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Duloxetine 30 mg daily x 1 week, then 60 mg daily x 4 weeks, then 30 mg daily x 2 weeks.

Patient reported pain and symptoms assessment for comparison at baseline.

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.

Duloxetine

Lynn Henry, MD, PhD

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.

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.

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.

Mechanistic Study of Duloxetine in Breast Cancer Patients With Chronic Pain

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

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

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)

American Cancer Society, Inc.

University of Michigan Rogel Cancer Center

Duloxetine 30 mg daily x 1 week, then 60 mg daily x 4 weeks, then 30 mg daily x 2 weeks.

Duloxetine: 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.

Arm 1 (Patients With Pain)

Arm 2 (Patients Without Pain -- Control)

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Excluding the 1 patient in Arm 1 who withdrew consent

Baseline

5 weeks

Only patients with pain were analyzed at week 5. Patients who discontinued study treatment early (n=4) have no data available for week 5.

Change in Patient-reported Worst Pain Between Baseline and 5 Weeks of Treatment With Duloxetine

5 week timepoint

Change in Patient-reported Average Pain Between Baseline and 5 Weeks of Treatment With Duloxetine

Only patients with pain were analyzed at week 5. Patients who discontinued study treatment early (n=4) have no data available for week 5. 1 patient in Arm 1 had missing data at baseline and the score could not be generated.

Change in Pain Interference Between Baseline and 5 Weeks of Treatment With Duloxetine

Change in Number of Sites of Pain Between Baseline and 5 Weeks of Treatment With Duloxetine

week 5 timepoint

Change in Fibromyalgia Symptom Severity Score Between Baseline and 5 Weeks of Treatment With Duloxetine

Only patients with pain were analyzed at week 5. Patients who discontinued study treatment early (n=4) have no data available for week 5. 1 patient in Arm 1 had missing data at baseline and 3 patients had missing data at week 5 and the scores could not be generated.

Change in PainDETECT Score Between Baseline and 5 Weeks of Treatment With Duloxetine

Only patients with pain were analyzed at week 5. Patients who discontinued study treatment early (n=4) have no data available for week 5. 1 patient in Arm 1 at baseline, 1 patient in Arm 1 at week 5, and 1 patient in Arm 2 had missing data and the scores could not be generated.

Change in Neuropathy Between Baseline and 5 Weeks of Treatment With Duloxetine

Change in Fatigue Between Baseline and 5 Weeks of Treatment With Duloxetine

Change in Sleep Disturbance Between Baseline and 5 Weeks of Treatment With Duloxetine

Change in Physical Function Between Baseline and 5 Weeks of Treatment With Duloxetine

week 4 timepoint

Change in Anxiety Between Baseline and 5 Weeks of Treatment With Duloxetine

Only patients with pain were analyzed at week 5. Patients who discontinued study treatment early (n=4) have no data available for week 5. 1 patient in Arm 1 at baseline and 1 patient in Arm 2 had missing data and the scores could not be generated.

Change in Depression Between Baseline and 5 Weeks of Treatment With Duloxetine

Only patients with pain were analyzed at week 5. Patients who discontinued study treatment early (n=4) have no data available for week 5. 1 patient in Arm 1 at week 5 had missing data and the score could not be generated.

Change in Cognitive Difficulties - Language Between Baseline and 5 Weeks of Treatment With Duloxetine

Change in Cognitive Difficulties - Visual-Perceptual Ability Between Baseline and 5 Weeks of Treatment With Duloxetine

Only patients with pain were analyzed at week 5. Patients who discontinued study treatment early (n=4) have no data available for week 5. 1 patient in Arm 1 at baseline, 1 patient in arm 1 at week 5, and 1 patient in Arm 2 had missing data and the scores could not be generated.

Change in Cognitive Difficulties - Verbal Memory Between Baseline and 5 Weeks of Treatment With Duloxetine

Only patients with pain were analyzed at week 5. Patients who discontinued study treatment early (n=4) have no data available for week 5. 1 patient in Arm 1 at week 5 and 1 patient in Arm 2 had missing data and the scores could not be generated.

Change in Cognitive Difficulties - Visual-Spatial Memory Between Baseline and 5 Weeks of Treatment With Duloxetine

Change in Cognitive Difficulties - Attention/Concentration Between Baseline and 5 Weeks of Treatment With Duloxetine

Only patients with pain were analyzed at week 5. Patients who discontinued study treatment early (n=4) have no data available for week 5. 1 patient in Arm 1 had missing data at week 5 and the score could not be generated.

Change in Objectively Assessed Pain Sensitivity Between Baseline and 5 Weeks of Treatment With Duloxetine

Only patients with pain were analyzed at week 5. Patients who discontinued study treatment early (n=4) have no data available for week 5. 1 patient in Arm 1 at baseline, 1 patient in Arm 1 at week 5, and 2 patients in Arm 2 had missing data and the scores could not be generated.

Change in Objectively Assessed Conditioned Pain Modulation Between Baseline and 5 Weeks of Treatment With Duloxetine

Duloxetine 30 mg daily x 1 week, then 60 mg daily x 4 weeks, then 30 mg daily x 2 weeks.

Duloxetine: 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.

Surveys administered at baseline and at 5 weeks.

Because of challenges with logistics of the protocol and pain testing, the trial was redesigned after only 7 patients with pain were enrolled. Three of the patients had been assigned to placebo arm. This arm is not included in any analysis.

Spots Global Cancer Trial Database for pain sensitivity