opioid taper might improve chronic pain outcomes. A theorized contributor to poor pain relief in 
this population is the presence of opioid-induced hyperalgesia (OIH)(25,26), defined as a 
counterintuitive increased sensitivity to pain related to ongoing opioid use.(59,60) Best described in 
samples of opioid abusers, cross-sectional data suggest a large effect size, indicating that opioid-
dependent subjects are 42%76% less tolerant of experimental pain than are matched controls.
(29-31,61-63) Cross-sectional data suggest the presence of OIH in chronic pain patients, showing those 
on opioids to have poor tolerance for experimental heat, cold and pressure pain.(2-11)  Assuming a 
causal relationship between opioids and hyperalgesia, it is hypothesized that tapering opioids would 
diminish OIH and thereby improve pain responses in patients with chronic pain. Group comparisons 
reveal that detoxified opioid addicts are more tolerant of experimental pain than those on opioid 
maintenance therapy(61-65), and with respect to patients with pain, case studies of those with chronic
(66,67) or cancer(68-73) pain show significant pain improvement within hours of opioid dose reduction. 
Conversely, decreased tolerance to experimental thermal pain has been demonstrated in prospective 
studies of patients with chronic pain following 1-6 months of opioid therapy.(74-76)  Characterization 
of Effect of Opioid-taper on Pain and Function Thus, although there is evidence that patients do better 
following opioid taper, the degree to which improvements are due to resolution of OIH is unclear. The 
findings described above suggest that a clearer description of the effect of opioid taper on pain 
perception is needed, including description of relationship to functional outcomes and identification of 
subject-level predictors.  Relationship to functional outcomes. As noted, accumulating evidence 
suggests that chronic pain, function and quality of life improve as patients successfully taper their 

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opioid dose. (21,22,51-58) The degree to which these improvements may be attributed to decreases in 
perceived pain severity or increases in pain tolerance are unknown. Empirically describing the 
relationship between pain perception as measured by the standardized CPT and QST assays and 
functional outcomes can enable prediction of degree of functional improvement to be appreciated as 
opioid dose is tapered. Predictors of opioid-taper pain responses. To identify chronic pain patients likely 
to benefit from opioid taper, the role of mediating and moderating variables on outcomes requires 
description. Predictors for the development of OIH include factors associated with (a) the patient (age, 
gender, ethnicity)(4,6,9,77-79), (b) the chronic pain condition (duration, severity)(7,8,80,81), and (c) 
opioid use history, including dose(3,6,9-11,57,82), potency(30), and duration of treatment.(3,5,9,82) 
Determining the role of these predictors will support guidelines on determination of which patients may 
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Study Design
Phase*
Not applicable
Design
A prospective time-series survey design will be utilized to measure the experimental (CPT and QST) 
pain responses of chronic pain patients on high-dose opioid therapy (200mg MED) prior to and then 
regularly during and following a voluntary opioid taper. Data will be collected weekly during the active 
taper period; once the subject has reached a stable maintenance dose (90 MED), assessments will occur 
monthly until month 12. Because our previous work has shown stability in pain responses in patients on 

Page 13 of 21
high-dose opioid therapy over time (6 months), and the clinical imperative of tapering patients to safer 
doses, a control group of patients maintained on high-dose therapy is not included. Consistent with 
expert opinion in the field, a longitudinal within-subject design is planned.
Study duration
The overall duration of the study is two years, during which time all subjects will be enrolled and 
complete the study. Data will be collected weekly during the active taper period; once the subject has 
reached a stable maintenance dose (less than or equal to 90 MED), assessments will occur monthly 
until month 12. If funded, the study would begin Oct 1, 2018.
Resources necessary for human research protection
Describe research staff and justify that the staff are adequate in number and qualifications to conduct 
the research. Describe how you will ensure that all staff assisting with the research are adequately 
informed about the protocol and their research related duties. Please allow adequate time for the 
researchers to conduct and complete the research. Please confirm that there are adequate facilities for 
the research.
The study will be staff by a 55% FTE Project Director assisted by two part time graduate student 
research assistants (10hr/week) who will assist with pain testing and data collection. The project 
director is well-trained and experienced in all study procedures and human subjects research; with the 
PI, he will ensure the research assistants are trained and qualified to conduct research. Weekly research 
meetings between the investigators and study staff will occur to ensure staff are adequately informed 
about the protocol and their research-related duties.  The PI has her own locking office space (Claire 
Fagin Hall 402, approximately 170 square feet). All faculty offices come equipped with locked filing 
cabinets, bookshelves, desk, minimum 4 GHz computer with HP printer, Windows XP service pack 3 
operating system, Microsoft Office Professional (Word, Excel, PowerPoint, Access), SPSS or SAS 
statistical analysis software, and e-mail and internet access. With the same resources, an adjacent 
cubicle space is dedicated to the study research assistant. NHS copier, printer, fax and scanner facilities 
are available on each floor.  Research visits will take place in a private office at the U Penn Pain 
Medicine clinic.The Penn Pain Medicine Center currently has eight clinical exam rooms, 7 
administrative offices (office manager, physician, fellow, and resident offices), 5 support staff offices (2 
billing/new patient coordinator, surgical coordinator, and research coordinator offices). There is a large 
clinical research area which houses the office of the clinical research coordinator along with 3 bays/
exam locations for research patients. Study sessions will occur one of several small (10 ft x 15 ft) 
private examination rooms located onsite, complete with examining table, chair, bedside stand, desk, 
computer, and sink.
Characteristics of the Study Population
Target population
The sample will consist of 25 male and female adults with chronic neuropathic pain on opioid therapy 
and preparing to voluntarily undergo a prescribed opioid taper.
Subjects enrolled by Penn Researchers
25
Subjects enrolled by Collaborating Researchers
0
Accrual
Participants will be recruited from those treated at the large and nationally-renowned Penn Pain 
Medicine Center at the University of Pennsylvania Penn Medicine Neuroscience Center. The Penn Pain 
Medicine Center provides interdisciplinary, multimodal pain care to over 12,000 outpatients annually, 
an estimated 20% of whom are taking opioids on a regular basis. At any one point in time an estimated 
50 patients are undergoing opioid taper, up to half of whom are tapered from opioid doses greater or 
equal to 200mg MED. Due to anticipated rates of dropout, 25% oversampling for these individuals is 
planned. Results from previous studies have demonstrated moderate to large effect size estimates of 
opioids on cold-pressor and QST experimental pain responses. Based on these estimates, a sample size 

Page 14 of 21
of 25 will have over 99% power to detect differences in outcome. Using an alpha of 0.05/4 (Bonferroni 
correction) to account for multiple outcomes, we will have over 90% power to detect significant 
changes at the 0.01 level for all of the outcomes. Cross-sectional and prospective studies demonstrate 
statistically significant differences in experimental pain responses with changes between 80-90mg MED
(10,11,70); since MED decreases in the proposed work will be 110 MED (tapers from 200MED to 
90MED), we anticipate having no difficulty discerning taper effects on pain responses.
Key inclusion criteria
(1) between ages of 21-60; (2) documented chronic neuropathic non-malignant pain condition of at 
least one year duration; (3) on 200mg MED for at least 6 months; (4) have fully engaged in all 
prescribed non-opioid pain management treatments; (5) willing to undergo prescribed opioid taper; (6) 
otherwise in good physical and mental health, or in the care of a physician who is willing to take 
responsibility for such treatment; and (7) able to understand the purpose and instructions of the study, 
and provide informed consent as approved by the University of Pennsylvania IRB.
Key exclusion criteria
(1) meet diagnostic criteria for an active substance use disorder other than nicotine; (2) be acutely 
psychotic, severely depressed, and/or in need of inpatient psychiatric treatment, (3) have a neurological 
or psychiatric illness that would affect pain responses, including anxiety disorders; or (4) have a history 
of heart disease, stroke, or a pacemaker or uncontrolled high blood pressure. Good cardiovascular 
health is stipulated to ensure subjects can tolerate the sympathetic nervous system responses associated 
with the pain induction procedures.
Vulnerable Populations
Children Form
Pregnant women (if the study procedures may affect the condition of the pregnant woman or 
fetus) Form
Fetuses and/or Neonates Form
Prisoners Form
Other
x None of the above populations are included in the research study
The following documents are currently attached to this item:
There are no documents attached for this item.
Populations vulnerable to undue influence or coercion
In the event that Penn students or employees present for screening, they will be informed that their 
decision regarding whether or not to participate will in no way impact their standing at the university.
Subject recruitment
IRB-approved flyers will be made available and posted at the Penn Pain Medicine Center, and treatment 
clinicians trained to identify potential subjects for study participation. Patients who indicate interest in 
study participation will meet with the trained RA for screening; if meeting all inclusion and no 
exclusion criteria, informed consent, using an IRB-approved consent form will be obtained by the study 
physician in a private room at the Center.
Will the recruitment plan propose to use any Penn media services (communications, marketing, etc.) for 
outreach via social media avenues (examples include: Facebook, Twitter, blogging, texting, etc.) or does 
the study team plan to directly use social media to recruit for the research?
No
The following documents are currently attached to this item:
Subject recruitment (recruitmentflyertaperstudy7.23.18sp.pdf)

Page 15 of 21
Subject compensation*
Will subjects be financially compensated for their participation?
Yes
The following documents are currently attached to this item:
There are no documents attached for this item.
If there is subject compensation, provide the schedule for compensation per study visit or session 
and total amount for entire participation, either as text or separate document
Subjects will be compensated $25 for each completed study visit, and receive this payment in the form 
of a gift card. Because each subject's taper schedule is individualized, the exact number of visits will 
vary among subjects, but it is anticipated that subjects will have between 30 to 40 study visits, thus may 
earn between $750 - $1000 over the course of the year-long study.
Study Procedures
Suicidal Ideation and Behavior
Does this research qualify as a clinical investigation that will utilize a test article (ie- drug or biological) 
which may carry a potential for central nervous system (CNS) effect(s)?
No
Procedures
Standard of Care: In light of the demonstrated health risks associated with daily opioid doses greater 
than 90mg MED, current practice at the Penn Pain Medicine Center is to taper all chronic pain patients 
down to or below this MED and to stabilize on the lowest effective dose as agreed upon by the patient 
and prescriber. The actual rate of taper varies with tolerability and availability of dosages of opioid, but 
averages 10-15% decrease/month. Final stabilization dose also varies between patients but the goal to 
achieve a daily dose of 90mg MED. Prior to attempting taper, an adequate trial of all non-opioid and 
non-pharmacologic interventions are provided so that the patients chronic pain is under maximal 
control. Research Purposes:  Baseline Study Session: Study data collection will begin immediately 
following consent, with the collection of urine toxicology, chronic pain and opioid use history, and 
baseline pain testing (see attached Data Collection Schedule). It is expected that it will take 30min to 
complete the baseline measures and another 30min to perform the pain testing battery, totaling 60min 
for the first session; subsequent sessions should last no longer than 30min. Study Sessions. All data 
collection will take place in a private office located in the Penn Pain Medicine Center, with sessions 
scheduled within 3hrs of morning opioid dose, and subjects instructed to ingest no caffeine or nicotine 
for 1hr prior to each session. Concurrent medication use since last visit, and last menstrual period date 
for female participants will be documented. A withdrawal score and urine sample for toxicology will be 
collected immediately prior to pain testing to verify compliance with opioid treatment. Sessions will be 
scheduled to coincide with regular clinic visits as possible. All study data will be collected using 
REDCap (Research Electronic Data Capture), utilizing PhenX data collection tools as available. Pain 
Responses: The primary dependent variable, pain, will be measured using two highly reliable and valid 
pain induction techniques, the CPT and QST, employing procedures consistent with those described in 
the literature. Order of pain testing will vary, and three aspects of the pain response will be captured at 
each study session: evoked pain; temporal summation; and conditioned pain modulation, which map on 
to the hypothesized peripheral, spinal and supra-spinal mechanisms of OIH. Protocols for each assay 
have been uploaded.  Evoked pain perception: The CPT apparatus consists of a circulating water bath 
maintained at 1°C ± 0.5°C, into which subjects immerse their dominant hand and forearm to elicit a 
nociceptive response. Elapsed time until pain threshold and tolerance are reached measures evoked 
pain. A stopwatch is simultaneously activated with arm immersion, and subjects instructed to indicate 
when the cold sensation becomes a painful sensation (pain threshold), and when the pain becomes 
subjectively intolerable or spontaneous hand removal (pain tolerance). Immediately after hand 
withdrawal, subjects are asked to mark maximal pain intensity on a computerized visual analogue scale 
(Co-VAS, 0-100).  Temporal Summation (TS): As a component of QST, a thermal testing analyzer 
(TSA; Medoc TSA-2001 device) with a sized 30 x 30 mm Peltier thermode, is used for the assessment 

Page 16 of 21
of thermal temporal summation (TS), reflecting increased rate of firing of ascending pre-synaptic 
neuron with ongoing stimulation. Specifically, tonic noxious heat stimulation will be applied to the 
dominant volar using a ramp-and-hold method. The baseline temperature will be set to 32.0°C and will 
be increased at a rate of 1°C/s up to a destination temperature of 46.5°C and then will remain constant 
for 120 sec. Along the entire test duration (a total duration of 135 seconds), subjects continuously will 
rate the magnitude of their perceived pain using a computerized visual analogue scale (Co-VAS, 0-100).  
Conditioned Pain Modulation (CPM): Again using QST apparatus, the TSA thermode is applied to the 
thenar eminence of the dominant hand, and subjects asked to verbally report pain intensity of five (5) 
heat pain stimuli of 47ºC (starting from 37ºC at an increasing and decreasing rate of 10ºC/s), each 
lasting 3 seconds with an interval of 12 seconds. Following these baseline measures, subjects are 
instructed to report the intensity of the same heat pain stimuli with their non-dominant hand immersed 
in a cold-water bath (12ºC) at 15 and 30 seconds of immersion. Finally, subjects are instructed to 
remove their hand from the cold water bath, and rate severity of two additional heat pain stimuli 
administered at 15 and 30 seconds. Comparison of perceived pain severity with and without counter- 
stimulation (heat pain, ice bath) provides evidence of supra-spinal modulation of pain responses. 
Concurrent with pain testing, the presence of opioid withdrawal symptoms using the well-validated 
clinical opiate withdrawal scale (COWS) (94,95) will be assessed. Although prescribed analgesics will 
not be introduced during the taper, the concurrent use of over-the-counter (OTC) analgesics will be 
recorded. In addition, urine toxicology is collected to ensure that subjects are taking only their 
prescribed opioid at each pain data collection session. To account for the effects of disease progression 
and increased physical activity on pain responses, the study physician will evaluate subjects monthly for 
evidence of disease progression, and each will be asked to complete a weekly Stanford Physical 
Activity Scale.(96)  Functional Outcomes. To evaluate if opioid taper improves functional outcomes 
vis-à-vis improved pain responses, the PROMIS® (Patient-Reported Outcomes Measurement 
Information System) person-centered measures will be utilized (http://www.healthmeasures.net/
explore-measurement-systems/promis).(97) Specifically, functional and quality of life indicators from 
the physical health (pain intensity, pain interference, physical function), mental health (life satisfaction), 
and social health (ability to participate in social roles and activities) PROMIS domains will be collected 
on a monthly basis and inspected for change in relationship to changes in experimental pain assay 
performance. Completion of monthly PROMIS measures is standard-of-care at the Penn Pain Medicine 
Center, so presents no additional burden to study participation. Predictor Variables. Demographic 
characteristics of the patient (age, ethnicity, gender), pain severity and chronicity, and a detailed opioid 
use history will be collected at baseline. The opioid use history assessment will assess the estimated no. 
months dependent on opioids, MED, and types/potency of opioids predominantly used at admission. 
Data will be gathered via patient self-report and extracted from the EMR.
The following documents are currently attached to this item:
Procedures (datacollectionschedule.docx)
Procedures (appacoldpressortestinginstructionsandscript.docx)
Procedures (appbquantitativesensorytestinginstructionsandscript.docx)
Deception
Does your project use deception?
No
International Research
Are you conducting research outside of the United States?
No
Analysis Plan
Preliminary Analyses. Preliminary analyses will include generating descriptive statistics for all baseline 
measures to characterize the sample, including measures of central tendency and variation for 
continuous variables; for dichotomous/categorical variables, measures will include frequencies and 
percentages. Distributional properties will be examined to determine if variance stabilizing or 
normalizing transformations are required. Non-inferential interim analyses will be performed to ensure 
data collection and archiving procedures are operating correctly. Outliers will be assessed by visual 
inspection and checked for accuracy. Normality will be assessed using Shapiro-Wilk tests; should 
violations emerge (i.e., cold-pressor data are anticipated to be bimodal), transformations or non-
parametric tests will be used. Due to known differences in pain responses between men and women, sex 

Page 17 of 21
as a biological variable will considered in all analyses.  Statistical Analyses. The effect of opioid taper 
on changes in pain responses (CPT, QST), and functional outcomes (PROMIS domains) over time will 
be examined using longitudinal mixed-effects regression modeling, using general linear regression 
modeling with regularization as a function of baseline dose, end dose, and taper rate. These longitudinal 
profiles will be examined using a linear mixed effects framework with SAS Proc Mixed in which all 
available data collected during follow-up are used. Mixed models can account for the correlation 
between repeated measures and handle non-excessive missing data better than traditional models and 
allow for use of time-independent and time-dependent covariates. To assess patterns of attrition over 
time, a comparison of withdrawal rates and time to withdrawal will be included. Separate mixed effects 
regression models will be generated for each of the continuous outcome measures of interest (pain 
responses, functional outcomes). Random slopes and intercepts will be modeled to represent the 
participant-level deviation from the fixed-effect slope over time and intercept, respectively. Restricted 
maximum likelihood estimation will be used and the most appropriate covariance structure examined. 
Scores will be analyzed as repeated observations of the dependent variable, with mean-centered 
baseline outcome scores serving as a covariate. Other predictor variables will include baseline 
demographic characteristics of the patient, severity and chronicity of pain suffered, and opioid use 
history. Baseline measures will be analyzed as time-independent covariates. The Akaike information 
criterion will be used to evaluate overall model fit and to select the best-fitting longitudinal change 
pattern. .
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Data confidentiality
x Paper-based records will be kept in a secure location and only be accessible to personnel involved 
in the study.
x Computer-based files will only be made available to personnel involved in the study through the 
use of access privileges and passwords.
x Prior to access to any study-related information, personnel will be required to sign statements 
agreeing to protect the security and confidentiality of identifiable information.
x Wherever feasible, identifiers will be removed from study-related information.
A Certificate of Confidentiality will be obtained, because the research could place the subject at 
risk of criminal or civil liability or cause damage to the subject's financial standing, 
employability, or liability.
A waiver of documentation of consent is being requested, because the only link between the 
subject and the study would be the consent document and the primary risk is a breach of 
confidentiality. (This is not an option for FDA-regulated research.)
Precautions are in place to ensure the data is secure by using passwords and encryption, because 
the research involves web-based surveys.
Audio and/or video recordings will be transcribed and then destroyed to eliminate audible 
identification of subjects.
Subject Confidentiality
All records will be kept strictly confidential. No one except the researchers will know the subjects are in 
a research study. Data forms for the collection of health and study data will be coded with each subjects 
unique identification number. No data form will identify the participants by name. Hardcopies of data 
forms will be kept in locked files with keys held only by the study investigator. No presentation or 
publication of the results of this study will refer to the individual participants or present information 
that would identify any participant. All persons working on the proposed work will have completed 
HIPAA training and the Collaborative Institutional Training Initiative (CITI) Basic Courses in the 
Protection of Human Research Subjects and Biomedical Focus Responsible Conduct of Research 
(RCR) modules.
Sensitive Research Information*
Does this research involve collection of sensitive information about the subjects that should be excluded 
from the electronic medical record?

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No
Subject Privacy
Privacy refers to the person's desire to control access of others to themselves. Privacy concerns people, 
whereas confidentiality concerns data. Describe the strategies to protect privacy giving consideration to 
the following: The degree to which privacy can be expected in the proposed research and the safeguards 
that will be put into place to respect those boundaries. The methods used to identify and contact 
potential participants. The settings in which an individual will be interacting with an investigator. The 
privacy guidelines developed by relevant professions, professional associations and scholarly 
disciplines (e.g., psychiatry, genetic counseling, oral history, anthropology, psychology). 
Privacy will be strictly maintained in all aspects of participation. Screening and testing sessions will 
take place in private rooms at the U Penn Pain Medicine Clinic where strict patient privacy is enforced 
and all staff are HIPAA certified.
Data Disclosure
Will the data be disclosed to anyone who is not listed under Personnel?
Study data will not be disclosed to anyone who is not listed under Study Personnel.
Data Protection*
x Name
x Street address, city, county, precinct, zip code, and equivalent geocodes
x All elements of dates (except year) for dates directly related to an individual and all ages over 89
x Telephone and fax number
Electronic mail addresses
x Social security numbers
x Medical record numbers
Health plan ID numbers
Account numbers
Certificate/license numbers
Vehicle identifiers and serial numbers, including license plate numbers
Device identifiers/serial numbers
Web addresses (URLs)
Internet IP addresses
Biometric identifiers, incl. finger and voice prints
Full face photographic images and any comparable images
Any other unique identifying number, characteristic, or code
None
Does your research request both a waiver of HIPAA authorization for collection of patient information 
and involve providing Protected Health Information ("PHI") that is classified as a "limited data set" 
(city/town/state/zip code, dates except year, ages less than 90 or aggregate report for over 90) to a 
recipient outside of the University of Pennsylvania covered entity?
No
Tissue Specimens Obtained as Part of Research*
Are Tissue Specimens being obtained for research?
No
Tissue Specimens - Collected during regular care*
Will tissue specimens be collected during regulator clinical care (for treatment or diagnosis)?
No

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Tissue Specimens - otherwise discarded*
Would specimens otherwise be discarded?
No
Tissue Specimens - publicly available*
Will tissue specimens be publicly available?
No
Tissue Specimens - Collected as part of research protocol*
Will tissue specimens be collected as part of the research protocol?
No
Tissue Specimens - Banking of blood, tissue etc. for future use*
Does research involve banking of blood, tissue, etc. for future use?
No
Genetic testing
If genetic testing is involved, describe the nature of the tests, including if the testing is predicative or 
exploratory in nature. If predictive, please describe plan for disclosing results to subjects and provision 
of genetic counseling. Describe how subject confidentiality will be protected Note: If no genetic testing 
is to be obtained, write: "Not applicable."
Not applicable
Consent
1. Consent Process
Overview
After expressing interest in the study to the co-investigator study physician, the project manager will 
meet with the prospective participant in a private office to review the consent document as well as 
provide an oral explanation of the study. Individuals will be given a chance to ask questions before 
making a considered decision about whether or not to participate in the study. Via the consent process, 
prospective subjects will be reminded that their participation in this study is entirely voluntary, and that 
they should carefully read the information in the consent, and ask questions about anything not 
understood, before deciding whether or not to participate. It will be emphasized that they have the right 
to refuse to participate in this study, and if they choose not to participate, it will not affect their 
relationship with the University and their right to health care or other services otherwise entitled. 
Prospective subjects will also be informed that if they decide to participate, they are free to withdraw 
consent and discontinue participation at any time without prejudice to future care at the University of 
Pennsylvania. As stipulated in the consent form, subjects may withdraw consent at any time and 
discontinue participation without penalty. No legal claims, rights or remedies are waived as a result of 
their participation in this research study. Consent will be obtained by the study physician.
Children and Adolescents
Not applicable
Adult Subjects Not Competent to Give Consent
Not applicable
2. Waiver of Consent
Waiver or Alteration of Informed Consent*
No Waiver Requested
Minimal Risk*
Impact on Subject Rights and Welfare*

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Waiver Essential to Research*
Additional Information to Subjects
Written Statement of Research*
No
If no written statement will be provided, please provide justificiation
The following documents are currently attached to this item:
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Risk / Benefit
Potential Study Risks
Cold-Pressor Pain Induction (CP): As it will induce acute pain, the cold-pressor (CP) procedure will 
cause the subject discomfort. Subjects will be assured via the consent process that they may discontinue 
their study participation at any time if they decide not to undergo the painful experience. The PI has 
performed these pain induction techniques on close to 200 subjects in past research endeavors without a 
single adverse event. Throughout the pain procedures, vital signs will be continuously monitored and 
staff available to communicate any discomforts they may experience. Potential CP risks to the subjects 
are minimal; injury including tissue damage is unlikely as exposure time is to be short ( 5min); the 
subject can remove the hand from the ice water should it become subjectively intolerable and all trials 
will be truncated at 300 seconds. No adverse effects have been reported with the CP pain induction 
technique in over 75 years of published research.  Quantitative sensory testing Pain Induction (QST): 
Like the cold-pressor procedure, the QST is designed to induce acute pain, thus will cause the subject 
discomfort. Subjects will be assured via the consent process that they may discontinue their study 
participation at any time if they decide not to undergo the painful experience. Vital signs will be 
measured before and after the test, and study staff available to communicate any discomforts they may 
experience. The heat devices are designed not to exceed safe temperatures and have automatic shut-off. 
Potential risks to the subjects are minimal, which include a burn such as a bad sunburn. These happen 
very infrequently (1%).  Breach of Confidentiality: Participation in this study may constitute a social 
risk to the participant in that others may learn that he or she takes opioids regularly for chronic pain. 
Due to the sensitive nature of this information, privacy and confidentiality will be strictly maintained in 
all aspects of participation. Testing sessions will take place in private rooms where strict privacy is 
enforced and all research and clinical staff are HIPAA certified.
Potential Study Benefits
The potential benefit for both the participants and broader segments of society is to improve the 
management of chronic pain so as to improve outcomes in this challenging and growing patient 
population, including increases in functionality, satisfaction with treatment and quality of life. Better 
understanding of the pros and cons of opioid therapy for the treatment of chronic pain can guide clinical 
practice based upon evidence.  Participants will be informed that, with the exception of study payment, 
no direct benefit is expected to accrue to them from participation in the study.
Alternatives to Participation (optional)
Data and Safety Monitoring
The Principal Investigator will have responsibility for monitoring the safety management of this trial, 
and comply with the reporting requirements. The PI will be responsible for monitoring the data to 
ensure safety of participants and will closely supervise the research staff by means of regularly 
scheduled weekly meetings to discuss interactions with the participants. Monitoring meetings will be 
conducted monthly with the investigative team throughout the study.
The following documents are currently attached to this item:
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Risk / Benefit Assessment
Participants will be informed that, with the exception of study payment, no direct benefit is expected to 
accrue to them from participation in the study. Based on the characteristics of the risks associated with 
study participation, and efforts in place to minimize these risks, the risks to subjects are reasonable in 
relation to the anticipated benefits to research participants and others. The potential benefit of this study 
is expected to far outweigh any minimal risk by providing valuable information on the effects of opioid 
therapy on chronic pain and functionality.
General Attachments
The following documents are currently attached to this item:
Informed consent form (icfopioidtapertrackedchanges9.17.18pc.doc)
Questionnaires (promis-paininterference.pdf)
Questionnaires (cows.pdf)
Questionnaires (lansstool.pdf)
Questionnaires (stanfordexercisequestionnaire.pdf)
Grant Application (comptonr21_egrant.pdf)
Informed consent form (icfopioidtaperfinal.doc)
Additional forms (references.docx)
Recruitment materials (recruitmentflyertaperstudy7.23.18sp.pdf)
Informed consent form (icfopioidtapercleancopy9.17.18pc.doc)
Cover Letter (responsestoirbstipulations9.17.18pc.docx)