Conditions: Pain
Keywords: Breast cancer Pain sensitivity
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 82
Healthy volunteers: no

Brief summary:
Early stage breast cancer is typically treated with surgery, chemotherapy, radiation therapy, and/or endocrine therapy. Following treatment, 25-60% of breast cancer survivors have reported chronic pain, which can be difficult to manage. Duloxetine is a serotonin norepinephrine reuptake inhibitor that is FDA approved for treatment of depression, anxiety, fibromyalgia, diabetic neuropathic pain, knee arthritis, and low back pain.

Pilot data suggest that duloxetine is effective in management of endocrine therapy-associated musculoskeletal pain, and a randomized placebo controlled trial of duloxetine has demonstrated efficacy for treatment of chemotherapy-induced neuropathic pain. In this mechanistic study of duloxetine, we will investigate the change in pain sensitivity with treatment in order to evaluate both why duloxetine is effective for management of pain for some patients, as well as predictors of who is likely to benefit from duloxetine. A total of 84 women with early stage breast cancer who have chronic pain following treatment, as well as 48 women who are pain free, will be enrolled. All subjects will undergo assessment of pain sensitivity and complete questionnaires. Subjects with pain will be treated with duloxetine for a total of 7 weeks, with pain sensitivity assessments before treatment and after 4 weeks of full-dose treatment.

Detailed description:
Early stage breast cancer is typically treated with surgery, chemotherapy, radiation therapy, and/or endocrine therapy. Following treatment, 25-60% of breast cancer survivors have reported chronic pain, which can be difficult to manage. Duloxetine is a serotonin norepinephrine reuptake inhibitor that is FDA approved for treatment of depression, anxiety, fibromyalgia, diabetic neuropathic pain, knee arthritis, and low back pain.

Data from a randomized, placebo-controlled clinical trial of duloxetine demonstrated that it is effective in management of both aromatase inhibitor-associated musculoskeletal pain and chemotherapy-induced neuropathic pain. In this mechanistic study, we investigated the change in pain sensitivity with treatment in order to evaluate both why duloxetine is effective for management of pain for some patients, as well as predictors of who is likely to benefit from duloxetine. The original protocol was designed as a randomized, placebo-controlled cross-over trial, with planned enrollment of a total of 84 women with early stage breast cancer who have chronic pain following treatment, as well as 48 women who are pain free. However because of challenges with logistics of the protocol and pain testing, the trial was redesigned after only 7 patients with pain were enrolled. The new design was a single arm trial, and all patients with pain were treated with duloxetine (no placebo); there was still a non-treatment comparator arm of patients without pain. Patients were enrolled first at the University of Michigan and then the University of Utah. A total of 39 patients with pain and 43 controls without pain were enrolled before the trial closed to enrollment. All subjects underwent assessment of pain sensitivity and completed questionnaires. Subjects with pain were treated with duloxetine for a total of 7 weeks, with pain sensitivity assessments before treatment and after 4 weeks of full-dose treatment. The data from the control patients (who did not receive any study medication) are being compared to those from the patients with pain to understand more about the differences between patients who do and do not experience treatment-related pain, and to interpret the post-intervention patient-reported and pain assessment results.

Arms:
arm 1: Duloxetine 30 mg daily x 1 week, then 60 mg daily x 4 weeks, then 30 mg daily x 2 weeks. arm 2: Patient reported pain and symptoms assessment for comparison at baseline.

Interventions: intervention 1: Duloxetine
Intervention descriptions: intervention 1: Subjects will receive 30 mg duloxetine orally for 7 days, then 60 mg duloxetine orally for 28 days, then 30 mg duloxetine orally x 14 days.

Protocol document:
Prot_SAP_000.pdf: 
Duloxetine for chronic pain, UMCC 2013.044 
 
Page i 
 
 
 
 
 
 
 
 
A STUDY TO IDENTIFY PREDICTORS OF RESPONSE TO DULOXETINE IN BREAST 
CANCER PATIENTS WITH CHRONIC PAIN, UMCC 2013.044 
 
Clinicaltrials.gov: NCT01912612 
 
 
Principal Investigator 
N. Lynn Henry, MD PhD 
 
Co-Investigators 
 
 
 
Anesthesiology: 
 
Steven Harte, PhD 
 
 
David A. Williams, PhD 
 
Biostatistics: 
 
Alexander Tsodikov, PhD 
 
Medical Oncology: 
 
Anne Schott, MD 
 
Study Coordinators: 
Katherine Scott 
 
Ryan Scott 
                                                                        
 
 
 
Protocol Version 1.0: April 10, 2013 
Protocol Version 1.1: April 25, 2013 
Amendment 1 
Protocol Version 1.2: May 20, 2013 
Protocol Version 2.0: June 27, 2013 
Amendment 2 
Protocol Version 2.1: August 8, 2013 
Amendment 3 
Protocol Version 3.0: October 2, 2013 
Amendment 4 
Protocol Version 4.0: Nov 30, 2013 
Amendment 5 
Protocol Version 5.0: May 15, 2014 
Amendment 6 
Protocol Version 6.0: Sept 6, 2014 
Amendment 7 
Protocol Version 7.0: May 5, 2015           Amendment 8 
Protocol Version 8.0: May 13, 2020 
Amendment 9 
 


Duloxetine for chronic pain, UMCC 2013.044 
 
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Amendment 1 (4/25/2013) 
 
Section 5.5. Added to ineligibility criterion #13 (page 12): Urine pregnancy test will be assessed at the 
baseline visit in women of child-bearing potential with chronic pain.  
 
Section 8.0 (page 16). Add urine pregnancy testing at baseline visit to schedule of events. Comment at 
bottom states only to be done in subjects with chronic pain, not in controls. 
Section 8.2 (page 18). Add urine pregnancy testing to list of events occurring at baseline visit. Should 
occur prior to randomization in order to confirm eligibility. 
 
Section 8.2 (pages 21-22). Added description of the stamped mailing envelope that patients will use to 
return the study drug bottle at the end of the study. 
 
 
Updates (5/20/2013) 
 
 
Section 8.2 – clarified information about data that will be abstracted from the medical record. 
 
 
Updates (5/31/2013) 
 
 
Section 5.4 – revised inclusion criterion #3 to state that patients must have completed surgery, 
chemotherapy, and/or radiation therapy at least 12 weeks prior to study enrollment 
 
 
Study synopsis (page 3) – corrected typographical error, and changed 3 months to 12 weeks in order to 
be consistent with change listed above in section 5.4 
 
Amendment 2 (6/27/2013) 
 
1. Section 5.3: Clarification of subject recruitment sites.  
2. Section 5.4: Inclusion criteria #5 was changed to omit “at screening visit”. Subjects will be asked 
verbally to rate their pain level at the time of screening. 
3. Section 5.5: Added exclusion criteria prohibiting enrollment of subjects unable to take or absorb 
oral medication. 
4. Section 5.7: Added that subjects who discontinue study medication for more than 7 days will be 
removed from protocol treatment 
5. Section 5.7: Clarified which subjects who discontinue therapy early should taper off study 
medication and which do not require a taper. Also clarified off study evaluation for those subjects 
who discontinue treatment early. 
6. Section 6.2. Defined notation for randomization groups. 
7. Section 6.4. Added information about dose given at each time point as well as instructions for 
taking study medication. 
8. Section 6.5. Added section about dose modifications. 
9. Section 8. Updated schema 
10. Section 8.2. Screening. Deleted 1 week pain recall questionnaire. 


Duloxetine for chronic pain, UMCC 2013.044 
 
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11. Section 8.2 and Appendix. Added concomitant medication form to be completed by subjects at 
each visit. 
12. Section 8.2. Deleted references to Days throughout the protocol because if subjects complete a 
visit early, the next time period should start the next day and should not be counted from the 
beginning of study treatment. For example, if subjects undergo Visit 2 assessment on day 33 
instead of day 35, visit 3 should still be scheduled between 18-21 days later, not 20-23 days later 
as would be determined based on the start date of the first medication. In addition, medication 
bottles including any remaining capsules should be collected at visits 2, 3, and 4. 
13. Section 8.2 and Appendix. Added medication logs for subjects to complete during each treatment 
period. 
14. Section 8.2. Added vital sign assessment to Visit 1 for those subjects who do not undergo 
screening and Visit 1 on the same day. 
15. Section 12. Changed database from Apolo to REDCap. 
16. Made minor clarifications and corrections throughout protocol. 
 
 
Amendment 3 (8/8/2013) 
 
1. Added Ryan Scott as study coordinator. 
 
Amendment 4 (10/2/2013) 
1. Added Christine Kwiatkowski and Andrew Clauw as study coordinators on the protocol. They 
were previously added to eResearch and to the consent. 
2. Removed the ineligibility criterion about narcotics (pages 11-12). Potential subjects are permitted 
to take narcotics as long as they have been on a stable dose. This change was made because of 
difficulty with accrual. Use of narcotics will be included as a covariate in the analysis. 
3. Clarified the eligibility criteria for control subjects (page 11). 
4. Clarified the procedures that control subjects will complete (section 8.2 page 18) 
 
Amendment 5 (11/30/2013) 
1. Clarified the eligibility criteria related to prior SNRI therapy (page 12) 
2. Change reimbursement for screen failures. 
 
Amendment 6 (5/15/2014) 
 
1. Clarified the eligibility criteria related to patient-reported pain rating from average pain at least 4 
out of 10 to worst pain at least 5 out of 10 (page 11). We are having difficulty with patient accrual 
because many patients report relatively high worst pain scores but when they are asked to 
provide an average pain score it is typically quite low. However we think it appropriate to accrue 
patients with this intermittent, relatively high pain since it is bothersome when it occurs, even 
though it isn’t sustained.  
2. Changed the eligibility criteria related to eligible timeframe for subject enrollment from 8 to 12 
years (page 11). Patients are continuing to take adjuvant therapy for up to 10 years starting after 
completion of all local therapy and chemotherapy. We wish to include patients up to a few years 
beyond completion of treatment in order to include the entire treatment period. 
3. Unblind patients after the completion of all 4 study assessments so that patients who wish to 
continue on commercial supply of duloxetine can transition seamlessly from study drug to 
commercial drug (page 23). 


Duloxetine for chronic pain, UMCC 2013.044 
 
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Amendment 7 (9/6/2014) 
 
 
1. The intent of this amendment is to remove the placebo control from the protocol because of 
difficulty with accrual to the study. There were significant difficulties with recruitment of patients to 
the trial as originally designed, in part because a high proportion of breast cancer survivors with 
chronic pain require an antidepressant/anxiolytic medication and are reluctant to be on placebo 
for 7 weeks. Therefore the study team decided to revise the study design and convert it to a 
single-arm open label trial. The study objectives are unchanged: predictors of response to 
duloxetine in patients with chronic pain, and mechanism of action of duloxetine. The placebo 
effect should be equally distributed across participants with and without centralized pain, and 
therefore should not influence the assessment of predictors of response to duloxetine. The new 
design more accurately reflect real world decisions that face providers and patients when 
deciding whether to switch from one antidepressant medication to another based on the potential 
benefit-risk profile. Revision of the study led to changes in the statistical plan, as outlined in the 
statistical section of the protocol, and reduction in the number of planned enrolled patients with 
chronic pain to 84. Controls will be increased to 48 (approximately 2 controls per case). Because 
this is a very substantial change to the study design there are a number of changes being made 
in this amendment. 
2. Change study title and running head 
3. Update Synopsis with new trial design 
4. Update section 4.0 with information provided in #1 above. 
5. Update section 5.0 with new trial design. 
6. Update schema with new trial design (section 5.2) 
7. Clarified eligibility criteria for cases and controls (sections 5.3 and 5.4) 
8. Update section 6.0 with new trial design. Information about emergency unblinding (section 6.6) 
was deleted. 
9. Update study calendar section 8.0 
10. Update schedule of assessments section 8.2 based on new trial design 
11. Adjusted statistical plan (section 11) based on change in study design. 
12. Update data and safety monitoring language (Section 13) to reflect the fact this will no longer be a 
randomized trial design. 
 
 
Amendment 8 (05/05/2015) 
 
1. Added study team member, Cindy Alsamarraie, to the cover sheet of the protocol.  
 
Amendment 9 (5/13/2020) 
 
1. Protocol clarification amendment to clarify trial endpoints that comprise the overall study 
objectives. 
2. Changed names on protocol cover sheet to reflect current listing in eResearch 
 


Duloxetine for chronic pain, UMCC 2013.044 
 
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Table of Contents 
 
1.0 SYNOPSIS ..................................................................................................................................... 6 
2.0 INTRODUCTION ......................................................................................................................... 6 
3.0 STUDY OBJECTIVES ............................................................................................................... 12 
4.0 RESEARCH DESIGN AND METHODS .................................................................................. 12 
5.0 OVERALL STUDY DESIGN AND PLAN: DESCRIPTION ................................................... 13 
5.1 Overview of Study Design ..................................................................................................................................... 13 
5.2 Schema ................................................................................................................................................................... 14 
5.3 Recruitment and Screening ..................................................................................................................................... 14 
5.4 Inclusion Criteria .................................................................................................................................................. 144 
5.5 Exclusion Criteria ................................................................................................................................................... 15 
5.6 Replacement Procedures ........................................................................................................................................ 15 
5.6 Removal of Patients from Therapy ......................................................................................................................... 15 
 
6.0. DESIGN ...................................................................................................................................... 16 
6.1 Treatments Administered ....................................................................................................................................... 16 
6.2 Method of Assigning Patients to Treatment ........................................................................................................... 16 
6.3 Selection of Dosages in the Study .......................................................................................................................... 16 
6.4 Selection and Timing of Dose for Each Patient ...................................................................................................... 17 
6.5 Dose Modifications ................................................................................................................................................ 17 
7.0 Concomitant Therapy .................................................................................................................. 17 
7.1 Allowable Concomitant Therapy ............................................................................................................................ 17 
7.2 Prohibited Concomitant Therapy ............................................................................................................................ 18 
7.3 Treatment Compliance ........................................................................................................................................... 18 
8.0. Specific Methods ......................................................................................................................... 19 
8.1 Vital Signs .............................................................................................................................................................. 20 
8.2 Schedule of Assessments ........................................................................................................................................ 20 
9.0 Outcome Measures ...................................................................................................................... 24 
9.1 Primary Outcome Assessment ................................................................................................................................ 24 
9.1.1 Brief Pain Inventory ............................................................................................................................................ 24 
9.2 Secondary Outcome Assessments .......................................................................................................................... 24 
9.2.1 Pressure Pain Threshold ...................................................................................................................................... 24 
9.2.2 Conditioned Pain Modulation (CPM) .................................................................................................................. 25 
9.3 Patient-Reported Outcome Assessments ................................................................................................................ 25 
10.0 Safety Assessments .................................................................................................................... 26 
10.1 Adverse Events ..................................................................................................................................................... 26 
10.2 Causality Assessment ........................................................................................................................................... 27 
10.3 Severity Assessment ............................................................................................................................................. 27 
11.0 Statistical Methods and Determination of Sample Size ........................................................... 27 
12.0 Data Handling ........................................................................................................................... 29 
13.0  Data Safety and Monitoring .................................................................................................... 29 
14.0  REFERENCE LIST ................................................................................................................. 30 
15.0  APPENDICES .......................................................................................................................... 37 


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1.0 SYNOPSIS 
 
CLINICAL STUDY SYNOPSIS 
A study to identify predictors of response to duloxetine in breast cancer patients 
with chronic treatment-related pain 
Title of Study 
The primary objectives of this clinical trial are to (1) assess breast cancer survivors 
with chronic pain for the presence and degree of pain centralization and (2) 
identify predictors of response to the predominantly centrally-acting analgesic 
duloxetine in breast cancer survivors with chronic treatment-emergent pain.  
Objective 
Single arm, open label study. Patients will be treated with the following: 
7 weeks of duloxetine (1 week of dose escalation [30 mg/d], 4 weeks of stable 
dose [60 mg/d], 2 weeks of dose de-escalation [30 mg/d]). 
Methodology 
Number of Patients 
Approximately 124 patients planned (84 cases with chronic pain, and 48 controls 
without chronic pain) 
Diagnosis and 
Main Criteria for Inclusion 
Female outpatients, age ≥25 years, stage 0-III breast cancer, diagnosed ≥1 year 
prior to enrollment, who developed new or worsened chronic pain since breast 
cancer diagnosis that has been present for at least 12 weeks, and have a worst pain 
score 5-10 on a 10 point scale will be eligible for enrollment in this study 
Test Product, Dosage, and Mode of 
Administration 
 
 
Duloxetine 60 mg/d, oral administration 
Duration of Treatment 
Each patient will receive 7 weeks of duloxetine  
 
 
 
 
2.0 INTRODUCTION 
Chronic pain in Breast Cancer Survivors 
Over 200,000 women are diagnosed with breast cancer each year in the United States, and more 
than 80% are alive 10 years after diagnosis.1 Treatment generally includes surgery, radiation therapy, 
chemotherapy, and/or targeted therapies such as endocrine therapy. Choice of treatment is 
determined by assessing the likely benefit of each therapy for an individual patient, taking into 
consideration tumor characteristics and likelihood of disease recurrence, as well as patient 
preferences. Almost all women undergo treatment with surgical resection of their primary breast 
tumor, as well as limited or extensive axillary surgery. More than half of women will subsequently 
undergo chemotherapy, and the majority of those will receive a taxane-containing regimen, which 
can cause both acute pain and chronic neuropathy.2,3  
 
Most long-term breast cancer survivors recover fully from treatment. However, 25-60% experience 
chronic pain and associated symptoms, including disturbances in energy, sleep, and mood, which 
negatively impact quality of life.4-6 The etiology of these symptoms in patients that otherwise remain 


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free from disease recurrence is unclear, especially since all patients typically undergo similar 
procedures or therapy regimens. These treatments can lead to the following syndromes: 
 
 Regional chest wall pain: Patients with breast cancer typically undergo resection of the primary 
breast mass as well as axillary lymph node(s). The extent of surgical resection depends on tumor 
burden and patient preference. Almost all patients who undergo lumpectomy, as well as a subset 
who undergo mastectomy, will also receive adjuvant radiation therapy. Chronic post-surgical pain 
has been reported to occur in 20-68% of breast cancer survivors, can occur in the breast or chest 
wall as well as the axilla, shoulder, and arm following surgery, and can persist for years.5 
Radiation therapy has also been associated with an increased risk of chronic breast, chest wall, 
and axillary pain in breast cancer survivors.4,7 Surgery- and/or radiation-related nerve injury is 
believed to be the cause of the chronic pain; however, definitive evidence is lacking.5,8-11 
 
 Post-chemotherapy pain: Cytotoxic chemotherapy is administered to patients with breast cancer 
at increased risk of disease recurrence.12 Most adjuvant chemotherapy regimens contain a 
taxane. Taxanes have been demonstrated to cause acute pain in the days immediately following 
infusion as well as chronic sensory neuropathy in 30-40% of treated patients, which can be 
painful.2,3 Chemotherapy has also been associated with a three-fold increased risk of persistent 
pain following breast cancer treatment, including chronic generalized arthralgias, although the 
etiology remains uncertain.13,14 
 
 Endocrine therapy-associated arthralgias: Adjuvant endocrine therapy is recommended for 
almost all patients with estrogen receptor positive breast cancer because it significantly improves 
breast cancer outcomes.15,16 Endocrine therapy, including tamoxifen and the aromatase 
inhibitors, is associated with an increased risk of musculoskeletal pain compared to placebo.17,18 
Typically the distal joints, such as the hands and feet, are affected to a greater degree than the 
axial skeleton or weight-bearing joints.19 Importantly, aromatase inhibitor-associated 
musculoskeletal symptoms (AIMSS) occur in up to 50% of treated patients and are severe 
enough to result in treatment discontinuation in 20%, although the mechanism remains 
unknown.20,21 Peripherally acting medications such as non-steroidal anti-inflammatory drugs 
(NSAID) and opioids are only modestly effective for the treatment of AIMSS.22 We recently 
demonstrated in an open-label pilot clinical trial that treatment of AIMSS with the predominantly 
centrally-acting serotonin and norepinephrine reuptake inhibitor (SNRI) duloxetine results in a 
60% decrease in average pain.23 These findings suggest that AIMSS may be due, at least in part, 
to centrally-mediated mechanisms. 
 
Acute vs Chronic Pain 
Many of the mechanisms that underlie chronic pain differ from those that underlie acute pain. Acute 
pain states are typically due to inflammation and/or mechanical damage in peripheral structures (i.e. 
nociceptive input).  In chronic pain states, peripheral nociceptive input plays an important role, but 
there is no chronic pain condition where the degree of peripheral nociceptive input (as measured by 
an X-ray, MRI, or nerve conduction studies) accurately predicts whether an individual will be 
experiencing pain, or how severe the pain will be. Especially in population-based studies, many 
individuals are identified with severe peripheral abnormalities and no pain, and vice versa.24 This 
discrepancy between pain and evidence of peripheral damage or inflammation is being increasingly 
felt to be due to central nervous system (CNS)-directed facilitation and maintenance of pain (i.e., pain 
centralization).  


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Recent evidence suggests that 
factors such as female gender, a 
prior history of pain or other CNS-
mediated somatic symptoms, and 
inherited variants in genes 
associated with pain sensitivity, may 
constitute a pain-prone phenotype 
(Figure 1).25 In these patients, 
subsequent exposure to a variety of 
pain and other stressors can lead to 
pain centralization, as is seen in 
chronic pain conditions such as 
fibromyalgia.25-31 These centralized 
pain states are believed to be due to 
dysfunction of brain regions involving 
pain processing, mood, and level of 
alertness. Centralized pain is 
identifiable by abnormal quantitative sensory testing (QST) and abnormal CNS activation patterns on 
functional neuroimaging studies.25 In addition, subsets of individuals with “traditional” peripheral pain 
states such as chronic low back pain and osteoarthritis can also have prominent pain centralization, 
such that peripheral nociceptive input (i.e., damage or inflammation in the periphery) is not the sole 
driver of symptom expression. The evidence for this includes epidemiologic studies, mechanistic 
studies (e.g., QST, functional neuroimaging, and genetic studies) and therapeutic trials (e.g., that the 
SNRI duloxetine decreases knee and low back pain).32-37 Although localized inflammatory processes 
typically respond to standard analgesics such as NSAIDs, centralized pain generally requires 
treatment with therapies such as SNRIs that target abnormal levels of CNS neurotransmitters 
involved in the pathogenesis of centralized pain. 
The impact of these CNS factors on chronic pain in breast cancer has not been directly investigated. 
However, a number of findings suggest that similar factors may be present in breast cancer patients 
who develop chronic pain following surgery, chemotherapy, and/or endocrine therapy. For example, 
multiple factors have been shown to be associated with centralization in chronic pain syndromes. In 
breast cancer survivors, CNS-driven somatic symptoms, such as fatigue, sleep disturbances, 
cognitive dysfunction, anxiety, and depression, are common.6 In addition, an association between 
chronic pain and fatigue in breast cancer survivors and a variant in the catechol-O-methyltransferase 
gene known to be associated with pain sensitivity has been reported.38,39 Taken together, these 
results suggest that pain centralization could play an important mechanistic role in chronic pain in 
breast cancer survivors, which is the basis of the hypothesis underlying this clinical protocol.   
Based on these preliminary data we hypothesize that a subset of breast cancer patients have a 
“pain-prone” phenotype and are predisposed to development of centrally-mediated treatment-related 
pain and co-morbid CNS-mediated somatic symptoms including fatigue, sleep disturbances, 
cognitive difficulties, and mood disturbances following diagnosis of their cancer. In order to 
investigate this hypothesis, we plan to enroll breast cancer patients with and without chronic pain on 
this clinical protocol. We expect to identify inter-patient differences in markers of pain centralization, 
including pain sensitivity, pain modulation patterns, and patient-reported symptom clusters. We will 
also investigate the mechanistic effects of the primarily centrally-acting analgesic duloxetine in breast 
cancer survivors with chronic pain, and hypothesize that response to the therapy is associated with a 
subject’s degree of pain centralization. This knowledge could lead to individualization of therapy for 
the thousands of breast cancer survivors with chronic pain and lead to decreased pain and improved 
quality of life for these women.   
Figure 1. Model depicting centralization of pain and development 
of chronic pain following nociceptive input 
Pain Prone Phenotype
•
Female
•
Personal history of centrally-mediated symptoms (widespread pain, 
fatigue, sleep disorders, mood disorders, cognitive disorders)
•
Functional abnormalities in pain processing
•
Abnormal quantitative sensory testing
•
Abnormal CNS activation on functional imaging
•
Genes associated with centralization of pain
•
Early life trauma
Exposure to stress and/or acute, peripheral nociceptive input
Centralization of pain
Chronic pain


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Interventional Phenotyping of Centralization of Pain 
Currently, there is no single biomarker of centralization of pain. However, its presence can be 
inferred by assessing constructs known to occur differentially in individuals with predominantly central 
pain (e.g., fibromyalgia, irritable bowel syndrome, temporomandibular joint disorder) versus those 
with predominantly peripherally maintained pain or healthy controls. The two primary methods that 
will be used in this trial are QST to assess pressure pain threshold and conditioned pain modulation 
and self-report measures to assess pain and a constellation of centrally-associated somatic 
symptoms 
Quantitative Sensory Testing 
Members of the Chronic Pain and Fatigue Research Center (CPFRC) at the University of Michigan 
have developed a reliable method for objectively determining pressure pain threshold in chronic pain 
patients. The literature on the evaluation of sensitivity to blunt pressure had previously been based 
on clinical methods involving manual palpation or on the use of devices termed pressure algometers 
or dolorimeters, and evaluated pain threshold using continuously increasing pressure. However, 
continuously ascending methods are vulnerable to extraneous factors such as distress. Therefore, 
investigators at the University of Michigan developed a computer-operated system in combination 
with random staircase paradigms. Delivering discrete pressure using “random” paradigms (where the 
test participant cannot guess what the next stimulus will be) leads to a measure of pressure pain 
threshold that is relatively immune to biases that confound other conventional measures of pain 
threshold. The results of these tests in either cross-sectional or longitudinal studies are highly 
correlated with changes in functional imaging activation patterns, clinical outcomes, and a number of 
other relevant domains.26,40,41 These measures have been extensively used and reported in all of the 
CPFRC’s studies for the past decade, and have not only been shown to be less influenced by 
psychological factors, but also have been superior in responsiveness to change in clinical trials, and 
correlation with biological data in neuroimaging studies.26,40,41 Dr. Harte and his colleagues at the 
University of Michigan College of Engineering developed a simple handheld device, called the 
Multimodal Automated Sensory Testing (MAST) System,42,43 which provides reliable measurements 
of mechanical pain sensitivity. We have previously demonstrated the feasibility of using this testing in 
postmenopausal breast cancer patients starting AI therapy, and will employ this methodology in this 
study to assess pain sensitivity in breast cancer survivors with chronic pain related to treatment, as 
one component of assessment of pain centralization.  
Threshold and suprathreshold indices of secondary 
hyperalgesia (i.e., as measured at a neutral site) will be 
assessed by pressure applied to the thumbnail, a site 
which was chosen because it is a neutral, pain-free site 
remote from the area of surgery with dense nociceptor 
innervation. We have extensive experience using 
thumbnail pressure as an evoked pain stimulus and its 
validity in the measurement of centralized pain has been 
discussed extensively.40,44-51 Using QST, fibromyalgia 
patients show significantly lower pain thresholds at the 
thumbnail compared to age- and sex-matched healthy 
controls (HC) (Figure 2). We have also demonstrated that 
experimental pain evoked by thumbnail pressure is 
associated with overall body tenderness,51 clinical 
pain,40,52 and functional neuroimaging,26 and is lowered 
following analgesic treatment.53  
Figure 2. Fibromyalgia (FM) patients have 
lower pressure pain thresholds compared to 
healthy controls (HC). Red bars represent 
mean threshold.


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Bilateral pressure pain testing will also be conducted using a digital algometer at the deltoid muscle 
to assess surgery-induced primary hyperalgesia. The inclusion of this site was based on recent 
evidence showing that pressure pain threshold was bilaterally reduced at the deltoid muscle in BCS 
compared to healthy controls, and that pressure pain threshold at the affected deltoid was negatively 
correlated to neck pain intensity.54  
Abnormal pain modulation patterns have also been shown to be associated with chronic pain 
disorders. In healthy humans and laboratory animals, application of a painful stimulus to one part of 
the body produces generalized whole-body analgesia, termed conditioned pain modulation 
(CPM).55,56 CPM has been consistently observed to be less efficient in approximately two-thirds of 
patients with centralized pain.57-60 Less efficient CPM is believed to reflect decreased descending 
inhibitory pain control and is thought to be a potential marker of centralization of pain. This less 
efficient CPM can lead to increased sensitivity to pain, which is believed to be mediated in part by an 
attenuated serotonin-norepinephrine system.61 Therefore, treatment with duloxetine, which inhibits 
serotonin and norepinephrine reuptake, may work in part by restoring CPM in patients with 
centralized pain, resulting in decreased pain. In support of 
this hypothesis, Yarnitsky et al recently reported that less 
efficient CPM was predictive of response to duloxetine in 
diabetic peripheral neuropathic pain.62 CPM is assessed by 
testing with a unilateral painful test stimulus (black bars in 
Figure 3), followed by reassessment with that stimulus in 
combination with a contralateral painful stimulus (grey bars 
in Figure 3), and is defined as the pain rating with both 
stimuli minus the pain rating with only the unilateral stimulus. 
Less efficient CPM (higher/positive values) is seen in large 
proportions of individuals with central pain conditions such 
as FM and in smaller proportions of individuals with 
conditions such as osteoarthritis.55-57,60,63-66 By evaluating 
CPM as a continuous rather than a dichotomous outcome, 
Yarnitsky and others have also shown that CPM magnitude 
is predictive of a variety of adverse pain outcomes, including 
chronic post-thoracotomy pain.63,64,67  
Patient reported outcomes  
Patient self-report data will be used to characterize pain and response to therapy, and to evaluate 
degree of centralization of pain, using the questionnaires listed below. The CPFRC has been 
involved in the development and validation of outcomes instruments for multiple chronic pain 
conditions.26 These measures have been used extensively by the CPFRC with a number of subjects 
with a variety of pain types as well as with healthy controls. This study will also take advantage of the 
heightened precision associated with the static short forms developed by the NIH Roadmap initiative 
PROMIS.68 PROMIS utilizes item response theory in the development of large item banks from which 
a relatively small number of highly informative items can be used to assess with precision a broad 
range of clinically relevant domains.31,69-74  
Assessment of pain  
o Clinical Pain. Pain severity and functional interference due to pain will be assessed using the 
Brief Pain Inventory (BPI),69  which has been recommended as a measure of choice for the 
assessment of pain in clinical research.75  The BPI has been extensively tested in numerous 
populations,76,77 and asks patients to rate their worst, least and average pain in the last week on a 
0-10 rating scale. A measure of functional interference from pain is also obtained from this 
measure.  
Measures of centralization of pain 
Figure 3. Comparison of CPM magnitude in 
healthy controls and fibromyalgia (FM) 
patients. 


Duloxetine for chronic pain, UMCC 2013.044 
 
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o The Michigan Body Map and Symptom Severity Scale, a modified version of the Wolfe Regional 
Pain Scale, will be used to quantify (a) any locations where patients experience pain using a 
checklist that allows for efficient scoring and (b) the severity of key symptoms associated with 
centralized pain, including fatigue, sleep disturbance, and disturbed cognitive function. Measures 
of pain distribution and the presence of this symptom cluster have been repeatedly found to be 
associated with centrally-mediated pain symptoms. 78-80 
o Qualitative Pain Characteristics. PainDETECT 70 is a 9-item measure of sensory descriptors, 
spatial, and temporal characteristics that has been shown to identify neuropathic components of 
pain in low back pain and in osteoarthritis.34 It distinguishes neuropathic from musculoskeletal 
pain.  
o Treatment-related toxicity. The FACT/GOG-NTX neurotoxicity module is an 11-item subscale 
specifically developed to address chemotherapy-associated peripheral neurotoxicity and its 
consequences on functional status.71 The subscale scores correlate with objective neuropathy 
measures, specifically pin sensibility, strength, and deep tendon reflexes.  
o Functional status, sleep, and fatigue. The following PROMIS short-forms will be used in this 
study: Fatigue, Sleep Disturbance, and Physical Function.68  The 7-item Fatigue scale assesses 
the experience of fatigue as well as its impact on physical, mental, and social activities. The 8-
item Sleep Disturbance scale assesses perceptions of sleep quality, sleep depth, and restoration 
associated with sleep. The 10-item Physical Function scale assesses self-reported function, 
including the ability to perform activities of daily living. The PROMIS scales possess favorable 
reliability and enhanced precision with lowered patient burden when compared to comparable 
legacy assessment instruments.   
o Psychiatric status. The Hospital Anxiety and Depression Scale (HADS) will be used to assess 
anxiety and depressive symptoms.81  The HADS is a 14 item questionnaire that has been 
extensively evaluated for the assessment of mood disorders in patients with cancer.93,94 
o Cognitive dysfunction. The 38-item Multiple Abilities Self-Report Questionnaire (MASQ),55,95,96  is 
comprised of five cognitive domains: language ability, visuo-perceptual ability, verbal memory, 
visual memory, and attention/concentration. Satisfactory reliability and validity have been 
demonstrated.72,82,83 
 
Treatment of Chronic Pain 
 
Many different kinds of medications are used in the treatment of chronic pain states such as 
fibromyalgia and irritable bowel syndrome; these medications have had varying degrees of 
success.84-86 Although antidepressants are the cornerstone of many treatment paradigms, other types 
of agents such as anticonvulsants, antispasticity agents, anxiolytics, sedatives, and opiates are also 
used. Many patients with chronic pain use NSAIDs and acetaminophen87 even though peripheral 
inflammation has not been demonstrated,88 and numerous studies have failed to confirm the efficacy 
of these analgesics in the treatment of fibromyalgia.89-93 These agents do, however, provide an 
element of protection against other peripheral pain generators such as osteoarthritis.  
 
Antidepressants of all varieties are a common form of therapy for many chronic pain states, including 
fibromyalgia.84-86,94 Most available antidepressants directly and/or indirectly increase the levels of 
serotonin (5-hydroxytryptamine) and/or norepinephrine in the CNS. Monoaminergic levels are 
increased either by inhibiting reuptake (by blocking transport proteins) or interfering with the 
breakdown of monoamine (by inhibiting the monoamine oxidase enzymes) after the monoamine is 
released into the synaptic cleft. Dual reuptake inhibitors, referred to as serotonin-norepinephrine 
reuptake inhibitors (SNRIs), are pharmacologically similar to tricyclic antidepressants such as 
amitriptyline and doxepin, exhibiting dual activity on serotonin and norepinephrine reuptake.95 
Fortunately, these newer agents are generally devoid of significant activity at other receptor systems, 


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resulting in diminished side effects and enhanced tolerability. Therefore, SNRIs have significant 
potential for the treatment of fibromyalgia and/or other chronic pain conditions.32,35,96,97 Although the 
mechanism of action is uncertain, Yarnitsky and colleagues recently reported that less efficient 
conditioned pain modulation was predictive of response to duloxetine in diabetic peripheral 
neuropathic pain,62 suggesting that increasing CNS levels of these neurotransmitters by blocking 
their reuptake may enhance descending analgesic pathways and decrease pain.  
 
Duloxetine, a selective SNRI with a preferential reuptake inhibition of norepinephrine over serotonin, 
has been approved by the United States Food and Drug Administration for the treatment of diabetic 
peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain. The plasma elimination 
half-life of duloxetine is about 12 hours. Elimination occurs mainly via the liver. A detailed description 
of the chemistry, pharmacology, and safety of duloxetine is provided in the Package Insert.98 
 
Significance and Innovativeness of the Study 
The majority of women diagnosed with early stage breast cancer in the United States have long-term 
disease-free survival. However, a subset develops treatment-related chronic pain, which can 
negatively impact quality of life and which is difficult to manage effectively. The etiology of this pain 
remains unexplained in the majority of cases. We hypothesize that a substantial percentage of breast 
cancer survivors with chronic pain has centralization of pain, and that the degree of centralization 
may predict responsiveness to centrally-acting analgesics such as duloxetine.  
 
We propose to perform quantitative sensory testing and assess patient-reported pain and centrally-
mediated symptoms in breast cancer survivors with chronic pain in order to determine if there is 
evidence of pain centralization. At the completion of this study we expect we will have investigated 
mechanisms that underlie both development of pain and response to the therapy, as well as 
identified predictors of benefit from the centrally-acting analgesic duloxetine on treatment-related 
chronic pain and co-morbid symptoms in breast cancer survivors. These results can potentially 
directly impact treatment of patients with chronic pain, as treatment with centrally-acting therapies 
such as duloxetine may be superior for decreasing pain and improving other symptoms compared to 
standard analgesics. In addition, we expect that these results will lead to additional mechanistic 
studies, such as investigating the role of CNS neurotransmitters in development of chronic pain and 
the impact of inherited genetic variants on predisposition to treatment-related pain. Ultimately, 
understanding the mechanisms underlying both development of chronic pain and response to 
therapy in breast cancer survivors could lead to individualized breast cancer treatment-decision 
making or preventive approaches for patients at increased risk of developing chronic pain, thereby 
improving quality of life. 
 
 
3.0 STUDY OBJECTIVES 
1) To assess breast cancer survivors with chronic pain for the presence and degree of pain 
centralization 
(2) To identify predictors of response to the primarily centrally-acting analgesic duloxetine in 
breast cancer survivors with chronic treatment-emergent pain. 
 
4.0 RESEARCH DESIGN AND METHODS 
 
The randomized, placebo-controlled, cross-over design was originally chosen because it enables 
each individual who enters the study to either support or refute our primary mechanistic hypothesis. 
However there were significant difficulties with recruitment of patients to the trial as originally 


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designed, in part because a high proportion of breast cancer survivors with chronic pain require an 
antidepressant/anxiolytic medication and are reluctant to be on placebo for 7 weeks. Therefore the 
study team decided to revise the study design and convert it to a single-arm open label trial. The 
study objectives are unchanged. The placebo effect should be equally distributed across participants 
with and without centralized pain, and therefore should not influence the assessment of predictors of 
response to duloxetine. The new design more accurately reflect real world decisions that face 
providers and patients when deciding whether to switch from one antidepressant medication to 
another based on the potential benefit-risk profile.  
 
5.0 OVERALL STUDY DESIGN AND PLAN: DESCRIPTION 
 
5.1 Overview of Study Design 
This is a single-center, single-arm, open-label study conducted at the University of Michigan’s 
Chronic Pain and Fatigue Research Center (Figure 4). Patients with stage 0-III breast cancer who 
have chronic pain that developed or worsened since breast cancer diagnosis and whose worst pain 
is rated at least 5 on a 10 point Likert-type scale and who meet the other inclusion and exclusion 
criteria outlined in Sections 5.4 and 5.5 will be eligible to enroll in the study.  
 
Patients with chronic pain (cases) who qualify for the study at Screening will begin a 1- to 4-week 
washout period (if necessary) to taper off antidepressants and other drugs that they are currently 
taken and that cannot be taken along with duloxetine therapy. Patients who successfully taper off all 
excluded medications and continue to meet all of the inclusion criteria (and no exclusion criteria) at 
Baseline/Randomization (Visit 1) will start treatment with duloxetine as indicated below and will 
undergo serial comprehensive assessment with questionnaires and QST. Patients will receive 7 
weeks of duloxetine (1 week of 30 mg/d, 4 weeks of 60 mg/d, and 2 weeks of 30 mg/d). QST and 
questionnaires will be completed prior to initiation of treatment and after 5 weeks of treatment, before 
reduction in dose to 30 mg/d. Patients who are tolerating duloxetine well, want to continue therapy 
using commercial supply, and do not want to taper off duloxetine will not be required to take the final 
2 weeks of 30 mg/d. 
 
The duration of participation in this study for cases with chronic pain will be 5-11 weeks, depending 
on the time required for patients to taper off excluded medications and depending on if patients wish 
to remain on commercial duloxetine following assessment #2. This study will randomize 
approximately 84 patients with chronic pain. 
 
Control subjects (n=48) who meet all eligibility criteria but who have average pain 0-1 on a 10 point 
scale will undergo assessment with questionnaires and QST at a single timepoint. 
 
In order to account for treatment heterogeneity, for both the case and control cohorts subjects will be 
enrolled in equal numbers into the following treatment “bins”: (1) surgery +/- radiation therapy, (2) 
surgery and chemotherapy +/- radiation therapy, (3) surgery and endocrine therapy +/- radiation 
therapy, (4) surgery, chemotherapy, and endocrine therapy +/- radiation therapy. 
 
 
 
 


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5.2 Schema 
 
Figure 4. Schema of clinical trial design. All subjects could have received radiation therapy. Chemo: 
chemotherapy, ET: endocrine therapy.   
 
5.3 Recruitment and Screening 
Approximately 84 patients with chronic pain will be enrolled. Female outpatients, age ≥25, who have 
chronic pain of at least 3 months duration that has developed or worsened since breast cancer 
diagnosis, and whose worst pain is rated at least 5 on a 0-10 scale, will be eligible for enrollment in 
this study. Subjects will be recruited from the Breast Oncology Clinics at the University of Michigan 
Comprehensive Cancer Center and from the Pain Clinics at the University of Michigan. Since many 
patients with chronic pain are treated in the Lymphedema Clinic (Occupational Therapy), the 
occupational therapists will be contacted in order to identify symptomatic and therefore potentially 
eligible patients in their clinics. In addition, 48 controls without chronic pain who otherwise meet the 
following eligibility criteria (inclusion #1-3, exclusion #1, 2, 4, 5, worst pain score 0-1, and not 
currently on medication for pain) will be recruited and will undergo baseline evaluation.  
 
5.4 Inclusion Criteria 
To be eligible to participate in this study as a case, patients must meet the following criteria: 
1. Written informed consent obtained from the patient before the initiation of any study-specific 
procedures 
2. Female patients at least 25 years of age  
3. Diagnosis of stage 0-III breast cancer within 12 years prior to enrollment. All indicated 
surgery, chemotherapy, and/or radiation therapy must have been completed at least 12 
weeks prior to enrollment. Concomitant endocrine therapy and trastuzumab are permitted. 
4. Pain that developed or worsened since breast cancer diagnosis and is not due to identifiable 
traumatic event or fracture  
5. Patient-reported  worst pain score between 5 and 10 (inclusive) on a 0-10 scale (assessed 
verbally) 
6. Female patients must be at least 1 year postmenopausal or surgically sterile; or must agree to 
use a medically acceptable form of contraception  
7. Willing to withdraw from selective serotonin reuptake inhibitors and tricyclic antidepressants 
prior to treatment initiation 
8. Patients who are currently taking NSAIDs and/or opioid pain medications must remain on a 
stable dosage throughout the duration of the study 


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5.5 Exclusion Criteria  
Patients who meet any of the following criteria will not be eligible to participate in the study as a case: 
1. Prior use of duloxetine or milnacipran. 
2. Prior use of venlafaxine specifically for treatment of pain (prior use for treatment of other 
indications, such as hot flashes, is permitted) 
3. Patients must not be taking any contraindicated medications listed on the duloxetine package 
insert including the following: phenothiazines, propafenone, flecanide, linezolid, or 
anticoagulation medication (e.g., heparin, warfarin); treatment with MAO inhibitor within 14 
days prior to registration 
4. Thumbnail abnormalities on either hand (such as due to chemotherapy or trauma, or artificial 
nails) that are likely to alter pain perception during testing 
5. Peripheral sensory neuropathy at the thumbs bilaterally that interferes with function and/or 
activities of daily living 
6. Significant risk of suicide based on the Investigator’s judgment  
7. History or behavior that would, in the Investigator’s judgment, prohibit compliance for the 
duration of the study. 
8. History of alcohol or other substance abuse or dependence within the year prior to registration 
9. Known chronic liver disease, end stage renal disease, or creatinine clearance <30 mL/min as 
defined by Cockroft-Gault equation 
10. Uncontrolled narrow-angle glaucoma. 
11. Clinically significant coagulation disorder 
12. Pregnant or breast-feeding. Urine pregnancy test will be assessed at the baseline visit in 
women of child-bearing potential with chronic pain. 
13. Unable to take oral medications or any medical condition that would interfere with the 
absorption of study medication capsules. 
 
Controls are patients without chronic pain who otherwise meet the following eligibility criteria 
(inclusion #1-3, exclusion #1, 2, 4, 5, worst pain score 0-1, and not currently on medication for pain) 
 
5.6 Replacement Procedures 
Patients with chronic pain who prematurely discontinue from this study after randomization may be 
replaced to obtain 84 completers.  
 
5.7 Removal of Patients from Therapy  
A premature discontinuation will occur when a patient who signed the informed consent form 
ceases participation in the study, regardless of the circumstances, before the completion of the 
protocol. Patients can be prematurely discontinued from the study for one of the following reasons: 
 
 
Failure to meet inclusion/exclusion criteria  
 
 
Adverse event (AE)  
 
 
Insufficient therapeutic response  
 
 
Discontinuation of study medication for more than 7 days 
 
 
Protocol violation, including lack of compliance 
 
 
Withdrawal of consent 


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 
Other reasons, such as administrative reasons or pregnancy  
 
All patients who prematurely discontinue from the study, regardless of the cause, should 
undergo a final assessment.  
 
Those subjects who are taking medication from the 4 week supply at the time of study 
discontinuation will be asked to undergo in person evaluation with QST and 
questionnaire completion). At that in person visit they will receive the 2 week supply of 
medication to taper off the study drug, will be called by the study team 1-2 weeks later 
to assess AEs, and will be given a stamped envelope in which to return the medication 
bottle. If they are not willing to return to clinic they will undergo the Final Evaluation 
(phone visit) and will be mailed the 2 week supply of medication to taper off the study 
drug. Subjects will be required to return all study drug and medication bottles. 
 
Those subjects who are taking medication from either the 1 week or 2 week supply at 
the time of study discontinuation will undergo the Final Evaluation (phone visit). No 
taper is required. Patients will be required to return all randomized study drug.   
 
6.0. DESIGN  
 
6.1 Treatments Administered 
The SNRI duloxetine was chosen because it is a predominantly centrally-acting analgesic with the 
broadest efficacy to date (in neuropathic pain, fibromyalgia, low back pain, and osteoarthritis), and 
the analgesic effects have consistently been shown to be independent of anti-depressive 
effects.99,100,96,101-104  SNRIs are thought to act primarily by increasing serotonin and norepinephrine 
transmission in the CNS, thereby augmenting and restoring pain modulation, resulting in decreased 
pain.61 The majority of patients who respond to duloxetine achieve a response within 2-4 weeks of 
initiating therapy.23,105 We have demonstrated the feasibility of treating cancer patients with 
duloxetine in trials evaluating its use for treatment of aromatase inhibitor-associated arthralgias23 as 
well as chemotherapy-induced painful neuropathy.106 This drug is also coming off patent soon so if 
these studies were to suggest efficacy in an identifiable subset of breast cancer patients, duloxetine 
would represent an inexpensive and safe treatment option, especially compared to the known 
toxicities associated with opioids and even NSAIDs.   
 
Study drug in the form of capsules will be provided by the University of Michigan Investigational Drug 
Service. An IND waiver has been obtained from the US Food and Drug Administration. 
 
6.2 Method of Assigning Patients to Treatment 
All patients will receive the same treatment regardless of treatment “bin.” Approximately equal 
numbers of patients will be enrolled in each treatment “bin”, which are: (1) surgery +/- radiation 
therapy, (2) surgery and chemotherapy +/- radiation therapy, (3) surgery and endocrine therapy +/- 
radiation therapy, (4) surgery, chemotherapy, and endocrine therapy +/- radiation therapy.  
 
6.3 Selection of Dosages in the Study 
The duloxetine dosage chosen for this study is based on experience obtained in previous dose-
finding and phase III studies. In a pilot study of duloxetine in aromatase inhibitor-associated 
arthralgias and in multiple placebo-controlled phase III clinical trials of duloxetine for a variety of 
chronic pain conditions, duloxetine 60 mg/d was demonstrated to be safe, generally well tolerated, 
and effective in the treatment of chronic pain.32,96,102,107 Therefore, duloxetine 60 mg/d is the selected 
dosage for this study. Subjects will initiate treatment with 30 mg/d and then increase to 60 mg/d in 
order to decrease the likelihood of developing nausea. Similarly, subjects will taper off the medication 


Duloxetine for chronic pain, UMCC 2013.044 
 
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during the final two weeks of treatment in order to decrease the chance of developing withdrawal 
symptoms. Those subjects who prefer to remain on duloxetine following completion of the 4 week 
full-dose treatment period are not required to taper the medication, and can be given a prescription 
by their treating provider to obtain the medication through standard of care, commercial supply. 
 
6.4 Selection and Timing of Dose for Each Patient 
Patients who meet eligibility criteria at Screening will begin a 1- to 4-week washout period (if 
necessary) to taper off all excluded medications that are contraindicated during duloxetine therapy. 
Patients who successfully withdraw from all excluded medications and continue to meet all inclusion 
criteria (and no exclusion criteria), as well as those who were not required to withdraw from any 
medications, will begin treatment with duloxetine. Two prescription bottles will be dispensed at the 
Baseline (Visit 1); one will contain tablets for 7 days of dose escalation (30 mg duloxetine), and the 
other will contain a 4-week supply of stable-dose drug (60 mg duloxetine). At the Post-Treatment 
Evaluation (Visit 2), patients will receive 1 prescription bottle containing medication for the 14 days of 
dose de-escalation (30 mg duloxetine). Patients who choose to remain on duloxetine following 
assessment #2 can take the study supply of 30 mg duloxetine until they are able to obtain a 
prescription from their PCP or other treating provider. 
 
Subjects will be instructed to take the medication each morning at approximately the same time. 
Subjects will be instructed to take the medication prior to study visits on the day of scheduled visits. 
 
6.5 Dose Modifications  
There will be no dose modifications for this study. If subjects develop grade 1 or 2 toxicities that are 
felt to be possibly, probably, or definitely related to study drug, monitor as needed until problem has 
resolved (i.e., Grade 0), stabilized (i.e., remains as Grade 1 or Grade 2), or is otherwise explained. If 
Grade 1 or Grade 2 symptoms persist, symptom management can be initiated (e.g., antiemetics). If 
grade 3 or 4 symptoms develop, or if grade 1 or 2 symptoms persist despite symptom management 
and are bothersome to the subject, the subject should be removed from protocol treatment. See 
section 5.7 for instructions regarding tapering of study medication. 
 
 
7.0 Concomitant Therapy 
 
7.1 Allowable Concomitant Therapy 
 
The following medications/therapies will be allowed for patient use during this study: 
 
• 
Serotonin (5-hydroxytryptamine) agonists (triptans), eg, rizatriptan (Maxalt), 
sumatriptan (Imitrex), zolmitriptan (Zomig)  
 
o The use of 5-hydroxytryptamine receptor agonists (triptans) is allowed in this 
study; however, serotonin syndrome may occur with agents that inhibit serotonin 
reuptake, including duloxetine, particularly with concomitant use of serotonergic 
drugs (including triptans) and with drugs that impair metabolism of serotonin 
(including monoamine oxidase inhibitors). Serotonin syndrome may include 
mental status changes (eg, agitation, hallucinations, coma), autonomic instability 
(eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations 
(eg, hyperreflexia, incoordination), and/or gastrointestinal symptoms (eg, nausea, 
vomiting, diarrhea). Careful observation of the patient is advised if triptans are 
used as concomitant therapy 
 


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• 
Epinephrine and other adrenergic agents, e.g., epinephrine (EpiPen), pseudoephedrine 
(Sudafed)  
 
○ Because duloxetine increases noradrenergic activity, epinephrine (EpiPen) should 
only be used in the event of a severe allergic reaction (anaphylaxis). Caution 
should be exercised with the use of local anesthetics that contain epinephrine, 
nasal decongestants that contain pseudoephedrine (e.g., Sudafed), and herbal 
supplements that contain stimulants (e.g., bitter orange), as these may increase 
heart rate or blood pressure  
 
• 
Nonbenzodiazepine hypnotics, eg, zaleplon (Sonata), zolpidem (Ambien)  
 
○ Zaleplon (Sonata) will be allowed as a first-tier selection for those patients 
requiring treatment of insomnia. Antihistamines and chloral hydrate are also 
allowed  
 
• 
Nonsteroidal anti-inflammatory agents, eg, ibuprofen (Motrin), naproxen (Naprosyn), 
ketorolac (Toradol)  
 
• 
Physical modalities  
 
○ Modalities commonly employed during routine physical therapy, chiropractic 
manipulation, and/or massage therapy are allowed provided they do not involve 
the use of injected medications  
 
7.2 Prohibited Concomitant Therapy 
 
The following medications/therapies will be prohibited throughout the course of this study: 
 
• 
Antidepressants, eg, escitalopram (Lexapro), venlafaxine (Effexor), milnacipran 
(Savella), fluoxetine (Prozac), bupropion (Wellbutrin), nortriptyline (Pamelor), 
monoamine oxidase (MAO) inhibitors (Parnate) 
 
• 
Phenothiazines 
 
• 
Propafenone and flecanide 
 
• 
Antiepileptics, e.g., phenytoin (Dilantin), topiramate (Topamax), carbamazapine 
(Tegretol), levetiracetam (Keppra), tiagabine (Gabitril) 
 
7.3 Treatment Compliance 
 
Study drug compliance during any period will be closely monitored by counting the number of 
tablets dispensed and returned. Every effort will be made to collect all unused study drug 
before dispensing new study drug at each relevant visit. 
 
 
 


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8.0. Specific Methods 
 
 
 
 
Screening Visit and Visit 1 can occur on the same day for those who do not have to withdraw from any 
medications.   
Subjects can be evaluated up to 4 days early for visit #2. The phone call should take place 7-14 days 
following Visit #2. 
Urine pregnancy test only in women of child-bearing potential with chronic pain. Not to be done in controls. 


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8.1 Vital Signs 
Vital signs will be measured at every visit. The parameters include: pulse rate; systolic and diastolic 
blood pressure (BP); and body weight. Pulse rate and BP readings will be taken using an automated 
BP monitor after the patient has been sitting for 5 minutes.  
 
8.2 Schedule of Assessments 
The schedule of study procedures and assessments is tabulated by visit in the Schedule of 
Events in Section 8.0. The descriptions of the procedures to be completed at each visit are 
provided below. Control subjects will complete questionnaires and pain testing as described 
under screening/baseline, and then their participation in the study will be complete. 
 
Screening  
At Screening, a review of inclusion/exclusion criteria will be conducted to determine the 
patient’s eligibility for enrollment. Study procedures will be reviewed with the patient, and 
documentation of informed consent will be obtained. After signing the informed consent form 
(ICF), patients will be assigned a unique study ID number in sequential order. Patients currently 
taking excluded medications will be required to complete a 1- to 4-week washout period before 
returning to study center for Baseline/Randomization (Visit 1). 
 
At Screening the following procedures will be completed: 
 
• 
Obtain signed and dated ICF  
• 
 
• 
Discuss study-specific procedures with the patient  
 
• 
Review inclusion and exclusion criteria  
 
• 
Question patient to ensure that the patient does not have major depression and does 
not have suicidal thoughts or wishes  
 
• 
Record demographic information  
 
• 
Record concomitant medications/therapies on concomitant medication form 
 
• 
Measure vital signs, including temperature, weight, height, sitting BP, and heart rate, 
and record values  
 
• 
Determine the required washout period and instruct the patient to taper off all 
excluded medications  
 
• 
If washout is required, schedule an appointment for the patient to return in 1 to 4 
weeks, depending on each patient’s required washout period  
 
The following data will be abstracted from the medical record: date of breast cancer 
diagnosis, tumor information (e.g., tumor histology, receptor status), treatment information 
(e.g., surgery type and dates, chemotherapy doses and dates, radiation therapy doses and 
dates, endocrine therapy dates), information about other medical co-morbidities. 
 
 


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Baseline (Visit 1) 
 
Baseline (Visit 1) will be conducted 0 to 4 weeks (depending on the patient’s washout 
period) after Screening to determine whether the patient is eligible to continue into the 
study treatment period. Those patients who do not need to discontinue any medications 
can proceed directly to Baseline (Visit 1). Patients who continue to meet inclusion criteria 
(and no exclusion criteria) will initiate treatment with duloxetine following baseline 
assessment. At this visit, patients will be given prescription bottles containing (1) a 1-week 
supply of study drug for the escalation period and (2) a 4-week supply of study drug for 
the treatment period, as well as the Period 1 medication log.  
 
At Baseline (Visit 1) the following procedures will be completed: 
 
• 
Review inclusion and exclusion criteria  
 
• 
Assess and record baseline AEs  
 
• 
Inquire as to any changes in physical symptoms, sleep and/or mood (to include suicidal 
ideation) (not required if screening and baseline are performed on the same day) 
 
• 
Record concomitant medications/therapies on concomitant medication form 
 
• 
Measure vital signs, including temperature, weight, height, sitting BP, and heart rate, 
and record values (not required if screening and baseline are performed on the same 
day) 
 
• 
Perform urine pregnancy test in women of childbearing potential (not controls) 
 
• 
Complete the following outcome assessments:  
 
○ Evaluation of pressure pain threshold 
 
○ Patient-reported outcome assessments:  
 
- 
Brief Pain Inventory (BPI) 
 
- 
Michigan Body Map and Symptom Severity Scale 
 
- 
PainDETECT 
 
- 
FACT/GOG-NTX subscale 
 
○ Evaluation of CPM 
 
○ Patient-reported outcome assessments 
 
- 
PROMIS (Fatigue-SF) 
 
- 
PROMIS (Sleep Disturbance-SF) 
 
- 
PROMIS (Physical Function-SF) 


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- 
Hospital Anxiety and Depression Scale (HADS) 
 
- 
Multiple Ability Self-Report Questionnaire (MASQ)  
 
(Control subjects will not participate in any additional study activities listed below.) 
 
• Dispense the prescription bottles containing study drug for the first 5 weeks of the first 
treatment period (7 days of dose escalation and 28 days of full-dose treatment) and 
review dosing instructions. The subject should take the medication in the morning 
starting the morning after the baseline visit at approximately the same time each day. 
She should record when she took the medication on the provided Period 1 medication 
log. On the study visit days she should take her dose prior to the visit. 
 
•  Schedule an appointment for the patient to return in 5 weeks. This visit may be scheduled up 
to 4 days early.  
 
Section 9.0  provides a detailed description of each outcome assessment. 
 
Post-Treatment Evaluation (Visit 2) 
 
Post-Treatment Evaluation (Visit 2) will be conducted 5 weeks after Baseline (Visit 1) to 
complete endpoint assessments. At this visit, patients will be given 1 prescription bottle 
containing the dose de-escalation for 14 days. Visit 2 can be performed up to 4 days 
early (should be conducted during week 4 of full-dose treatment). 
 
At Post-Treatment Evaluation (Visit 2) the following procedures will be completed: 
 
• 
Assess patient tolerance of medication and record AEs  
 
• 
Inquire as to any change in physical symptoms, sleep, and/or mood (to include suicidal 
ideation) 
 
• 
Record concomitant medications/therapies on concomitant medication form 
 
• 
Measure vital signs and record values  
 
• 
Collect study drug from the previous visit and perform drug accountability. If the subject has 
pills remaining, either because she missed a pill or because this visit was conducted early, the 
pills should not be returned to the subject.  
 
• 
Complete the following outcome assessments:  
 
○ Evaluation of pressure pain threshold 
 
○ Patient-reported outcome assessments:  
 
- 
Brief Pain Inventory (BPI) 
 
- 
Michigan Body Map and Symptom Severity Scale 
 


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- 
PainDETECT 
 
- 
FACT/GOG-NTX subscale 
 
○ Evaluation of CPM 
 
○ Patient-reported outcome assessments 
 
- 
PROMIS (Fatigue-SF) 
 
- 
PROMIS (Sleep Disturbance-SF) 
 
- 
PROMIS (Physical Function-SF) 
 
- 
Hospital Anxiety and Depression Scale (HADS) 
 
- 
Multiple Ability Self-Report Questionnaire (MASQ)  
 
 
• 
Dispense the prescription bottle containing study drug for the dose de-escalation (2 
weeks) and review dosing instructions. 
 
 
• 
For those patients who wish to continue to take commercially-available duloxetine after 
study completion, the patient can transition directly to duloxetine 60 mg daily using a 
prescription provided by her PCP or other treating physician, and she does not need to 
taper off and then restart drug. If she does not yet have the prescription, she will be given 
the two week supply of dose de-escalation study drug. Once she obtains the medication 
from her pharmacy she can stop the 30 mg dose and start the commercial supply. 
 
Section 9.0 provides a detailed description of each outcome assessment. 
 
         
Final Evaluation (Phone visit) 
 
Final Evaluation (Phone visit/ET) will be conducted 7-14 days after Post-Treatment 
Evaluation (Visit 2). This will be the final assessment for the study. For patients who 
prematurely discontinue participation in the study, this will be the ET visit, and the PI will 
determine whether outcome assessments should be obtained at this visit in addition to the 
procedures listed below. Patients who have switched to commercially available duloxetine do 
not need to be contacted if there are no ongoing AEs that require follow-up and if they do not 
have study medication bottles to return. 
 
At Final Evaluation (Phone visit/ET) the following procedures will be completed: 
 
• 
Assess patient tolerance of medication and record AEs  
 
• 
Inquire as to any change in physical symptoms, sleep, and/or mood (to include suicidal ideation) 
 
• 
Review concomitant medications/therapies  
 


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• 
Remind subjects to return the study drug bottle in the stamped envelope. 
 
       Section 9.0 provides a detailed description of each outcome assessment 
 
9.0 Outcome Measures 
 
9.1 Primary Outcome Assessment 
 
9.1.1 Brief Pain Inventory 
 
The Brief Pain Inventory (BPI) is a 17-item patient self-rating scale that assessed sensory and reactive 
components of pain.69 For sensory components, it addresses severity, location, chronicity, and degree of 
relief due to therapy. For reactive components, it assesses depression, suffering, and perceived 
availability of relief. Reliability has been demonstrated over short intervals using test retest item 
correlation; worst pain, r=0.93, usual pain, r=0.78, pain now r=0.59. It has been validated in patients with 
both cancer and non-cancer pain.76,77 Ratings of pain interference with various activities increased as 
ratings of pain severity were higher. The proportion of patients receiving opioid analgesics also increased 
with increased severity rating.  
 
The BPI uses 0 to 10 numeric rating scales for item rating because of its simplicity and lack of ambiguity. 
Since pain can be variable over a day, the BPI asks patients to rate their pain at the time of completing 
the questionnaire, and also at its worst, least, and average over the previous 24 hours. The primary 
endpoint for this clinical trial will be based on the 24-hour average pain as reported on the BPI. The 
ratings can be combined to give a composite index of pain severity. Also, using numeric 0 to 10 scales, 
with 0 being “no interference” and 10 being “interferes completely”, the BPI asks for ratings of the degree 
to which pain interferes with mood, walking and other physical activity, works, social activity, relations 
with others, and sleep. The mean of these scores can be used as a pain interference score.  
 
9.2 Secondary Outcome Assessments 
 
9.2.1 Pressure Pain Threshold  
Most QST will be performed using the MAST System. The MAST System is a wireless QST platform 
featuring a control computer, a touch screen for patient feedback, and an automated pressure actuator. 
Forces are delivered by a 1-cm2 conformal-rubber probe attached to a cylindrical transducer driven by a 
miniature servo-motor and housed within a polyurethane case that is held comfortably in either hand. 
Load-cells measure each applied force while a closed-looped control system monitors and adjusts motor 
output ensuring accurate pressure delivery. All subjects will undergo bilateral pressure pain testing (PPT) 
at the thumbnail.52 The thumbnail was chosen as a neutral, pain-free site remote from the area of 
surgery. Increased pain sensitivity at the thumbnail (i.e., secondary hyperalgesia) suggests a state of 
widespread hyperalgesia that may be indicative of centralized pain.47,51,54,108 Subjects will undergo testing 
bilaterally to determine the effect, if any, of prior breast and axillary surgery on thumbnail pressure 
sensitivity. Testing will be counter-balanced between left and right thumbs. The MAST System will first 
deliver an ascending series of pressures (5-s duration; 4 kg/cm2/s) at 25-s intervals, beginning at 0.25 
kg/cm2 and increasing in 0.25 – 0.50 kg/cm2 intervals up to tolerance or to a maximum of 10 kg/cm2.to 
the thumbnail. Pain intensity will be rated after each stimulus on a 0-100 numerical rating scale (NRS), 
with “0” representing “no pain” and “100” representing “extreme pain”. Patient responses obtained in the 
ascending series will be used to compute a set of 5-7 stimuli between that patient’s threshold and 
tolerance. These stimuli will then be delivered and rated 3 times each (5-s duration; 25-s inter-stimulus 
interval) in randomized order. These ratings will be used to compute a psychophysical function of each 
subject’s pain sensitivity with pressure intensity and response magnitude represented on the x- and y-


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axes, respectively.  These curves will be used to compare single subject and group changes in pain 
sensitivity longitudinally throughout the project. Pressure pain threshold and tolerance levels will also be 
calculated for each subject at each thumbnail.   
Because we are aware that the presence of peripheral neuropathy could influence the results of PPT 
threshold in the thumb, we will also test this at another site not affected by peripheral neuropathy: the 
deltoid muscle. The inclusion of this particular site was based on recent evidence showing that pressure 
pain threshold was bilaterally reduced at the deltoid muscle in BCS compared to healthy controls, and 
that pressure pain threshold at the affected deltoid was negatively correlated to neck pain intensity.54 
Testing will be conducted using a 1 cm2 rubber probe attached to a digital algometer. Test order will be 
counter-balanced between affected and non-affected sides. Pressure will be manually increased at a rate 
of 0.3 kg/cm2/s to a maximum 10 kg following an ascending method of limits. Subjects will indicate the 
point at which the pressure sensation becomes painful (pressure pain threshold) and the point in which 
the pain becomes intolerable (pressure pain tolerance). A tolerance of 10 kg/cm2 will be used for patients 
that fail to press the button before test completion. Measurements will be conducted 3 times at each side 
(20-60 second inter-stimulus interval) with mean values used for analysis. 
 
9.2.2 Conditioned Pain Modulation (CPM)   
Endogenous pain modulation will be evaluated using a CPM paradigm.63 CPM procedures incorporate a 
conditioning stimulus (a noxious stimulus that activates pain modulatory systems) and a test stimulus (a 
noxious stimulus used to evaluate the analgesic response to the conditioning stimulus). In this study, 
painful pressure stimuli will be delivered via two MAST actuators positioned on opposite thumbs with 
pressure at one thumb serving as the test stimulus and pressure at the other thumb serving as the 
conditioning stimulus. The test stimulus will be applied continuously for 30-s to the thumbnail of the 
affected side at an intensity that induces a moderate level of pain for that patient (i.e., a rating of 30-
50/100). Patients will rate the intensity of the pressure at 10-, 20-, and 30-s on a NRS. CPM will be 
induced 5-min later by applying 60-s of continuous pressure to the thumbnail of the non-affected side at 
the same pain intensity as the test stimulus. CPM magnitude will be calculated as the difference in mean 
pain rating to the test-stimulus applied prior to and during the conditioning stimulus. Previous work by our 
group and others demonstrated this to be a valid method of CPM assessment in patients with chronic 
pain.55-57,60,63-66 
 
9.3 Patient-Reported Outcome Assessments 
 
All enrolled subjects and controls will complete the battery of questionnaires described above, which will 
take approximately 1 hour to complete. All questionnaires that assess self-reported pain will be 
completed prior to QST; the remainder will be completed between PPT and CPM assessment. 
Measures of centralization of pain 
o The Michigan Body Map and Symptom Severity Scale, a modified version of the Wolfe Regional 
Pain Scale, will be used to quantify (a) the locations of breast cancer treatment-related pain using a 
checklist that allows for efficient scoring and (b) the severity of key symptoms, including fatigue, 
sleep disturbance, and cognitive function. Measures of pain distribution and the presence of this 
symptom cluster have been repeatedly found to be associated with centrally-mediated pain 
symptoms. 78-80 
o Qualitative Pain Characteristics. PainDETECT 70 is a 9-item measure of sensory descriptors, spatial, 
and temporal characteristics that has been shown to identify neuropathic components of pain in low 
back pain and in osteoarthritis.34 It distinguishes neuropathic from musculoskeletal pain.  
o Treatment-related toxicity. The FACT/GOG-NTX neurotoxicity module is an 11-item subscale 
specifically developed to address chemotherapy-associated peripheral neurotoxicity and its 
consequences on functional status.71 The subscale scores correlate with objective neuropathy 
measures, specifically pin sensibility, strength, and deep tendon reflexes.  


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o Functional status, sleep, and fatigue. The following PROMIS short-forms will be used in this study: 
Fatigue, Sleep Disturbance, and Physical Function.68  The 7-item Fatigue scale assesses the 
experience of fatigue as well as its impact on physical, mental, and social activities. The 8-item Sleep 
Disturbance scale assesses perceptions of sleep quality, sleep depth, and restoration associated 
with sleep. The 10-item Physical Function scale assesses self-reported function, including the ability 
to perform activities of daily living. The PROMIS scales possess favorable reliability and enhanced 
precision with lowered patient burden when compared to comparable legacy assessment 
instruments.   
o Psychiatric status. The Hospital Anxiety and Depression Scale (HADS) will be used to assess 
anxiety and depressive symptoms.81  The HADS is a 14 item questionnaire that has been extensively 
evaluated for the assessment of mood disorders in patients with cancer.93,94 
o Cognitive dysfunction. The 38-item Multiple Abilities Self-Report Questionnaire (MASQ),55,95,96  is 
comprised of five cognitive domains: language ability, visuo-perceptual ability, verbal memory, visual 
memory, and attention/concentration. Satisfactory reliability and validity have been 
demonstrated.72,82,83 
 
10.0 Safety Assessments 
Patients must be seen by an appropriately trained health professional at every visit and the 
evaluation must be documented. The procedures discussed in section 9.0 will be performed at the 
designated visits. 
 
10.1 Adverse Events 
 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
 
An AE, therefore, can be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
 
Examples of AEs are as follows: 
• 
Changes in the general condition of the patient  
 
• 
Subjective symptoms offered by or elicited from the patient  
 
• 
Objective signs observed by the Investigator or other study personnel  
 
• 
All concurrent diseases that occur after the start of the study, including any change in 
severity or frequency of preexisting disease  
 
• 
All clinically relevant abnormalities in laboratory values or clinically relevant physical 
findings that occur during the study  
 
In general, AE reporting for this clinical trial will follow the University of Michigan IRBMED 
guidelines. However, changes in the pain or occurrence of symptoms noted in the patient’s 
baseline self-report questionnaires will not be recorded as AEs.  In addition, if patients are 
undergoing treatment with anticancer agents such as aromatase inhibitors, tamoxifen, 
bisphosphonates, and/or trastuzumab, expected side effects of these medications will not be 
reported to the IRB. Changes that are clinically significant, as assessed by the Investigator, or that 
qualify as serious will be reported as SAEs. 


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10.2 Causality Assessment 
 
For all AEs, the Investigator must provide an assessment of causal relationship to study drug. 
Causal relationship must be assessed according to the following scale: 
 
Related: 
Reasonable temporal relation to study drug administration AND 
cannot be reasonably explained by other factors (eg, the patient’s 
clinical state, concomitant therapy, and/or other interventions). 
 
Possibly Related:    Relationship to study drug cannot be ruled out. 
 
Not Related: 
 
Data are available to identify a clear alternative cause for the reaction (eg, 
positive test for viral antigen in a case of suspected drug-induced hepatitis, 
hemorrhage due to mechanical injury). 
 
10.3 Severity Assessment 
 
The Investigator will provide an assessment of the severity of each AE. Severity, which is a 
description of the intensity of manifestation of the AE, is distinct from seriousness, which implies a 
patient outcome or AE-required treatment measure associated with a threat to life or functionality. 
Severity of AEs will be graded according to CTCAE criteria, version 4. 
 
11.0 Statistical Methods and Determination of Sample Size 
 
The overall study objectives are broad: (1) to assess breast cancer survivors with chronic pain for the 
presence and degree of pain centralization and (2) to identify predictors of response to the predominantly 
centrally-acting analgesic duloxetine in breast cancer survivors with chronic treatment-emergent pain. In 
order to examine these objectives, as noted in section 9 of the protocol, the primary outcome measure is 
the Brief Pain Inventory and the secondary outcome measures are objective measures of pain sensitivity 
and other patient-reported outcomes questionnaires. These measures are used to assess patients with 
chronic pain who are treated with duloxetine, in order to assess change in these outcomes with therapy, 
and also to assess control patients without chronic pain in order to define differences in these measures 
between the two cohorts and to facilitate interpretation of the change in these scores in duloxetine-
treated patients. These results will be used to explore centralized pain in this patient population including 
identification of predictors of response to duloxetine.  
 
Primary outcome: 
Change in worst pain from baseline to week 5 with 5 weeks of duloxetine therapy, using the worst pain 
score from the BPI 
 
Secondary outcomes: 
a. Change in average pain from baseline to week 5 with 5 weeks of duloxetine therapy, using the 
average pain score from the BPI 
b. Change in pain interference from baseline to week 5 with 5 weeks of duloxetine therapy, using 
the pain interference score from the BPI 


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c. Change in number of sites of pain from baseline to week 5 with 5 weeks of duloxetine therapy, 
using the Michigan Body Map 
d. Change in Fibromyalgia Severity Score from baseline to week 5 with 5 weeks of duloxetine 
therapy, using the Michigan Body Map and Symptom Severity Scale 
e. Change in Neuropathic Pain from baseline to week 5 with 5 weeks of duloxetine therapy, using 
the PainDETECT 
f. Change in Neuropathy from baseline to week 5 with 5 weeks of duloxetine therapy, using the 
FACT/GOG-NTX 
g. Change in Fatigue from baseline to week 5 with 5 weeks of duloxetine therapy, using the 
PROMIS Fatigue 7a 
h. Change in Sleep Disturbance from baseline to week 5 with 5 weeks of duloxetine therapy, using 
the PROMIS Sleep Disturbance 8b 
i. 
Change in Physical Function from baseline to week 5 with 5 weeks of duloxetine therapy, using 
the PROMIS Physical Function 10a 
j. 
Change in Anxiety from baseline to week 5 with 5 weeks of duloxetine therapy, using the Hospital 
Anxiety and Depression Scale 
k. Change in Depression from baseline to week 5 with 5 weeks of duloxetine therapy, using the 
Hospital Anxiety and Depression Scale 
l. 
Change in the 5 components of Cognitive Difficulties from baseline to week 5 with 5 weeks of 
duloxetine therapy, using the Multiple Ability Self-Report Questionnaire 
m. Change in pain sensitivity from baseline to week 5 with 5 weeks of duloxetine therapy, using the 
Pain50 assessed using quantitative sensory testing 
n. Change in CPM from baseline to week 5 with 5 weeks of duloxetine therapy, using quantitative 
sensory testing 
 
Exploratory analyses: 
Assessment of Centralized Pain. Centralized pain will be assessed within the unsupervised classification 
paradigm. Measures of pain centralization (pain severity (BPI) and distribution (Michigan Body Map)), 
symptom severity scale, neuropathic pain (PainDETECT), functional status (PROMIS), anxiety and 
depression (HADS), cognitive measures (MASQ), and experimental pain (QST)) will be treated as a 
multivariate phenotype informing about the latent centrality status of the subject. Demographic (e.g., age, 
BMI) and clinical (treatment “bin”) variables will be added as covariates. We will assume that the 
hypothesized centrality status is expressed by a latent variable specific to the subject, a random effect. 


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This variable will be used as an effect modifier in 
a regression model linking the primary response 
of pain severity and other response variables with 
the phenotype variables. The resultant mixture of 
regression models where the latent centrality 
variable will be shared by all regression models 
within the subject will be fit by the EM algorithm 
with iterative imputation of the latent centrality 
status. Regression models for each response 
variable will be of the generalized linear models 
(GLM) family. The data will have ample 
information to bear on the distribution of patients 
over the latent classes as the model will borrow 
strength from all contributing GLMs. The model 
will be refined in layers by adding response and 
predictor variables deemed informative of the 
latent centrality. The performance of the model 
will be measured by the Akaike Information 
Criterion (AIC). A threshold of 2 per 1 degree of 
freedom will be applied to AIC differences 
between models as a measure of significant 
difference between models. The model showing 
the highest AIC will be selected as the best 
model for subsequent analysis and prediction. 
The latent centrality status will be predicted for 
each subject by a Bayesian argument using the 
best model. Continuous, ordered categorical 
and binary latent centrality status will be 
explored in search for the model that provides the best explanation for the heterogeneity of pain 
responses in the breast cancer survivors.  
As an illustration of the method we fitted a binary centrality status (central vs. non-central) model (a 
mixture of two different latent linear regression models specific for the centrality class) to cross-sectional 
pain severity data on 199 breast cancer patients from an unpublished cross-sectional study we 
conducted on breast cancer survivors 1-3 years following diagnosis. PainDETECT, age, BMI, HADS 
depression and anxiety, sleep disturbance, fatigue, Perceived Stress Scale, and treatment bin (listed in 
Figure 4) were used as explanatory phenotype variables. The model resulted in identification of two 
clusters (cluster 1: 64% of patients; cluster 2: 36%) of breast cancer patients defined by dissimilar 
regression relationships between pain and phenotype and clinical variables. Cluster 2 is characterized by 
persistently higher levels of pain (Figure 5).  Age, BMI and fatigue are significant variables in Cluster 1 
while neuropathic pain and depression mark Cluster 2 regression. While in the data analysis we will favor 
continuous characterization of centrality, this binary model is used as a source of information for the 
power analysis below. Using the AIC criterion, the two-cluster model is significantly better than the 
homogeneous patient population (one regression, no latent heterogeneity explained by centrality). We 
note that treatment was not significant (p=0.39), in line with our hypothesis of common pain mechanism 
regardless of the type of insult. 
Analysis. The planned sample size for Aim 1 is 132 (84 cases and 48 controls). For Aim 2, latent 
dichotomous pain centrality status will be hypothesized and regressed on explanatory variables including 
the ones involved in the CNS pain regulation. We will assume that the causality of the effect of the 
centrality block of variables on the Duloxetine (DLX) treatment outcome will follow through the centrality 
status. In addition to the random effect representing the interaction between the drug effect and the 
Fig. 5. Clustering of 199 BCS using a mixture of 2 (pain ~ 
phenotype + treatment + demographics) regression 
models. Red high pain latent cluster is loosely identified with 
predicted centralized pain classification, and the blue cluster 
with non-centralized. Note that none of the phenotype 
variables taken alone serves as a particularly good surrogate 
for the classification, and the mixture approach that borrows 
strength across various phenotypes is essential. 


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central status, subject specific random intercept will be introduced to model correlation due to repeated 
measurements. A generalized linear mixed model will be used with the two response variables (self-
report pain questionnaires and experimental pain testing scores). The form of the link function and 
variable transformations will be determined based on the data using AIC criteria. A full likelihood model-
based approach will be used to fit the model. Hypotheses will be tested by the likelihood ratio test. A 
clinically relevant response is defined as 50% reduction in pain within the patient. The following effects 
are hypothesized based on our pilot studies: Central patients will constitute approximately 30% of the 
breast cancer population; 10% of non-central patients are hypothesized to show clinically relevant 
improvement under DLX while the rate of at least 70% is hypothesized in the central group. Overall, this 
leads to the expected 28% response rate. Placebo effects in this kind of studies are expected not to 
exceed 3%. Conservatively we would be looking to detect improvement over twice the expected placebo 
rate (6%). Using a two-sided test for the proportion of improvement vs. 6% at alpha=0.05 we will have 
the power of 81% with 21 patients in each “bin” (total of 84 patients).  
  
12.0  Data Handling  
 
MICHRs Data Management (DM) unit supports research at the University of Michigan by providing 
expertise in all areas of data management, from study start to completion, meeting best practices and 
ensuring data integrity. DM works closely with each study team to help develop an efficient method of 
data collection and management based on project needs, following Standard Operating Procedures and 
Good Clinical Practice. The unit creates study-specific data collection instruments either as paper or 
electronic Case Report Forms (CRFs). Database development is done using web-based applications. 
Throughout the life of the project, this unit provides the necessary services and expertise to help 
manage and report data. DM will track and store Case Report Forms, perform data entry and provide a 
number of reports to monitor data quality and study progress. The Data Management Unit also works 
collaboratively with other MICHR units to provide researchers with comprehensive services needed to 
effectively conduct research. The self-report data will be collected via REDCap, an electronic data 
capturing system developed at Vanderbilt University.  REDCap is an open-source, secure, web-based 
application designed to support data capture for research studies, and is provided through MICHR. 
REDCap provides: 1) an intuitive interface for data entry; 2) audit trails for tracking data manipulation 
and export procedures; 3) automated export procedures for seamless data downloads to common 
statistical packages; 4) procedures for importing data from external sources; and 5) advanced features, 
such as branching logic and calculated fields within electronic forms. Servers are physically located in 
the UM Medical School Information Systems data center. Physical security for the databases is provided 
in a professionally managed and equipped tier-2 data center with tightly controlled access. Remote data 
access employs SSL encryption and 2-tier Kerberos and UMHS level 2 password challenges via LDAP 
authentication. Access to the application, the database, and the underlying systems infrastructure 
comply with industry best practices, supporting HIPAA security and privacy requirements and the 
HITECH Act. Backup of data is managed by MSIS, and vulnerability testing is performed regularly. Daily 
backups and VM snapshots of the application and database servers are stored on a remote storage 
device. 
 
13.0 Data and Safety Monitoring  
 
This is a phase II trial that does not require an independent data and safety monitoring board because it 
is designed to look at mechanism of effect rather than efficacy. Monitoring of accrual and adverse events 
will be performed by UM investigators and research personnel during (1) routine weekly Breast Oncology 
Program research meetings which are attended by faculty and staff, research nurses, and data 
management and regulatory personnel from the University of Michigan Clinical Trials Office and (2) 


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quarterly Chronic Pain and Fatigue Research Center meetings which are attended by the co-
Investigators and study coordinator listed on the protocol.  In addition, the trial will be monitored quarterly 
by the UM Comprehensive Cancer Center DSMB per institutional guidelines. 


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15.0  APPENDICES 
 
The following documents have been attached as appendices to this protocol: 
 
1. Brief Pain Inventory (BPI) 
2. Michigan Body Map 
3. Symptom Severity Scale 
4. PainDETECT 
5. FACT/GOG-NTX 
6. PROMIS (Physical function-SF) 
7. PROMIS ( Fatigue-SF) 
8. PROMIS (Sleep disturbance-SF) 
9. Hospital Anxiety and Depression Scale (HADS) 
10. Multiple Ability Self-Report Questionnaire (MASQ)  
11. Demographics 
12. Cymbalta (duloxetine) Highlights of Prescribing Information 
13. Concomitant medication form 
14. Medication log 


Duloxetine vs placebo, UMCC 2013.044 
 
 
 
Concomitant Medications 
 
Subject ID: _____________________ 
Date: __________________ 
 
 
Please list any prescription and nonprescription drugs, vitamins and dietary supplements that 
you have taken since your last clinic visit. 
 
 
Drug name 
Total 
Daily 
Dosage 
Why do you take the 
medication? 
Is this a 
medication 
you take 
daily? 
Start 
Date  
(if not a 
daily 
medicine) 
End Date 
(if not a 
daily 
medication) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Reviewed by: _________________________________________________ 


Duloxetine vs placebo, UMCC 2013.044 
 
 
 
Medication Log 
 
Subject ID: _____________________ 
 
 
        
 
Please record when you take your study medication on this log. You should take your medication in the 
morning at approximately the same time each day, including the days that you have your study visits. 
 
Please list any problems that you had (e.g., forgot to take medication, too much nausea, etc) in the 
comments box. If you are having side effects that are causing you to not take the medication, please call 
Dr. Henry at 734-936-6000. 
 
 
Date 
Bottle 
Number 
Time 
Comments 
Date 
Bottle 
Number 
Time 
Comments 
 
1 
 
 
 
2 
 
 
 
1 
 
 
 
2 
 
 
 
1 
 
 
 
2 
 
 
 
1 
 
 
 
2 
 
 
 
1 
 
 
 
2 
 
 
 
1 
 
 
 
2 
 
 
 
1 
 
 
 
2 
 
 
 
2 
 
 
 
2 
 
 
 
2 
 
 
 
2 
 
 
 
2 
 
 
 
2 
 
 
 
2 
 
 
 
2 
 
 
 
2 
 
 
 
2 
 
 
 
2 
 
 
 
2 
 
 
 
2 
 
 
 
2 
 
 
 
2 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
Reviewed by: _________________________________________________