Abstract
Aromatase inhibitors (AIs), which are used to treat breast cancer, inhibit estrogen
production in postmenopausal women. AI-associated musculoskeletal symptoms occur in
approximately half of treated women and lead to treatment discontinuation in 20 to
30%. The etiology may be due in part to estrogen deprivation. In premenopausal women,
lower estrogen levels have been associated with increased pain as well as with impairment
of descending pain inhibitory pathways, which may be a risk factor for developing
chronic pain. We prospectively tested whether AI-induced estrogen deprivation alters
pain sensitivity, thereby increasing the risk of developing AI-associated musculoskeletal
symptoms. Fifty postmenopausal breast cancer patients underwent pressure pain testing
and conditioned pain modulation (CPM) assessment prior to AI initiation and after
3 and 6 months. At baseline, 26 of 40 (65%) assessed patients demonstrated impaired
CPM, which was greater in those who had previously received chemotherapy (P = .006). No statistically significant change in pressure pain threshold or CPM was
identified following estrogen deprivation. In addition, there was no association with
either measure of pain sensitivity and change in patient-reported pain with AI therapy.
AI-associated musculoskeletal symptoms are not likely due to decreased pain threshold
or impaired CPM prior to treatment initiation, or to effects of estrogen depletion
on pain sensitivity.
Perspective
This article presents our findings of the effect of estrogen deprivation on objective
measures of pain sensitivity. In postmenopausal women, medication-induced estrogen
depletion did not result in an identifiable change in pressure pain threshold or CPM.
Impaired CPM may be associated with chemotherapy.
Key words
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References
- Effect of a switch of aromatase inhibitors on musculoskeletal symptoms in postmenopausal women with hormone-receptor-positive breast cancer: The ATOLL (Articular Tolerance of Letrozole) study.Breast Cancer Res Treat. 2010; 120: 127-134
- American Society of Clinical Oncology clinical practice guideline: Update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer.J Clin Oncol. 2010; 28: 3784-3796
- Prevalence of joint symptoms in postmenopausal women taking aromatase inhibitors for early-stage breast cancer.J Clin Oncol. 2007; 25: 3877-3883
- Letrozole suppresses plasma estradiol and estrone sulphate more completely than anastrozole in postmenopausal women with breast cancer.J Clin Oncol. 2008; 26: 1671-1676
- Meta-analysis of breast cancer outcomes in adjuvant trials of aromatase inhibitors versus tamoxifen.J Clin Oncol. 2010; 28: 509-518
- Aromatase inhibitors and the syndrome of arthralgias with estrogen deprivation.Arthritis Rheum. 2005; 52: 2594-2598
- Cerebral blood flow alterations in pain-processing regions of patients with fibromyalgia using perfusion MR imaging.AJNR Am J Neuroradiol. 2011; 32: 1873-1878
- Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study.J Clin Oncol. 2002; 20: 751-757
- A psychophysical study of auditory and pressure sensitivity in patients with fibromyalgia and healthy controls.J Pain. 2008; 9: 417-422
- The association between experimental and clinical pain measures among persons with fibromyalgia and chronic fatigue syndrome.Eur J Pain. 2007; 11: 202-207
- Quantitative sensory testing in vulvodynia patients and increased peripheral pressure pain sensitivity.Obstet Gynecol. 2004; 104: 126-133
- Evidence of augmented central pain processing in idiopathic chronic low back pain.Arthritis Rheum. 2004; 50: 613-623
- The relationship between depression, clinical pain, and experimental pain in a chronic pain cohort.Arthritis Rheum. 2005; 52: 1577-1584
- Subgrouping of fibromyalgia patients on the basis of pressure-pain thresholds and psychological factors.Arthritis Rheum. 2003; 48: 2916-2922
- A multiple random staircase method of psychophysical pain assessment.Pain. 1988; 32: 55-63
- Pain is associated with short leukocyte telomere length in women with fibromyalgia.J Pain. 2012; 13: 959-969
- Sleep measures.in: Stewart A.L. Ware J.E. Measuring Functioning and Well-Being: The Medical Outcomes Study Approach. Duke University Press, Durham, NC1992: 235-259
- Pain perception across the menstrual cycle phases in women with chronic pain.Percept Mot Skills. 2003; 96: 201-211
- Predictors of aromatase inhibitor discontinuation due to treatment-emergent symptoms in early-stage breast cancer.J Clin Oncol. 2012; 30: 936-942
- Pilot study of duloxetine for treatment of aromatase inhibitor-associated musculoskeletal symptoms.Cancer. 2011; 117: 5469-5475
- Aromatase inhibitor-associated musculoskeletal symptoms: Etiology and strategies for management.Oncology. 2008; 22: 1401-1408
- Genetic associations with toxicity-related discontinuation of aromatase inhibitor therapy for breast cancer.Breast Cancer Res Treat. 2013; 138: 807-816
- Changes in temporomandibular pain and other symptoms across the menstrual cycle.Pain. 2003; 106: 253-261
- Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity.Arthritis Rheum. 2010; 62: 2545-2555
- Brain correlates of phasic autonomic response to acupuncture stimulation: An event-related fMRI study.Hum Brain Mapp. 2013; 34: 2592-2606
- Increased pain sensitivity in fibromyalgia: Effects of stimulus type and mode of presentation.Pain. 2003; 105: 403-413
- Differences in unpleasantness induced by experimental pressure pain between patients with fibromyalgia and healthy controls.Eur J Pain. 2005; 9: 325-335
- Central pain mechanisms in the rheumatic diseases: Future directions.Arthritis Rheum. 2013; 65: 291-302
- The CES-D scale: A self-report depression scale for research in the general population.J Appl Psychol Meas. 1977; 1: 385-401
- Superiority of gas chromatography/tandem mass spectrometry assay (GC/MS/MS) for estradiol for monitoring of aromatase inhibitor therapy.Steroids. 2007; 72: 666-671
- Development and validation of a Multiple Ability Self-Report Questionnaire.J Clin Exp Neuropsychol. 1994; 16: 93-104
- Risk factors for joint symptoms in patients enrolled in the ATAC trial: A retrospective, exploratory analysis.Lancet Oncol. 2008; 9: 866-872
- The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue.J Psychosom Res. 1995; 39: 315-325
- Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: A randomized clinical trial.J Am Med Assoc. 2013; 309: 1359-1367
- Pronociceptive and antinociceptive effects of estradiol through endogenous opioid neurotransmission in women.J Neurosci. 2006; 26: 5777-5785
- MOS Sleep Scale: A Manual for Use and Scoring, Version 1.0.Rand, Los Angeles, CA2003
- Can neuroimaging studies identify pain endophenotypes in humans?.Nat Rev Neurol. 2011; 7: 173-181
- Central sensitization: Implications for the diagnosis and treatment of pain.Pain. 2011; 152: S2-S15
- Prediction of chronic post-operative pain: Pre-operative DNIC testing identifies patients at risk.Pain. 2008; 138: 22-28
- Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy.Pain. 2012; 153: 1193-1198
Article info
Publication history
Published online: January 24, 2014
Accepted:
January 4,
2014
Received:
December 5,
2013
Footnotes
Research funding: N.L.H. is a Damon Runyon-Lilly Clinical Investigator supported (in part) by the Damon Runyon Cancer Research Foundation (grant number CI-53-10). This work was also supported in part by the Michigan Institute for Clinical and Health Research (N.L.H.) and the Fashion Footwear Association of New York/QVC Presents Shoes on Sale (D.F.H.). This publication was made possible by Grant Number UL1RR024986 from the National Center for Research Resources, a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of National Center for Research Resources or National Institutes of Health.
N.L.H. receives research funding from AstraZeneca, Lilly Pharmaceuticals, and sanofi aventis. D.F.H. received research funding from AstraZeneca, Novartis, Pfizer, and Veridex LLC. D.J.C. has received consulting income and grant support from Pfizer, Forest, Wyeth, Cerephex, and Nuvo, and consulting income from Lilly, UCB, Cerephex, Tonix, and Purdue Labs. S.E.H. has received grant support from Cerephex, Merck, and Forest Laboratories.
No other authors reported conflicts of interest.
Supplementary data accompanying this article are available online at www.jpain.org/ and www.sciencedirect.com/.
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© 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.
