Article

Pilot study of duloxetine for treatment of aromatase inhibitor-associated musculoskeletal symptoms

Breast Oncology Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan, USA.
Cancer (Impact Factor: 4.89). 12/2011; 117(24):5469-75. DOI: 10.1002/cncr.26230
Source: PubMed
ABSTRACT
Approximately 50% of postmenopausal women with hormone receptor-positive early stage breast cancer treated with an aromatase inhibitor (AI) develop musculoskeletal symptoms. Standard analgesics are relatively ineffective. Duloxetine is a serotonin norepinephrine reuptake inhibitor with proven efficacy for treatment of multiple chronic pain states. The authors investigated the hypothesis that duloxetine is efficacious for treatment of AI-associated musculoskeletal symptoms.
The authors performed a single-arm, open-label phase 2 study of duloxetine in postmenopausal women with breast cancer who developed new or worsening pain after treatment with an AI for at least 2 weeks. Patients were treated with duloxetine for 8 weeks (30 mg for 7 days, then 60 mg daily). The primary endpoint was a 30% decrease in average pain score over 8 weeks, and secondary outcomes included change in average and worst pain, pain interference, depression, sleep quality, and hot flashes. Statistical analysis was done with t tests for paired data.
Twenty-one of 29 evaluable patients (72.4%) achieved at least a 30% decrease in average pain, and 18 of 23 patients (78.3%) who completed protocol-directed treatment continued duloxetine. The mean percentage reduction in average pain severity between baseline and 8 weeks was 60.9% (95% confidence interval [CI], 48.6%-73.1%), and in maximum pain severity it was 59.9% (95% CI, 47.0-72.7%). The most common adverse events were grade 1 or 2 fatigue, xerostomia, nausea, and headache.
Duloxetine appears to be effective and well tolerated for treatment of AI-associated musculoskeletal symptoms. Future randomized, placebo-controlled studies are warranted.

Full-text

Available from: Max S Wicha, Jan 04, 2015
Pilot Study of Duloxetine for Treatment of
Aromatase Inhibitor-Associated
Musculoskeletal Symptoms
N. Lynn Henry, MD , PhD
1
; Mousumi Banerjee, PhD
2
;MaxWicha,MD
1
; Catherine Van Poznak, MD
1
; Jeffr e y B. Smer age, M D , Ph D
1
;
Anne F. Schott, MD
1
; Jennifer J. Griggs, MD
1
; and Daniel F. Hayes, MD
1
BACKGROUND: Approximately 50% of postmenopausal women with hormone receptor-positive early stage breast
cancer treated with an aromatase inhibitor (AI) develop musculoskeletal symptoms. Standard analgesics are rela-
tively ineffective. Duloxetine is a serotonin norepinephrine reuptake inhibitor with proven efficacy for treatment of
multiple chronic pain states. The authors investigated the hypothesis that duloxetine is efficacious for treatment of
AI-associated musculoskeletal symptoms. METHODS: The authors performed a single-arm, open-label phase 2 study
of duloxetine in postmenopausal women with breast cancer who developed new or worsening pain after treatment
with an AI for at least 2 weeks. Patients were treated with duloxetine for 8 weeks (30 mg for 7 days, then 60 mg
daily). The primary endpoint was a 30% decrease in average pain score over 8 weeks, and secondary outcomes
included change in average and worst pain, pain interference, depression, sleep quality, and hot flashes. Statistical
analysis was done with t tests for paired data. RESULTS: Twenty-one of 29 evaluable patients (72.4%) achieved at
least a 30% decrease in average pain, and 18 of 23 patients (78.3%) who completed protocol-directed treatment con-
tinued duloxetine. The mean percentage reduction in average pain severity between baseline and 8 weeks was 60.9%
(95% confidence interval [CI], 48.6%-73.1%), and in maximum pain severity it was 59.9% (95% CI, 47.0-72.7%). The
most common adverse events were grade 1 or 2 fatigue, xerostomia, nausea, and headache. CONCLUSIONS: Duloxe-
tine appears to be effective and well tolerated for treatment of AI-associated musculoskeletal symptoms. Future
randomized, placebo-controlled studies are warranted. Cancer 2011;117:5469–75.
V
C
2011 American Cancer Society.
KEYWORDS: breast cancer, aromatase inhibitor, arthralgia, duloxetine, serotonin-norepinephrine reuptake inhibitor.
Aromatase inhibitors (AIs) have been shown to be more effective than tamoxifen for decreasing the risk of breast
cancer recurrence in postmenopausal women with early stage, hormone receptor-positive breast cancer in multiple large,
randomized controlled trials.
1,2
Although aromatase inhibition was initially reported to be well tolerated, subsequent stud-
ies have demonstrated that up to 50% of patients report new onset or worsening arthralgias and myalgias associated with
treatment.
3,4
The underlying mechanism for development of this toxicity remains unknown. Proposed etiologies include
estrogen deprivation, local or systemic inflammatory processes, and alterations in the growth hormone/insulin growth fac-
tor pathways.
4,5
Standard analgesics do not appear to effectively manage the symptoms for most women,
6
but acupuncture
has been shown in a randomized, placebo-controlled trial to lessen joint pain.
6,7
Because standard adjuvant AI therapy is
administered for 2 to 5 years, successful treatment of these symptoms is important for both adherence to therapy and
improvement in the quality of life of breast cancer survivors.
Duloxetine (Cymbalta, Eli Lilly Pharmaceuticals, Indianapolis, Ind) is a serotonin and norepinephrine reuptake in-
hibitor (SNRI) that was initially approved by the US Food and Drug Administration (FDA) for treatment of major
depressive disorder.
8
Subsequently, it has been found to be efficacious for treatment of multiple chronic pain states,
including low back pain and osteoarthritis, and is FDA approved for the treatment of fibromyalgia, diabetic peripheral
neuropathic pain, and chronic musculoskeletal pain.
9-12
Small pilot studies have also suggested a potential benefit from
DOI: 10.1002/cncr.26230, Received: February 3, 2011; Revised: March 24, 2011; Accepted: Apri l 11, 2011, Published online June 20, 2011 in Wiley Online Library
(wileyonlinelibrary.com)
Corresponding author: N. Lynn Henry, MD, PhD, 1500 East Medical Center Drive, Med Inn Building C450, Ann Arbor, MI 48109-5843; Fax: (734) 936-4940;
norahh@med.umich.edu
1
Breast Oncolog y Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan;
2
Department of Biostatistics, University of Michigan
School of Public Health, Ann Arbor, Michigan
The results contained in this article were presented in part at the San Antonio Breast Cancer Symposium, San Antonio, Texas, December 8-12, 2010.
Cancer December 15, 2011 5469
Original Article
Page 1
duloxetine on sleep disturbance and menopausal symp-
toms such as hot flashes.
13,14
The mechanism by which
duloxetine decreases pain is unclear, but it may alter cen-
tral pain processing.
Because duloxetine is an effective adjunctive treat-
ment for multiple chronic pain states, we performed this
open-label pilot study to determine whether it may be
effective for management of AI-associated musculoskel-
etal symptoms. We also performed exploratory analyses to
investigate whether duloxetine may impact other AI-asso-
ciated toxicities, including hot flashes, sleep disturbance,
and mood alterations.
MATERIALS AND METHODS
Subject Population
Postmenopausal women who developed new or worsen-
ing pain during adjuvant AI therapy for stage I to III hor-
mone receptor-positive breast cancer were enrolled on this
pilot study between December 2008 and June 2010
(www.clinicaltrials.gov NCT01028352). Surgical resection,
chemotherapy, and radiation therapy, when indicated, were
completed before study enrollment. Patients must have been
taking standard-dose AI therapy (anastrozole (Arimidex;
AstraZeneca Pharmaceuticals, Wilmington, Del) 1 mg,
exemestane (Aromasin; Pfizer, New York, NY) 25 mg, or
letrozole (Femara; Novartis, Basel, Switzerland) 2.5 mg
orally daily for at least 2 weeks before enrollment. Patients
were required to have grade 1 or higher musculoskeletal pain
or sensory neuropathy that developed or worsened during
AI therapy, average pain during the week before enrollment
ratedatleast4ona0to10Likertscale,andEasternCooper-
ative Oncology Group performance status 0 to 2. Patients
were ineligible if they had new pain specifically because of
trauma or fracture, liver dysfunction, creatinine clearance
<30 mL/min, a clinically significant coagulation disorder,
narrow-angle glaucoma, schizophrenia, psychosis, suicidal
ideation, seizure disorder, or substance abuse or dependence
within the year before enrollment, or if they had taken mon-
oamine oxidase inhibitors (MAOIs) within 14 days before
enrollment. Patients were not permitted to take concomitant
selective serotonin reuptake inhibitors (SSRIs) or SNRIs,
MAOIs, phenothiazines, tricyclic antidepressants, triptans,
or other medications as described in the duloxetine package
insert, although they were permitted to discontinue the
medications at the time of study enrollment. The protocol
was approved by the University of Michigan Institutional
Review Board before patient enrollment, and all patients
provided written informed consent.
Treatment Plan
Enrolled patients were treated with duloxetine 30 mg
orally daily for 7 days, then 60 mg daily for 21 days. At
that time, patients had the option of continuing duloxe-
tine 60 mg daily or increasing the dose to duloxetine
60 mg twice daily. Patients who developed grade 3 or 4
adverse events based on Common Terminology Criteria
for Adverse Events discontinued therapy for up to 7 days
and restarted therapy at 60 mg daily once symptoms
resolved to grade 2 or less. If symptoms did not resolve
within 7 days, study participation was discontinued. In
addition, any patient who was unable to tolerate the
60 mg daily dose discontinued study participation. At the
completion of the study, patients had the option of con-
tinuing duloxetine therapy off protocol. Patients who dis-
continued duloxetine therapy at any time, regardless of
reason, tapered off treatment over 4 to 7 days.
Patients who had been taking a stable dose of medi-
cation for treatment of pain (eg, nonsteroidal anti-inflam-
matory medications, cyclooxygenase-2 inhibitors,
opioids, gabapentin, pregabalin, cyclobenzaprine, gluco-
samine chondroitin) at the time of enrollment were per-
mitted to continue the medication; otherwise, patients
were permitted to take up to 2 g of acetaminophen daily
for treatment of pain and up to 325 mg of aspirin daily
for cardiac prophylaxis, and were instructed to avoid
initiation of new treatments for pain during study partici-
pation. Patients were also instructed to avoid taking con-
comitant medications with the potential to interact with
duloxetine as described in the package insert.
Subject Assessment
During study participation, patients underwent toxicity
assessment every 2 weeks. Patients completed the follow-
ing questionnaires at baseline and every 2 weeks to evalu-
ate change in pain and functional status: Brief Pain
Inventory (BPI),
15
2-page Health Assessment Question-
naire (HAQ) and Pain Visual Analog Scale,
16
and
National Surgical Adjuvant Breast and Bowel Project
symptom checklist. To assess depression, menopausal
symptoms, and sleep difficulties, the following question-
naires were completed at baseline and every 4 weeks:
Center for Epidemiologic Studies-Depression Scale,
17
Menopause-Specific Quality of Life Questionnaire,
18
Hot Flash Related Daily Interference Scale,
19
and Pitts-
burgh Sleep Quality Index (PSQI).
20,21
Patients also com-
pleted a protocol-specific questionnaire specifically
designed to collect information about arthralgia severity
and management and to assess reasons for continuation or
Original Article
5470 Cancer December 15, 2011
Page 2
discontinuation of duloxetine therapy after completion of
the trial.
Statistical Analysis
The primary endpoint of the study was assessment of the
percentage of patients who achieved at least a 30%
decrease in average pain with 8 weeks of duloxetine ther-
apy based on patient-reported scores on the BPI. On the
basis of data from duloxetine treatment of other chronic
pain conditions,
9-12
we estimated that at least 55% of our
patients treated with duloxetine would experience a 30%
decrease in average pain with 8 weeks of therapy. We
expected that placebo likely would not result in a response
rate higher than 40%. With a sample size of 30 patients, a
1-sided 95% confidence interval (CI) for the true propor-
tion of patients who experienced a 30% decrease in aver-
age pain was expected to be 40% to 70%. Patients were
considered evaluable for the primary endpoint and for
toxicity assessment if they met all eligibility criteria and
took at least 1 dose of duloxetine. Subjects who did not
complete 8 weeks of protocol-directed therapy were con-
sidered nonresponders for the primary endpoint.
Secondary measures included the percentage of
patients treated with duloxetine who experienced 1) a
30% reduction in worst pain from baseline to 8 weeks,
2) a 50% decrease in average pain from baseline to
8 weeks, and 3) a 50% reduction in worst pain from
baseline to 8 weeks. Descriptive statistics were used for the
primary and secondary measures. The change in average
and worse pain score, pain interference score, depression
score, HAQ score, vasomotor symptom scores, and sleep
scores in this patient cohort from baseline to 8 weeks were
analyzed using t test for paired data. Statistical significance
was defined as a P value of <.05.
RESULTS
Between December 2008 and May 2010, 35 patients en-
rolled and completed baseline questionnaires. One subject
withdrew from the study before initiating therapy. After
initiating protocol-directed duloxetine therapy, 5 patients
were found to be ineligible because their baseline average
pain as assessed using the BPI was <4 on a 10-point scale,
and therefore the primary endpoint could not be assessed
(see Fig. 1 for Patient Flow Diagram). The demographics
of the 29 eligible, treated patients are summarized in
Table 1. All eligible patients reported new or worsening
joint aches or pains rated at least 4 on a 10-point scale
since starting AI therapy. As assessed using the BPI, mean
average pain at time of study enrollment was 5.5 (range,
4-7), mean worst pain was 7.2 (range, 4-10), and mean
pain interference score was 4.32 (range, 1.57-7.86).
Fewer enrolled patients were being treated with
anastrozole (21%) compared with the other 2 AI medica-
tions (approximately 40% each). Approximately 55% of
enrolled patients had previously switched from 1 AI to a
second AI because of toxicity before study enrollment,
and 1 subject had received treatment with all 3 AI
medications.
Reduction of Pain With Duloxetine
Of the 29 evaluable patients who initiated protocol-
directed therapy, 21 (72.4%) experienced the protocol-
specified primary endpoint of at least a 30% decrease in
average pain score with 8 weeks of therapy, and 16
(55.2%) experienced at least a 50% decrease in average
pain score. Of the 23 patients who completed study ther-
apy, 21 (91.3%) experienced at least a 2 point absolute
decrease in average pain between baseline and 8 weeks,
and the mean percent reduction in average pain was
60.9%, with a 95% CI of 48.6% to 73.1% (Table 2).
Only 1 subject chose to increase the dose of duloxetine to
60 mg twice daily after 4 weeks of daily therapy. The time
course of response to duloxetine is pictured in Figure 2.
Of the 29 evaluable patients, 19 (65.5%) experi-
enced at least a 30% decrease in worst pain with 8 weeks
of therapy, and 17 (58.6%) experienced at least a 50%
Figure 1. Patient flow diagram is shown.
Duloxetine for AI-Associated Arthralgias/Henry et al
Cancer December 15, 2011 5471
Page 3
decrease in worst pain. Of the 23 patients who completed
study therapy, 20 (87%) experienced at least a 2-point
absolute decrease in worst pain between baseline and 8
weeks, and the mean percentage reduction in worst pain
was 59.9% (95% CI, 47.0%-72.7%; Table 2).
Change in interference of pain with activities of
daily living as measured using the BPI demonstrated that
the mean percentage reduction in pain interference with 8
weeks of duloxetine therapy was 78.9% (95% CI, 68.1%-
89.8%; Table 2).
Eighteen of the 23 patients (78.3%) who completed
all 8 weeks of study treatment chose to remain on duloxe-
tine therapy. After completion of study therapy, 3 patients
discontinued treatment because of lack of improvement in
pain symptoms, and 2 chose to stop therapy because of
duloxetine-associated side effects. Comparison of the base-
line characteristics, including duration of AI therapy, prior
chemotherapy, and prior tamoxifen therapy, between the
responders and the nonresponders did not reveal any statis-
tically significant differences (data not shown).
Safety and Tolerability
Safety was assessed in all 34 patients who received at least
1 dose of study medication. Adverse events and treatment
discontinuation of duloxetine were similar to safety findings
in previously reported duloxetine studies.
9-12
Seven patients
(20.6%) discontinued therapy because of adverse events,
including 6 evaluable patients and 1 who was subsequently
Table 1. Baseline Demographic and Clinical Characteristics of
Eligible, Enrolled Patients (n¼29)
Characteristic Value
Median age, y [range] 56 [36-70]
Race
White
89.7%
African American
6.9%
Native American
3.4%
BMI, mean SD 30.5 6.5
Prior treatments
Chemotherapy
21 (72.4%)
Taxane
18 (62.1%)
Tamoxifen
10 (34.5%)
AI while on study
Anastrozole
6 (20.7%)
Exemestane
11 (37.9%)
Letrozole
12 (41.4%)
Median duration of AI therapy
Current AI treatment, mo [range]
7.9 [0.7-46.1]
Total AI therapy, prior plus current,
mo [range]
14.4 [2.3-46.1]
Abbreviations: AI, aromatase inhibitor; BMI, body mass index; SD, standard
deviation.
Table 2. Change in Outcome Measures With Duloxetine Therapy
Outcome Measure Baseline,
n 5 29
2 Weeks,
n 5 25
4 Weeks,
n 5 23
6 Weeks,
n 5 23
8 Weeks,
n 5 23
P
a
Average pain, 0-10 5.48
b
(1.09) 2.48 (1.53) 2.09 (2.04) 2.26 (1.79) 2.09 (1.62) <.0001
Worst pain, 0-10 7.21 (1.40) 3.36 (2.38) 3.13 (2.55) 3.30 (2.01) 2.87 (2.32) <.0001
Pain interference, 0-10 4.32 (1.96) 1.58 (1.73) 1.33 (1.70) 1.06 (1.04) 0.96 (1.26) <.0001
HAQ, 0-3 0.484 (0.312) 0.197 (0.260) 0.245 (0.330) 0.212 (0.286) 0.234 (0.283) .0012
Hot flash interference, 0-100; HFRDIS 17.10 (21.87) 10.09 (14.49) 6.96 (12.48) .0194
Hot flash interference, 1-8;
MENQOL vasomotor subscale
2.86 (1.99) 2.20 (1.38) 2.56 (1.67) .31
Depression; CESD 10.14 (8.77) 5.83 (4.70) 3.52 (3.19) .0035
Sleep, 0-21 8.00 (3.25) 7.87 (4.09) 6.91 (4.04) .025
Abbreviations: CESD, Center for Epidemiologic Studies-Depression Scale; HAQ, Health Assessment Questionnaire; HFRDIS, Hot Flash Related Daily Interfer-
ence Scale; MENQOL, Menopause-Specific Quality of Life Questionnaire.
a
The difference between baseline and 8 weeks; 2-tailed paired t test.
b
Mean (standard deviation).
Figure 2. Average pain over time during duloxetine therapy
was assessed using the Brief Pain Inventory. Error bars reflect
standard deviation at each time point. The number of evalu-
able patients at each time point is listed below the graph.
Original Article
5472 Cancer December 15, 2011
Page 4
found to be ineligible. The majority of subjects who discon-
tinued therapy because of adverse events did so within a few
days of starting treatment. Reasons for treatment discontinu-
ation included grade 1 and/or 2 drowsiness, headache, and
nausea. The majority of reported adverse events were grade
1 and/or 2 fatigue and drowsiness, nausea, xerostomia, con-
stipation, and headache, consistent with prior studies of
duloxetine (Table 3), and 76.5% of patients reported at least
1 adverse event. The single reported grade 3 adverse event
was tachycardia, categorized as unlikely to be related to ther-
apy by the treating physician. The affected patient com-
pleted study-directed therapy, but then discontinued
duloxetine because of lack of benefit.
Patient-Reported Nonpain Outcomes
Because other SSRIs and SNRIs have been reported to
improve symptoms such as hot flashes, the effect of 8 weeks
of duloxetine therapy on hot flashes, depression, sleep, and
functional status was assessed. Twenty-nine evaluable
patients completed the battery of questionnaires at baseline,
and 23 completed them at the 8-week time point. Intrapa-
tient reduction in hot flash interference with daily life, as
assessed with the 10-item Hot Flash Related Daily Interfer-
ence Scale questionnaire, revealed an improvement (baseline,
17.1; 8 weeks, 7.0; P ¼ .019), but no change was observed
when using the Menopause-Specific Quality of Life Ques-
tionnaire vasomotor subscale (Table 2). Assessment of intra-
patient change in depression (as assessed using the Center for
Epidemiologic Studies-Depression Scale), sleep (as assessed
using the PSQI), and functional status (as assessed using the
HAQ) with 8 weeks of duloxetine therapy revealed statisti-
cally significant improvements in all 3 measures (Table 2).
DISCUSSION
AIs have been shown to cause arthralgias in up to 50% of
patients, can be difficult to treat, and can negatively
impact quality of life and potentially persistence with
therapy. In this pilot clinical trial of duloxetine, we dem-
onstrated that 93% of patients with AI-associated joint
aches and pains who completed 8 weeks of therapy experi-
enced at least a 2-point decrease in patient-reported aver-
age pain, an improvement that has been shown to be
clinically meaningful in studies of other chronic pain con-
ditions and that is the cutoff recommended by the Initia-
tive on Methods, Measurement, and Pain Assessment in
Clinical Trials consensus committee.
22
This response rate
compares favorably with that observed in studies of dulox-
etine in other chronic pain conditions, including fibro-
myalgia and chronic low back pain.
11,12
Likewise, the
improvement in pain was rapid, occurring primarily
within the first 2 weeks of study treatment, and sustained
through the 8 weeks of protocol-directed therapy in the
majority of patients. These findings suggest that duloxe-
tine may be effective for treatment of AI-associated mus-
culoskeletal pain, and are particularly striking in this
patient cohort, the majority of whom had already
switched from 1 AI to another because of intolerable med-
ication-associated musculoskeletal pain.
In addition to the impact of duloxetine on pain, we
also explored potential changes in other symptoms fre-
quently experienced by women treated with aromatase
inhibitors. Duloxetine appeared to cause clinically signifi-
cant improvements in both functional status and depres-
sion, although only 4 patients were classified as possibly
or probably depressed based on Center for Epidemiologic
Studies-Depression Scale scores at baseline. In a published
study of patients with major depressive disorder and pain-
ful physical symptoms, the improvement in pain was
independent of the decrease in depression.
23
These results
suggest that the analgesic effect of duloxetine is separate
from its antidepressant activity.
Improvements in other aspects of quality of life were
less apparent. Although the change in PSQI scores was
Table 3. Adverse Events That Affected at Least 3 Subjects (n¼34)
Toxicity Any Grade Grade 1 Grade 2 Grade 3 Grade 4 Cause of Treatment
Discontinuation
a
Fatigue 7 (20.6%) 6 (17.7%) 1 (2.9%) 0 0 0
Constipation 6 (17.7%) 6 (17.7%) 0 0 0 0
Nausea 6 (17.7%) 4 (11.8%) 2 (5.9%) 0 0 3 (8.8%)
Headache 5 (14.7%) 4 (11.8%) 1 (2.9%) 0 0 3 (8.8%)
Dry mouth 5 (14.7%) 5 (14.7%) 0 0 0 1 (2.9%)
Drowsiness 4 (11.8%) 0 4 (11.8%) 0 0 2 (2.9%)
Heartburn 3 (8.8%) 1 (2.9%) 2 (5.9%) 0 0 1 (2.9%)
Anxiety 3 (8.8%) 2 (5.9%) 1 (2.9%) 0 0 1 (2.9%)
a
Some subjects reported >1 adverse event, leading to treatment discontinuation.
Duloxetine for AI-Associated Arthralgias/Henry et al
Cancer December 15, 2011 5473
Page 5
statistically significant, treatment with duloxetine did not
appear to result in clinically significant improvements in
sleep quality. Hot flash diaries were not used during this
clinical trial; instead, assessment of change in hot flash
interference in daily life was assessed with questionnaires.
Analysis of the Menopause-Specific Quality of Life Ques-
tionnaire vasomotor subscale revealed no change in symp-
toms with 8 weeks of duloxetine therapy. However, when
the more detailed, 10-item Hot Flash Related Daily Inter-
ference Scale questionnaire was used, a significant
improvement in hot flashes was observed. Although the
Hot Flash Related Daily Interference Scale data are con-
sistent with a previously reported small pilot study of
duloxetine for management of vasomotor symptoms,
13
determination of actual benefit from duloxetine for hot
flashes will require further evaluation in subsequent stud-
ies. Overall, these results suggest that treatment with
duloxetine may result in improvements in multiple AI-
associated symptoms, rather than simply reduction of
pain symptoms, which could lead to more substantial
improvements in overall quality of life.
The findings of this study are limited by its small
sample size, fairly high treatment discontinuation rate,
and lack of a concurrent control group. As in our study,
up to 20% of patients have been unable to tolerate duloxe-
tine in multiple clinical trials of various medical condi-
tions.
9-12
However, despite these limitations, for those
women who are able to tolerate the medication, duloxe-
tine appears to be effective for treating AI-associated mus-
culoskeletal symptoms. One other potential limitation is
the repeated assessment of pain during the 8-week clinical
trial, which can be a source of bias. However, we believe
this bias had minimal impact in this study, because most
patients reported significant improvement at the first on-
treatment assessment, and more than
3
=
4
of those patients
who completed 8 weeks of treatment chose to continue
duloxetine therapy at the time of study completion.
Multiple clinical studies have been performed to
elucidate the mechanism underlying development of AI-
associated musculoskeletal symptoms, but all have been
unrevealing.
4
Therefore, in this study we were dependent
on patient-reported outcomes to assess efficacy of duloxe-
tine. Regardless, the BPI is a well-validated measure of
pain in cancer and noncancer populations that has been
used in multiple other published studies of AI-associated
musculoskeletal toxicity.
7,15,24
The most plausible cause of AI-associated musculo-
skeletal symptoms appears to be local or systemic estrogen
deprivation. Estrogen is known to play a role in pain proc-
essing in the central nervous system. AI therapy could
therefore lead to an abnormality of central pain processing,
thereby causing chronic pain such as arthralgias. Duloxe-
tine is believed to act via modulation of central pain proc-
essing, and has been shown to be effective for management
of other central pain disorders, including fibromyalgia.
12
Although feasible, an estrogen agonistic effect of duloxetine
has not been demonstrated in preclinical or clinical studies.
In addition, there are no in vitro or in vivo data to suggest
that there are any pharmacologic interactions between
duloxetine and any of the AIs that could decrease the effec-
tiveness of AI therapy.
25
Taken together, these observations
support our preliminary conclusions that duloxetine could
be an effective treatment for AI-associated musculoskeletal
symptoms via its direct effect on nociceptive pathways.
We exceeded our prestudy, protocol-stipulated criteria
for success in this uncontrolled pilot clinical trial. However,
many studies testing the efficacy of agents for treatment of
symptoms such as pain and hot flashes have had a substantial
placebo effect.
26
In this study, the benefit of duloxetine
(72%) was substantially higher than the reported response
rates for placebo (19%-40%) in other chronic pain condi-
tions, including fibromyalgia, knee osteoarthritis, and dia-
betic neuropathic pain.
9,10,12
Therefore, we conclude that
these preliminary phase 2 data support the efficacy of dulox-
etine in reducing symptoms related to AI-associated muscu-
loskeletal symptoms, and that this agent deserves study in a
larger, definitive, placebo-controlled trial.
In this regard, this pilot trial was too small to pro-
vide meaningful subgroup analysis of potential baseline
clinical predictors of response to duloxetine therapy or to
investigate changes in biomarkers such as inflammatory
biomarkers. In addition, longer term studies are necessary
to confirm the durability of the response. Such analyses will
be integral to design of larger randomized, placebo-
controlled clinical trials, which are currently being planned.
In conclusion, these preliminary results strongly
suggest that duloxetine was effective in decreasing AI-
associated musculoskeletal pain and its interference with
daily activities in the majority of women with early stage,
hormone receptor-positive breast cancer. Given the high
incidence of AI-associated musculoskeletal symptoms,
identification of a therapy to ameliorate these treatment-
emergent toxicities is important to optimize persistence
with therapy and quality of life.
FUNDING SOURCES
This study was supported by an investigator-initiated award to
N.L.H. from Lilly Pharmaceuticals.
Original Article
5474 Cancer December 15, 2011
Page 6
CONFLICT OF INTEREST DISCLOSURES
N.L.H. receives research funding from Lilly Pharmaceuticals and
AstraZeneca. D.F.H. receives research funding from Astra-
Zeneca, Novartis, Pfizer, and Veridex, and has an immediate fam-
ily member who is employed by Lilly. C.V.P. receives research
funding from Novartis and Amgen. J.B.S. received honoraria
from Lilly Pharmaceuticals until July 2008. M.W. is a consultant
for Pfizer. M.B., A.F.S., and J.J.G. have no disclosures.
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Duloxetine for AI-Associated Arthralgias/Henry et al
Cancer December 15, 2011 5475
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    • "Another treatment approach could be pharmacological, based on antidepressants' use: in fact, some of them (serotonin norepinephrine reuptake inhibitors (SNRIs)) are known to be effective in the treatment not only of depression and anxiety but also of chronic pain [44]. Recently, Henry et al. [45] studied a small group of patients receiving AI and found a reduction in joint and muscle pain following 8 weeks of duloxetine (SNRI). However, these interesting results will have to be confirmed in a randomized study involving a larger number of patients and a control group. "
    [Show abstract] [Hide abstract] ABSTRACT: The aim of this study was to explore associations between arthralgia and fear of recurrence in breast cancer patients treated by aromatase inhibitors (AI). We sent a set of questionnaires to 100 patients examining their pain characteristics, anxiety (STAI), depression (BDI-SF), quality of life (SF-36), fear of recurrence (FCRI), and representations of AI treatment (ad hoc questionnaire). Nonparametric tests were used to investigate between-group comparisons (arthralgia vs. nonarthralgia) in these domains as well as the associations between arthralgia and fear of recurrence. Of the 77 patients who returned the questionnaires (response rate = 77 %), 60 (78 %) reported arthralgia. The mean score of fear of recurrence exceeded the pathological threshold in the arthralgia group and was significantly higher than that in the nonarthralgia group (14.8 vs. 10.7, p < 0.01). Significant associations were observed between fear of recurrence and pain intensity (r = 0.274, p < 0.05) and pain relief (r = -0.409, p < 0.05). More than 80 % of the total sample declared that they were well informed about the aim of AI, their side effects, and the risk of developing arthralgia. Fear of recurrence did not appear to be associated with representations of AI. The study revealed a close relationship between pain intensity and fear of recurrence. In particular, it showed that effective pain management was accompanied by a reduced fear of recurrence. Information, although essential, appeared insufficient to overcome patients' concerns about pain. Therefore, the implement of a systematic screening for arthralgia and the improvement of analgesic treatment are essential issues. New strategies for pharmacological and nonpharmacological treatment must be developed.
    Full-text · Article · Apr 2015 · Supportive Care in Cancer
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    • "Effective management of AIMSS is still a mystery in clinical practice, as the mechanisms behind AIMSS are not clearly understood. A number of small interventional trials investigating acupuncture [19,20], vitamin D [18], glucosamine [21], short-term low-dose prednisolone [22], thymosin α1 [23], duloxetine [24] and yoga [25] have provided various treatment strategies. However, most of these trials have had some methodological and practical limitations, including small sample sizes, larger-than-anticipated drop-out, a single-center design, lack of control group and blinding, and a short follow-up period. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Aromatase inhibitors (AIs) are widely used as an adjuvant endocrine treatment in postmenopausal women with early-stage breast cancer. One of the main adverse effects of AIs is musculoskeletal symptoms, which leads to a lower quality of life and poor adherence to AI treatment. To date, no effective management of aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) has been developed. Methods/design To determine whether the traditional Chinese medicine Yi Shen Jian Gu granules could effectively manage AIMSS we will conduct a multicenter, randomized, double-blind, placebo-controlled clinical trial. Patients experiencing musculoskeletal symptoms after taking AIs will be enrolled and treated with traditional Chinese medicine or placebo for 12 weeks. The primary outcome measures include Brief Pain Inventory-Short Form, Western Ontario and McMaster Universities Osteoarthritis Index, and Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands, which will be obtained at baseline and at 4, 8, 12 and 24 weeks. Discussion The results of this study will provide a new strategy to help relieve AIMSS. Trial registration ISCTN: ISRCTN06129599 (assigned 14 August 2013).
    Full-text · Article · May 2014 · Trials
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    • "In addition, if a patient population could be identified that is at high risk for development of a specific toxicity, such as AIMSS, this cohort could be targeted for interventional trials to prevent or reduce the burden of such toxicities. In this regard, we have reported a pilot phase II trial suggesting duloxetine reduces pain related to AIMSS by *60 % [13] . If validated , the association between AIMSS and the SNP in ESR1 could be used to personalize this strategy. "
    [Show abstract] [Hide abstract] ABSTRACT: Up to 25 % of patients discontinue adjuvant aromatase inhibitor (AI) therapy due to intolerable symptoms. Predictors of which patients will be unable to tolerate these medications have not been defined. We hypothesized that inherited variants in candidate genes are associated with treatment discontinuation because of AI-associated toxicity. We prospectively evaluated reasons for treatment discontinuation in women with hormone receptor-positive breast cancer initiating adjuvant AI through a multicenter, prospective, randomized clinical trial of exemestane versus letrozole. Using multiple genetic models, we evaluated potential associations between discontinuation of AI therapy because of toxicity and 138 variants in 24 candidate genes, selected a priori, primarily with roles in estrogen metabolism and signaling. To account for multiple comparisons, statistical significance was defined as p < 0.00036. Of the 467 enrolled patients with available germline DNA, 152 (33 %) discontinued AI therapy because of toxicity. Using a recessive statistical model, an intronic variant in ESR1 (rs9322336) was associated with increased risk of musculoskeletal toxicity-related exemestane discontinuation [HR 5.0 (95 % CI 2.1-11.8), p < 0.0002]. An inherited variant potentially affecting estrogen signaling may be associated with exemestane-associated toxicity, which could partially account for intra-patient differences in AI tolerability. Validation of this finding is required.
    Full-text · Article · Apr 2013 · Breast Cancer Research and Treatment
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