Mechanistic Study of Duloxetine in Breast Cancer Patients With Chronic Pain

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Study to Identify Predictors of Response to Duloxetine in Breast Cancer Patients With Chronic Pain

Conditions
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Pain

Intervention / Treatment
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* Drug: Duloxetine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients at least 25 years of age 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 targeted therapies such as palbociclib, pertuzumab, and trastuzumab are permitted. Pain that developed or worsened since breast cancer diagnosis and is not due to identifiable traumatic event or fracture Patient-reported worst pain score between 5 and 10 (inclusive) on a 0-10 scale (assessed verbally) Female patients must be at least 1 year postmenopausal or surgically sterile; or must agree to use a medically acceptable form of contraception Willing to withdraw from selective serotonin reuptake inhibitors (SSRI) and tricyclic antidepressants (TCA) prior to treatment initiation Patients who are currently taking non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, naproxen, meloxicam, gabapentin, pregabalin) and/or opioid pain medications must remain on a stable dosage throughout the duration of the study Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines. Exclusion Criteria: Prior use of duloxetine or milnacipran. Prior or current use of venlafaxine specifically for treatment of pain (prior or current use for treatment of other indications, such as hot flashes, is permitted, although cases currently taking venlafaxine must discontinue use prior to study treatment initiation) Patients must not be taking any contraindicated medications listed on the duloxetine package insert including the following: phenothiazines, propafenone, flecainide, linezolid, or anticoagulation medication (e.g., heparin, warfarin, or direct oral anticoagulants); treatment with monoamine oxidase inhibitor within 14 days prior to registration. Thumbnail abnormalities on either hand (such as due to chemotherapy or trauma, or artificial nails) that are likely to alter pain perception during testing Peripheral sensory neuropathy at the thumbs bilaterally that interferes with function and/or activities of daily living Significant risk of suicide based on the Investigator's judgment History or behavior that would, in the Investigator's judgment, prohibit compliance for the duration of the study. History of alcohol or other substance abuse or dependence within the year prior to registration Known chronic liver disease, end stage renal disease, or creatinine clearance <30 mL/min as defined by Cockcroft-Gault equation Uncontrolled narrow-angle glaucoma. Clinically significant coagulation disorder History of seizure disorder Pregnant or breast-feeding. Urine pregnancy test will be assessed at the baseline visit in women of child-bearing potential with chronic pain. Unable to take oral medications or any medical condition that would interfere with the absorption of study medication capsules. Currently taking SSRI, serotonin-norepinephrine reuptake inhibitor (SNRI), or TCA regimen (including Wellbutrin) for treatment of major depressive disorder or generalized anxiety disorder (without approval and involvement of the patient's treating psychiatrist to taper cases off these medications prior to study treatment). Controls are patients without chronic pain who otherwise meet the following eligibility criteria (inclusion #1, 2, 8, exclusion #1, 2, 4, 5, worst pain score 0-1, and not currently on medication for pain)

Ages Eligible for Study
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Minimum Age: 25 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Interventional Model Description: Trial was initially a randomized cross-over design. Soon after study initiation the trial design was amended because of poor accrual, and instead was a single arm open label trial in which all patients with pain were treated with study drug. Since so few patients had been enrolled at the time of study redesign, the only data analyzed were from the single treatment arm portion of the trial, and the non-intervention (baseline only) comparator.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1 (Patients with pain, duloxetine)<br>Duloxetine 30 mg daily x 1 week, then 60 mg daily x 4 weeks, then 30 mg daily x 2 weeks. | Drug: Duloxetine<br>* 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.<br>* Other names: Cymbalta;|
| No Intervention: Arm 2 (Patients without pain -- control)<br>Patient reported pain and symptoms assessment for comparison at baseline. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Patient-reported Worst Pain Between Baseline and 5 Weeks of Treatment With Duloxetine | Worst pain will be assessed at baseline and 5 weeks for each individual patient using the Brief Pain Inventory. Baseline: Mean worst pain for all individual patients in arm 1 (intervention) and arm 2 (control) 5 weeks: Mean worst pain for all individual patients in arm 1 (intervention) Range of pain score 0-10 (0=no pain; 10=worst pain) | 5 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Patient-reported Average Pain Between Baseline and 5 Weeks of Treatment With Duloxetine | Average pain will be assessed at baseline and 5 weeks for each individual patient using the Brief Pain Inventory. Baseline: Mean average pain for all individual patients in arm 1 (intervention) and arm 2 (control) 5 weeks: Mean average pain for all individual patients in arm 1 (intervention) Range of pain score 0-10 (0=no pain; 10=worst pain) | 5 weeks | 
| Change in Pain Interference Between Baseline and 5 Weeks of Treatment With Duloxetine | Pain interference will be assessed at baseline and 5 weeks for each individual patient using the Brief Pain Inventory. Baseline: Mean pain interference for all individual patients in arm 1 (intervention) 5 weeks: Mean pain interference for all individual patients in arm 1 (intervention) Range of pain interference score 0-10 (0=no interference; 10=worst interference) | 5 weeks | 
| Change in Number of Sites of Pain Between Baseline and 5 Weeks of Treatment With Duloxetine | Number of sites of pain will be assessed at baseline and 5 weeks for each individual patient using the Michigan Body Map. Baseline: Mean number of sites of pain for all individual patients in arm 1 (intervention) 5 weeks: Mean number of sites of pain for all individual patients in arm 1 (intervention) Range of number of sites of pain 0-35 (0=no pain; 35=every pre-defined body site has pain) | 5 weeks | 
| Change in Fibromyalgia Symptom Severity Score Between Baseline and 5 Weeks of Treatment With Duloxetine | Fibromyalgia Symptom Severity Score will be assessed at baseline and 5 weeks for each individual patient using the Michigan Body Map and Symptom Severity Scale. Baseline: Mean Fibromyalgia Symptom Severity Score for all individual patients in arm 1 (intervention) 5 weeks: Mean Fibromyalgia Symptom Severity Score for all individual patients in arm 1 (intervention) Range of Fibromyalgia Symptom Severity Score 0-12 (0=not consistent with fibromyalgia; 12=most consistent with fibromyalgia) | 5 weeks | 
| Change in PainDETECT Score Between Baseline and 5 Weeks of Treatment With Duloxetine | PainDETECT score will be assessed at baseline and 5 weeks for each individual patient using the PainDETECT questionnaire. Baseline: Mean PainDETECT score for all individual patients in arm 1 (intervention) 5 weeks: Mean PainDETECT score for all individual patients in arm 1 (intervention) Range of PainDETECT score -1-38 (-1=no neuropathic pain; 38=most consistent with neuropathic pain) | 5 weeks | 
| Change in Neuropathy Between Baseline and 5 Weeks of Treatment With Duloxetine | Neuropathy will be assessed at baseline and 5 weeks for each individual patient using the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-NTX) questionnaire. Baseline: Mean neuropathy score for all individual patients in arm 1 (intervention) 5 weeks: Mean neuropathy score for all individual patients in arm 1 (intervention) Range of neuropathy score 0-44 (0=no neuropathy; 44=most consistent with neuropathy) | 5 weeks | 
| Change in Fatigue Between Baseline and 5 Weeks of Treatment With Duloxetine | Fatigue will be assessed at baseline and 5 weeks for each individual patient using the Patient Reported Outcomes Measurement Information System (PROMIS) Fatigue Short Form 7a v1.0 questionnaire. Raw scores are converted to standardized T scores based on national norms for patients with cancer. Baseline: Mean fatigue T score for all individual patients in arm 1 (intervention) 5 weeks: Mean fatigue T score for all individual patients in arm 1 (intervention) Average fatigue T score for the reference population of patients with cancer is 50.0, with standard deviation of 10.0 (higher score=more fatigue) | 5 weeks | 
| Change in Sleep Disturbance Between Baseline and 5 Weeks of Treatment With Duloxetine | Sleep Disturbance will be assessed at baseline and 5 weeks for each individual patient using the PROMIS Sleep Disturbance Short Form 8b v1.0 questionnaire. Raw scores are converted to standardized T scores based on national norms for patients with cancer. Baseline: Mean sleep disturbance T score for all individual patients in arm 1 (intervention) 5 weeks: Mean sleep disturbance T score for all individual patients in arm 1 (intervention) Average sleep disturbance T score for the reference population of patients with cancer is 50.0, with standard deviation of 10.0 (higher score=more sleep disturbance) | 5 weeks | 
| Change in Physical Function Between Baseline and 5 Weeks of Treatment With Duloxetine | Physical Function will be assessed at baseline and 5 weeks for each individual patient using the PROMIS Physical Function Short Form 10a v1.0 questionnaire. Raw scores are converted to standardized T scores based on national norms for patients with cancer. Baseline: Mean physical function T score for all individual patients in arm 1 (intervention) 5 weeks: Mean physical function T score for all individual patients in arm 1 (intervention) Average physical function T score for the reference population of patients with cancer is 50.0, with standard deviation of 10.0 (higher score=better physical function) | 5 weeks | 
| Change in Anxiety Between Baseline and 5 Weeks of Treatment With Duloxetine | Anxiety will be assessed at baseline and 5 weeks for each individual patient using the Hospital Anxiety and Depression Scale. Baseline: Mean anxiety score for all individual patients in arm 1 (intervention) 5 weeks: Mean anxiety score for all individual patients in arm 1 (intervention) Range of anxiety score 0-21 (0=no anxiety, 21=maximum anxiety) | 5 weeks | 
| Change in Depression Between Baseline and 5 Weeks of Treatment With Duloxetine | Depression will be assessed at baseline and 5 weeks for each individual patient using the Hospital Anxiety and Depression Scale. Baseline: Mean depression score for all individual patients in arm 1 (intervention) 5 weeks: Mean depression score for all individual patients in arm 1 (intervention) Range of depression score 0-21 (0=no depression, 21=maximum depression) | 5 weeks | 
| Change in Cognitive Difficulties - Language Between Baseline and 5 Weeks of Treatment With Duloxetine | Cognitive Difficulties - Language will be assessed at baseline and 5 weeks for each individual patient using the Multiple Ability Self-Report Questionnaire. Baseline: Mean language score for all individual patients in arm 1 (intervention) 5 weeks: Mean language score for all individual patients in arm 1 (intervention) Range of language score 0-40 (0=no language difficulties, 40=maximum language difficulties) | 5 weeks | 
| Change in Cognitive Difficulties - Visual-Perceptual Ability Between Baseline and 5 Weeks of Treatment With Duloxetine | Cognitive Difficulties - Visual-Perceptual Ability will be assessed at baseline and 5 weeks for each individual patient using the Multiple Ability Self-Report Questionnaire. Baseline: Mean visual-perceptual ability score for all individual patients in arm 1 (intervention) 5 weeks: Mean visual-perceptual ability score for all individual patients in arm 1 (intervention) Range of visual-perceptual ability score 0-30 (0=no visual-perceptual difficulties, 30=maximum visual-perceptual difficulties) | 5 weeks | 
| Change in Cognitive Difficulties - Verbal Memory Between Baseline and 5 Weeks of Treatment With Duloxetine | Cognitive Difficulties - Verbal Memory will be assessed at baseline and 5 weeks for each individual patient using the Multiple Ability Self-Report Questionnaire. Baseline: Mean verbal memory score for all individual patients in arm 1 (intervention) 5 weeks: Mean verbal memory score for all individual patients in arm 1 (intervention) Range of verbal memory score 0-40 (0=no verbal memory difficulties, 40=maximum verbal memory difficulties) | 5 weeks | 
| Change in Cognitive Difficulties - Visual-Spatial Memory Between Baseline and 5 Weeks of Treatment With Duloxetine | Cognitive Difficulties - Visual-Spatial Memory will be assessed at baseline and 5 weeks for each individual patient using the Multiple Ability Self-Report Questionnaire. Baseline: Mean visual-spatial memory score for all individual patients in arm 1 (intervention) 5 weeks: Mean visual-spatial memory score for all individual patients in arm 1 (intervention) Range of visual-spatial memory score 0-40 (0=no visual-spatial memory difficulties, 40=maximum visual-spatial memory difficulties) | 5 weeks | 
| Change in Cognitive Difficulties - Attention/Concentration Between Baseline and 5 Weeks of Treatment With Duloxetine | Cognitive Difficulties - Attention/Concentration will be assessed at baseline and 5 weeks for each individual patient using the Multiple Ability Self-Report Questionnaire. Baseline: Mean attention/concentration score for all individual patients in arm 1 (intervention) 5 weeks: Mean attention/concentration score for all individual patients in arm 1 (intervention) Range of attention/concentration score 0-40 (0=no attention/concentration difficulties, 40=maximum attention/concentration difficulties) | 5 weeks | 
| Change in Objectively Assessed Pain Sensitivity Between Baseline and 5 Weeks of Treatment With Duloxetine | Pain sensitivity will be assessed at baseline and 5 weeks for each individual patient using quantitative sensory testing to assess pressure pain threshold (Pain50). Baseline: Mean Pain50 for all individual patients in arm 1 (intervention) and arm 2 (control) 5 weeks: Mean Pain50 for all individual patients in arm 1 (intervention) Range of Pain50 score: 0-10 kg/cm2 (higher number reflects higher pain threshold or lower pain sensitivity) | 5 weeks | 
| Change in Objectively Assessed Conditioned Pain Modulation Between Baseline and 5 Weeks of Treatment With Duloxetine | Conditioned pain modulation (CPM) will be assessed at baseline and 5 weeks for each individual patient using quantitative sensory testing Baseline: Mean CPM for all individual patients in arm 1 (intervention) and arm 2 (control) 5 weeks: Mean CPM for all individual patients in arm 1 (intervention) Range of CPM score: -60 to +60 (more positive values reflect more impaired CPM) | 5 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pain sensitivity, Breast cancer