breast pain management
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Mayo Clin Proc, March 2004, Vol 79 Breast Pain 353
Mayo Clin Proc. 2004;79:353-372 353 © 2004 Mayo Foundation for Medical Education and Research
Review
From the Breast Diagnostic Clinic, Division of General InternalMedicine (R.L.S., S.P.) and Division of Endocrinology, Diabetes,Metabolism, Nutrition and Internal Medicine (L.A.F.), Mayo ClinicCollege of Medicine, Rochester, Minn.
This work was supported in part by grants NCRR K24 andRR017593 from the Public Health Service, Mayo Foundation, andan unrestricted educational grant from Solvay Pharmaceuticals forthe Women’s Health Fellowship.
Address reprint requests and correspondence to Robin L. Smith,MD, Division of General Internal Medicine, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905.
Evaluation and Management of Breast Pain
ROBIN L. SMITH, MD; SANDHYA PRUTHI, MD; AND LORRAINE A. FITZPATRICK, MD
Pain is one of the most common breast symptoms experi-enced by women. It can be severe enough to interfere withusual daily activities, but the etiology and optimal treat-ment remain undefined. Breast pain is typically ap-proached according to its classification as cyclic mastal-gia, noncyclic mastalgia, and extramammary (nonbreast)pain. Cyclic mastalgia is breast pain that has a clear rela-tionship to the menstrual cycle. Noncyclic mastalgia maybe constant or intermittent but is not associated with themenstrual cycle and often occurs after menopause.Extramammary pain arises from the chest wall or other
sources and is interpreted as having a cause within the
breast. The risk of cancer in a woman presenting withbreast pain as her only symptom is extremely low. Afterappropriate clinical evaluation, most patients with breastpain respond favorably to a combination of reassuranceand nonpharmacological measures. The medicationsdanazol, tamoxifen, and bromocriptine are effective;however, the potentially serious adverse effects of thesemedications limit their use to selected patients with se-vere, sustained breast pain. The status of other thera-peutic strategies and directions for future research arediscussed.
Mayo Clin Proc. 2004;79:353-372
Mastalgia, or breast pain, was described in the medicalliterature as early as 18291 and was likely known tomedical practitioners much earlier.2 Pain is one of the
most common breast disorders experienced by women. In
the United Kingdom, breast pain vies with palpable mass
as the symptom described most frequently by women
presenting to general practitioners or seeking consulta-
tion in specialty breast clinics.3-7 In a large cohort of
2400 women enrolled in a health maintenance organiza-
tion in the United States during a 10-year period, pain was
the most common breast symptom, prompting medicalevaluation and accounting for 47% of breast-related vis-
its.8 Similarly, in a study of 1171 women attending an
obstetrics-gynecology clinic in the United States, 69%
experienced regular premenstrual breast discomfort, and
11% had moderate to severe breast pain more than 7 days
per month.9
Although increased awareness and overestimation of
breast cancer risk 10 may prompt more women to seek medi-
cal attention for breast symptoms, mastalgia generally is
underreported. In a survey of working women in South
Wales, 45% described mild breast pain, and 21% described
severe breast pain, but fewer than half of the women with
severe pain had reported this symptom to a physician.11
Breast pain is uncommon in men, although pain and tender-
ness may occur in men who develop gynecomastia second-
ary to medications, hormonal imbalance, cirrhosis, or other
conditions.12,13
The evaluation of breast pain varies according to its
assignment within the 3 broad classifications of cyclic
mastalgia, noncyclic mastalgia, and extramammary (non-
breast) pain.4,11,14-20 Cyclic mastalgia, by definition, occurs
in premenopausal women and connotes breast pain that isclearly related to the menstrual cycle. Noncyclic mastalgia
is defined as constant or intermittent breast pain that is not
associated with the menstrual cycle. Extramammary pain
from various sources may present with symptoms of breast
pain. Cyclic mastalgia accounts for approximately two
thirds of breast pain in specialty clinics, whereas noncyclic
mastalgia accounts for the remaining one third.21 The dis-
tinctions are important because the evaluation and the like-
lihood of response to intervention vary among the different
types of breast pain.18,22
Mastalgia is a common and enigmatic condition; the
cause and optimal treatment are still inadequately defined.
Mastalgia may be severe enough to interfere with usualdaily activities, and its effect on quality of life often is
underestimated.9 Outcome can be successful in most pa-
tients with reassurance, nonpharmacological measures, and
in some instances, one of several effective medica-
tions.14,17,22-24 We review the literature regarding the poten-
tial etiology, clinical evaluation, and treatment of mastalgia
to assist the clinician caring for women with breast pain.
Articles selected were obtained from a MEDLINE search
and from bibliographies and include all relevant studies,
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Breast Pain Mayo Clin Proc, March 2004, Vol 79354
clinical trials, published clinical experience, and recent
reviews available in the English language.
CYCLIC MASTALGIA
Minor breast discomfort and swelling within the few daysbefore onset of menses is considered a normal physiologi-
cal occurrence. In order of decreasing frequency, premen-
strual breast symptoms reported by women are tenderness,
swelling, pain, and lumpiness.9 Women who experience
more severe and prolonged pain are considered to have
cyclic mastalgia. Research criteria for the diagnosis of cyclic
mastalgia are (1) pain severity greater than 4.0 cm measured
on a 10.0-cm visual analog scale and (2) pain duration of at
least 7 days per month.9 This information is most accurate
when obtained from a patient’s prospective breast pain
record.22,23 Applying this threshold in a clinic-based study in
the United States, approximately 11% of premenopausal
women could be diagnosed as having cyclic mastalgia.
However, an additional 9% of premenopausal women expe-
rienced breast pain of severity greater than 4.0 cm on the
visual analog scale for 5 to 6 days per month.9
Clinical FeaturesCyclic breast pain usually starts during the luteal phase
of the menstrual cycle and increases in intensity until onset
of menses, when it dissipates. Some pain may be present to
a lesser degree during the entire cycle with premenstrual
intensification of symptoms. The pain typically involves
the upper outer breast area and radiates to the upper arm
and axilla. Most cyclic mastalgia is diffuse and bilateral butmay be more severe in one breast. Patients often describe
the pain as “dull,” “heavy,” or “aching.”
The consequences of cyclic mastalgia are not trivial. In
a large clinic-based sample of women, symptoms inter-
fered with sleep in 10%; with work, school, and social
functioning in 6% to 13%; with physical activity in 36%;
and with sexual activity in 48% of women whose symp-
toms met the criteria for cyclic mastalgia.9 In addition,
women whose symptoms meet the criteria have different
breast-related health behaviors. They are more likely to
undergo mammography before age 35 years, engage in
self-treatment of breast pain, consult a physician regarding
other breast concerns, and undergo breast biopsies thansymptomatic women whose symptoms do not meet the
diagnostic criteria for cyclic mastalgia or asymptomatic
women.9,25-27
Cyclic mastalgia typically presents during the third or
fourth decade of life.21 The symptoms tend to persist with a
relapsing course. Remission often occurs with hormonal
events such as pregnancy or menopause. Only 14% of
women with cyclic mastalgia experience spontaneous reso-
lution; however, 42% experience resolution at menopause.21
Etiology
Despite extensive studies done to identify causative his-
topathological, hormonal, nutritional, or psychiatric abnor-
malities, few consistent findings have been uncovered, and
the etiology of cyclic mastalgia is unknown.Histological Associations .—For many years, the clini-
cal manifestations of breast pain, tenderness, and nodular-
ity were considered synonymous with fibrocystic histology
of the breast. Accordingly, clinical evaluation of breast
pain was directed toward identifying underlying histo-
pathological diagnoses.28 However, the association be-
tween breast pain and fibrocystic histology has been incon-
sistent. In one study, the fibrocystic histological findings of
intraductal proliferation, adenosis, sclerosing adenosis,
papillomatosis, duct ectasia, intraductal debris, apocrine
metaplasia, microcysts, and proliferative periductal con-
nective tissue were common but did not differ among
groups with cyclic breast pain, noncyclic pain, and no
symptoms.29 In a study of 39 women with cyclic breast pain
who underwent breast biopsy, all had fibrocystic histologi-
cal changes. These findings were also present in 61 of 68
women without breast pain who underwent biopsy for
other reasons.30 Additionally, 58% to 89% of autopsy
breast specimens have shown varying degrees of fibro-
cystic histology.31
Thus, fibrocystic changes of the breast comprise various
histological findings in both asymptomatic and symptom-
atic women. Except for proliferative change or atypia,
which confers an increased risk of breast cancer,32 these
histological findings are considered part of the spectrumof normal involutional patterns in the breast33 and a
“nondisease.”31 This emphasis has been evolving in the
literature, which contains several thoughtful perspec-
tives.31,33,34 The designation “fibrocystic” remains popular
because it encompasses the common clinical findings of
breast pain, tenderness, and nodularity; however, it empha-
sizes potential histopathological correlates. For women
with mastalgia, it may be more helpful to distinguish the
symptom of pain in planning evaluation and treatment.
Recently, the potential role of inflammation and inflam-
matory cytokines in mastalgia was studied. No differences
were found between 29 premenopausal women with breast
pain and 29 matched asymptomatic women regarding thedegree of inflammatory cell infiltration and cytokine ex-
pression (interleukin 6 and tumor necrosis factor α) in
breast tissue specimens.35
Hormonal Associations .—That hormonal factors have
a role in cyclic mastalgia is intuitive because this condition
is defined by its relationship to the menstrual cycle and its
tendency to change during pregnancy, menopause, and
hormone therapy.36,37 Nonetheless, consistent hormonal ab-
normalities have not been identified. Several hormonal
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Mayo Clin Proc, March 2004, Vol 79 Breast Pain 355
Table 1. Theories Regarding Hormonal Etiology of Cyclic Mastalgia
References
Proposed hormonal imbalance Support Oppose
Estrogen excess (luteal phase)* 38 39-45Progesterone deficiency (luteal phase)* 39, 43, 46 41, 42, 44, 45, 47, 48Progesterone-estrogen ratio decreased
(luteal phase) 39, 46 45, 53Increased levels or dynamic release of FSH
and LH† 41, 49Prolactin excess (luteal phase)* 38, 40, 50, 54 41, 42, 45, 46, 51, 53Increased dynamic release of prolactin‡ 41, 43, 52, 53 45, 54Thyroid hormone abnormality 52Altered lipid metabolism§ 42, 55, 56
*Excess and deficiency refer to luteal-phase hormone levels in subjects with cyclic mastalgiacompared with asymptomatic controls.
†Increased release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) duringstimulation with thyrotropin and gonadotropin-releasing hormones in subjects with cyclicmastalgia compared with asymptomatic controls.
‡Increased release of prolactin during stimulation with thyrotropin and gonadotropin-releasing
hormones in subjects with cyclic mastalgia compared with asymptomatic controls.§Hypothesis from studies assessing change in essential and saturated fatty acid levels insubjects with cyclic mastalgia compared with asymptomatic controls, suggesting effects onprostaglandins and receptor sensitivity to normal circulating hormones.55,57
imbalances with potential causative roles in cyclic mas-
talgia have been investigated, and each has findings in
support and opposition (Table 138-57). One hormonal ab-
normality frequently detected in mastalgia is increased
thyrotropin-induced prolactin secretion.41,43,52,53
Few recent investigations have examined hormonal cau-
sation in cyclic breast pain. The inconsistent findings of
prior studies may be due to differences in patient selection,
sampling methods, and circadian and cyclic variations inhormone levels. Thus, a definitive causal hormonal abnor-
mality has not been identified.
Fluid-Electrolyte Balance and Nutritional Associa-
tions .—Premenstrual breast swelling is associated with
mastalgia and has been considered a possible etiologic
factor. Some investigators posit that shifts in the water-
electrolyte balance in nonlactating breasts related to pro-
lactin lead to cyclic painful swelling of breast microcysts.50
In fact, breast volume may increase by more than 100 mL
during the luteal phase of the menstrual cycle.58 However,
measurements of body weight and total body water are
not increased in women with cyclic mastalgia,59 and most
investigators do not recommend diuretics for its treat-ment.11,14,17,18 A relationship between mastalgia and dietary
factors has been considered, including aberrant lipid me-
tabolism55-57 and methylxanthine effects. Reductions in
dietary fat or caffeine consumption are frequently proposed
as therapeutic options for mastalgia.
Psychological Associations .—The potential psycho-
logical origin of breast pain has been explored throughout
the medical literature. In 1829, Sir Astley Cooper1 wrote
that women seeking advice for breast pain usually had “a
nervous and irritable temperament.” Although endocrine
and neuralgic aspects of breast pain were also considered,
similar views of the psychological element predominated
for many years.60 In 1978, the opinion that breast pain was
primarily an “expression of psychoneurosis” was chal-
lenged by a study61 that found that women with mastalgia
and a control group of women with varicose veins had
similar measures of anxiety, phobia, obsessionalism, and
somatic anxiety. Women with varicose veins had higherscores for depression (P
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Mayo Clin Proc, March 2004, Vol 79 Breast Pain 357
Figure 1. Timeline of subjects with cyclic mastalgia. High level (top) and low level (bottom) of other premenstrual symptoms. Mastalgia was measured with a 10-cm visual analog scale;other menstrual symptoms were measured with a 100-point menstrual severity scale. FromTavaf-Motamen et al,68 with permission. Copyrighted 1998, American Medical Association.
and 3.89 mm in women with noncyclic mastalgia (P
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Breast Pain Mayo Clin Proc, March 2004, Vol 79358
Table 2. Medications Associated With
Breast Pain in Women*
Hormonal medicationsEstrogens
ProgestogensCombination medications
Oral contraceptivesMenopausal hormonal therapy
DiethylstilbestrolClomipheneCyproterone
Antidepressant, antipsychotic, and anxiolytic medicationsSertraline (and other serotonin reuptake inhibitors)VenlafaxineMirtazapineChlordiazepoxideAmitriptyline†Doxepin†Haloperidol (and other antipsychotic agents)
Antihypertensive and cardiac medicationsSpironolactone†
MethyldopaMinoxidilDigoxin†Reserpine†
Antimicrobial agentsKetoconazole†Metronidazole†
Miscellaneous agentsCimetidine†CyclosporineDomperidonePenicillamineMethadone†Carboprost, dinoprostone (and other prostaglandins)Estramustine
*Information obtained from MEDLINE, MICROMEDEX, and discussion
with breast specialists and pharmacists.† Medications causing galactorrhea and gynecomastia and believed to beassociated with breast pain. Other medications (not listed) also may beassociated with breast pain and should be considered according to clini-cal circumstances.
ate pain, there were no differences between the mammo-
graphic findings and frequency of malignancy in women
with pain compared with a matched control group undergo-
ing routine screening.84
Relationship to Breast Surgery
The incidence of pain relating to prior breast surgery
appears to be high. In a retrospective survey of 282 women
at least 1 year after breast surgery, the incidence of breastpain after mastectomy, mastectomy with reconstruction,
augmentation, and reduction was 31%, 49%, 38%, and
22%, respectively. For analysis, women undergoing lump-
ectomy and axillary lymph node dissection were included
in the group who had undergone mastectomy. The use of
breast implants for reconstruction and the submuscular
placement of implants for augmentation were associated
with increased pain. Breast pain did not differ on the basis
of silicone vs saline implants.85
Proposed causes for postsurgical breast pain vary with
the procedure and include dysesthetic scar pain, nerve re-
generation, and focal nerve injury due to ischemia, radia-
tion therapy, lymphedema, and implant capsule forma-
tion.85 Ipsilateral axillary and arm pain also may result frominjury to the intercostobrachial nerve (injured in 80%-
100% of patients undergoing axillary dissection), brachial
plexopathy secondary to radiation therapy, implant com-
pression, complex regional pain syndrome, and referred
pain.85
Postmastectomy pain syndrome describes pain resulting
from surgical treatment of breast cancer, including pain
resulting from breast surgery (lumpectomy or mastec-
tomy), axillary dissection, and phantom symptoms.86 Phan-
tom breast syndrome is a sensation of persistence of the
breast after mastectomy. Phantom breast pain can be distin-
guished from pain related to scarring and occurs in 12% of
women interviewed 1 year after mastectomy.87 Phantom
breast pain is associated with preoperative pain and is
believed to arise when constant painful sensory input estab-
lishes a durable sensory pattern in the brain.86,87
EXTRAMAM M ARY PAINExtramammary pain due to various conditions may present
as breast pain. The differential diagnosis for mastalgia is
extensive (Table 4); however, the causes most commonly
encountered in the evaluation of breast pain are costo-
chondritis and other chest wall syndromes.11,14,88 Distin-
guishing between pain localized to the breast or chest wall
or radiating from elsewhere is usually straightforward, al-though diagnosis of patients with inconsistent findings or
more than 1 source of pain is more challenging. Establish-
ing the diagnosis allows for appropriate, economical evalu-
ation and management and minimizes unnecessary patient
concern.
Chest wall syndromes comprise a group of conditions
causing musculoskeletal chest pain, including costochon-
dritis, Tietze syndrome, slipping and clicking ribs, and ar-
thritis, which may be nontraumatic and insidious at onset.89-92
The absence of a clear precipitating event increases the
patient’s concern regarding a sinister or malignant cause.89
An estimated 12% to 30% of patients evaluated in emer-
gency departments for suspected cardiac chest pain havepain due to a musculoskeletal syndrome.90,92 Similarly, chest
wall pain frequently accounts for the symptom of breast
pain.4,11,14,15,19,26,88 Costochondritis is characterized by pain
and tenderness of the costochondral or chondrosternal joints,
with involvement of the second through fifth costal
cartilages.89-91 Tietze syndrome presents with similar symp-
toms but also has nonsuppurative swelling of the cartilagi-
nous articulations and particular involvement of the second
and third costochondral junctions.89-91
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Table 4. Differential Diagnosis of Mastalgia
Breast-relatedMastalgiaMastitis
Breast traumaThrombophlebitis/Mondor diseaseBreast cystsBenign breast tumorsBreast cancer
MusculoskeletalChest wall painCostochondritis/Tietze syndromeChest wall trauma/rib fractureFibromyalgiaCervical radiculopathyShoulder painHerpes zoster
Miscellaneous causesCoronary artery disease/anginaPericarditisPulmonary embolus
PleurisyGastroesophageal refluxPeptic ulcer diseaseCholelithiasis/cholecystitisSickle cell anemiaPsychologicalPregnancy
Medication (see Table 2)
In many medical centers, ultrasonography is used alone
to evaluate focal breast pain in younger women and as an
adjunct to mammography in older women.77,93 In a study of
110 directed ultrasonographic examinations performed for
focal breast pain, no breast cancer was found, and a benignfinding at the site of pain was identified in 18 women.
Although these results were reassuring, the women were
relatively young, and most had no family history of breast
cancer, limiting generalization from this low-risk group.93
Breast imaging should be tailored to the age of the patient,
risk for breast cancer, and other aspects of the clinical
presentation.
Young women with cyclic breast pain do not require a
mammogram in the absence of focal pain, suspicious find-
ings, or risk factors. A mammogram should be considered
in women with focal breast pain who are aged 30 to 35
years or older, have a family history of early breast cancer,
or have other risk factors for breast cancer. Ultrasonogra-phy should be considered for focal breast pain in women of
any age.
Laboratory studies are generally not useful; however,
a pregnancy test must be considered in women of re-
productive age if the history or examination suggests
pregnancy. Other hormone levels (such as estrogen, pro-
gesterone, and prolactin) are typically within the normal
range in women with breast pain; therefore, testing is
unnecessary.
BREAST PAIN ASSESSMENT
Quantifying breast pain may be difficult because of its
variability.16,22,23 Women may note that symptoms wax and
wane without provocation, with certain activities, or with
the menstrual cycle. Assessment with use of a pain-ratinginstrument such as a visual analog scale may be helpful in
initially evaluating breast pain, for making decisions re-
garding treatment, and for monitoring response to therapy.
Prospective assessment with a daily breast pain diary to
document the occurrence and severity of pain, aggravating
and alleviating factors, use of medications, and interfer-
ence with lifestyle is helpful for women considering treat-
ment. These measures are particularly important for cyclic
mastalgia because diagnosis based on recall of symptoms is
only 65% sensitive, and diagnosis based on the prospective
breast pain diary is 69% specific.68
In one study, in which a modified version of the McGill
Pain Questionnaire (SF-MPQ) was administered to 271
women with cyclic or noncyclic breast pain, the mean pain-
rating index was 12.0 of 45 (similar to pain ratings in
rheumatoid arthritis and cancer). The total breast pain
score was most efficiently estimated by a combination of
a visual analog scale, present pain index, and quality-of-
life questions.94 At a minimum, the patient’s description of
her symptoms and their effect on usual activities, a simple
quantitative assessment of the pain, and decisions regard-
ing any evaluation, follow-up, or therapeutic interven-
tion should be documented during encounters for breast
pain.
BREAST PAIN MANAGEMENT
Breast pain prompts many women to seek medical atten-
tion because of concerns about cancer.14,23,59,93,95-97 The risk
of subsequent occult malignancy after normal findings on
clinical and mammographic evaluation for breast pain is
estimated to be only 0.5%, making reassurance in this
setting appropriate.17,64,78 In clinical practice, 78% to 85%
of symptomatic women are reassured after normal findings
on evaluation and do not want specific intervention to
alleviate the breast pain.17,97 Approximately 10% to 22%
experience more severe pain and elect treatment to improve
or relieve symptoms.11,15,18,23,95 There is overlap between the
initial therapeutic approaches for patients with cyclic andnoncyclic mastalgia; however, response to intervention
varies.97 Hormonally active medications are more effective
for patients with cyclic mastalgia and are indicated only for
patients with severe, prolonged symptoms.11,14,15,17,20
Numerous difficulties arise when reviewing the effec-
tiveness of therapies for breast pain because the pain is
subjective, cyclic, or fluctuating in severity and is occa-
sionally self-limited. These characteristics make assess-
ment of response to an intervention challenging. Addition-
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Mayo Clin Proc, March 2004, Vol 79 Breast Pain 361
ally, the definition of a therapeutic response differs be-
tween studies, and there is a placebo effect of at least 20%
(range, 10%-40%).11,18 A wide variety of nonpharmaco-
logical measures are used to treat breast pain with little or
no scientific support. Although applying evidence-basedcriteria to determine the studies to include for review would
be more rigorous, use of this approach would exclude many
interesting older studies and published clinical experience
that warrant discussion. Instead, we have been more inclu-
sive but have qualified the studies to guide clinicians and
define areas for future research.
Nonpharmacological InterventionsNonpharmacological interventions to improve breast
pain are appropriate for women experiencing either cyclic
or noncyclic mastalgia.11,14,98 Although there has been little
scientific investigation into the effectiveness of these inter-
ventions, they frequently improve breast pain in clinical
practice and are of low risk and expense to the patient.
Physical Measures .—Improved mechanical support
may relieve breast pain. An estimated 70% of women wear
an improperly fitted brassiere.14 Symptomatic women may
benefit from counseling regarding proper selection and
fitting of a brassiere, wearing a soft supportive brassiere
during sleep, and use of a “sports bra” during exercise.
Although this advice is ubiquitous as a recommendation for
women with breast pain or discomfort, 4,14,15,96-100 there are
surprisingly few clinical investigations into its utility. In
1976, a study of this intervention enrolled 114 women
whose breast pain lasted more than 7 days each menstrualcycle, interfered with daily activities or sleep, and was
severe enough that the women desired treatment. Subjects
were fitted with a comfortable brassiere by a trained nurse,
provided with 2 brassieres, and monitored every 3 months
for 6 to 18 months. One hundred subjects completed fol-
low-up, of whom 26 experienced complete relief, 49 had
improvement, 21 derived no benefit, and 4 became worse.
Interestingly, 11 of 15 patients who had required medica-
tion for breast pain experienced improvement or relief with
this intervention.101
Breast pain during exercise may occur in as many as
56% of women and is attributed to movement of breast
tissue.102 In recent work, breast motion was assessed in 3women during running, jogging, aerobics marching, and
walking as they wore 4 different types of breast support. As
expected, a sports bra provided the greatest support with
regard to decreased amplitude of movement, deceleration
forces, and discomfort of the breast.102 Currently available
sports bras were also analyzed with a view to improving
design and performance.103 Although there are numerous
limitations in these uncontrolled studies, they lend cre-
dence to the widely held clinical impression that a properly
fitted brassiere has therapeutic value for symptomatic
women, including some in whom other treatments had
failed.
The application of heat (eg, warm compresses) or cold
(eg, ice packs) and gentle massage may reduce pain, par-ticularly when symptoms are cyclic or intermittent and of
short duration. Measures such as ultrasonography and acu-
puncture are used occasionally and are undergoing prelimi-
nary investigation for breast pain104 (L. A. Thicke, RN, MSN,
personal communication).
Relaxation Training .—Relaxation techniques were
evaluated in the management of women with breast pain in
one clinical trial.63 Approximately 61% of women who
listened daily for 4 weeks to an audiocassette of progres-
sive muscular relaxation experienced substantial or com-
plete relief of breast pain compared with 25% of con-
trol subjects who did not use the audiocassettes (P
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work in this area has focused on the relationship between
methylxanthines and other aspects of fibrocystic change,
including nodularity and cyst formation. In this context,
little evidence supports an association between caffeine
and fibrocystic breast disease.113
Early proponents of the relationship between fibrocystic
breast change and methylxanthines reported resolved, im-
proved, and unchanged fibrocystic nodularity in 82%,
15%, and 2% of 45 women, respectively, who completely
abstained from caffeine in an uncontrolled trial.114 In a
randomized trial, a statistically significant improvement
in premenstrual palpable nodularity of the breast was
identified in subjects who restricted caffeine compared
with controls who received no dietary advice. However,
the absolute change was minor, and it was concluded
that the intervention had limited effectiveness for fibro-
cystic nodularity of the breast. These authors observed,
but did not measure, an improvement in premenstrual
breast discomfort during the study.115 An association be-
tween methylxanthines (caffeine or theophylline) and
breast symptoms of pain, tenderness, nodularity,25,116,117
and fibrocystic histology118,119 has been reported by other
investigators.
In contrast, a single-blind randomized trial of decreased
caffeine consumption in 56 women showed no differences
in breast pain or tenderness among those following a caf-
feine-free diet, a low-cholesterol diet, or an unrestricted
diet.120 Other investigators have found no association be-
tween caffeine and fibrocystic change of the breast, with
many of the studies assessing histological change, notbreast symptoms.121-124
The nonendocrine mechanism by which methylxanthines
are believed to influence fibrocystic change in the breast
relates to their mediation of elevated 3′,5′−cyclic adeno-sine monophosphate (cAMP) in fibrocystic tissue speci-
mens and circulating catecholamines.125 High caffeine
intake also may be associated with altered hormone lev-
els in postmenopausal women, with increased plasma
estrone, sex hormone–binding globulin, and decreased
testosterone.126
Overall, no consistent evidence supports women re-
stricting caffeine to improve physical examination, mam-
mographic, or histological findings. Completely elimi-nating methylxanthines from the diet is difficult, even in
clinical trials, which may mask the effectiveness of this
intervention. On the basis of the few studies with breast
pain as a discrete outcome,25,114-117 it may be reasonable to
consider this intervention in women with problematic
breast pain who have moderate to heavy caffeine consump-
tion. However, because of the nature of the studies and
conflicting results, the possibility that improvement is
solely due to placebo effect cannot be excluded.
Vitamins.—Several vitamins have been evaluated as
potential treatments for breast pain, including vitamins B1,
B6, and E.127-131 Of these, vitamin E is used most commonly
for breast pain. Early studies with small numbers of pa-
tients suggested a potential beneficial effect of vitamin E(α-tocopherol) in fibrocystic breast disease.131-133 Proposedmechanisms include its potential to alter steroidal hormone
production (dehydroepiandrosterone or progesterone), to
correct abnormal serum cholesterol–lipoprotein distribu-
tion, and to function as an antioxidant.132-136
Subsequently, a few small randomized, double-blind,
placebo-controlled studies have shown no differences in
breast pain using dosages of 150 to 600 IU of vitamin E
per day.134,135 Additionally, mean serum concentrations of
estradiol, progesterone, testosterone, and dehydroepian-
drosterone did not differ between vitamin E- and placebo-
treated women.136 Many practitioners continue to recom-
mend vitamin E for breast pain, although uncertain of
whether the relatively low doses and short duration of
treatment in these trials exclude a beneficial effect. Small
studies of vitamins B1 and B
6 showed no benefit compared
with placebo for the treatment of cyclic breast pain.128,129 At
this time, evidence is insufficient to support routine use of
vitamins for breast pain.127,137
Evening Primrose Oil.—For women with cyclic breast
pain who elect treatment, evening primrose oil (gamma-
linolenic acid) has been widely advocated as an initial op-
tion.4,11,14-19,24,127,137-140 Two small randomized, double-blind,
placebo-controlled studies of evening primrose oil have
shown efficacy in the treatment of breast pain.141,142
Also,several researchers have reported favorable response and
adverse effect rates for evening primrose oil from sequential
uncontrolled studies and clinical series.22,24,127,143,144
A recent trial145 used a randomized, double-blind fac-
torial design to evaluate evening primrose oil and fish oil
for premenopausal women with chronic, severe cyclic or
noncyclic mastalgia. Women were randomized into 4
groups: fish oil and control oil, evening primrose oil and
control oil, fish and evening primrose oil, or both control
oils. The control oils were corn oil and corn with wheat
germ oil. All groups experienced a 10.6% to 15.5% de-
crease in days with pain. Neither fish oil nor evening
primrose oil showed benefit over corn and wheat germ oils.Fish oil was associated with increased gastrointestinal ad-
verse effects, whereas evening primrose oil had no more
adverse effects than control oils. Proposed explanations for
these findings include lack of effect of any oil, similar
effect of all the oils or the vitamin E used with them to
prevent oxidation, and the effect of time and care on im-
proving pain.145
Thus, results of studies and clinical series assessing
evening primrose oil in the treatment of mastalgia are
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Table 5. Evening Primrose Oil in Studies of Women With Mastalgia
Study* EPO† Placebo Adverse effects Comments
Before After Before After
Pashby et al,141 1981Cyclic mastalgia 50 32 45 42 NR Randomized, double-blind, placebo-controlledNoncyclic mastalgia 54 40 56 60 crossover study (N=73) at mastalgia clinic; pain
score (LAS) at 3 mo (P
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nancy or lactation has not been established. Although widely
considered effective, its benefits are only modestly better
than placebo in some studies, and views differ regarding its
therapeutic value for breast pain.96,105,146,148
Soy.—Soy is a rich source of the isoflavones genisteinand daidzen, which exert their effect by binding to estrogen
receptors (preferentially the β-receptor subtype).154 In pre-
menopausal women, a diet rich in soy protein increases the
duration of the follicular phase of the menstrual cycle and
delays menstruation.155 Other hormonal effects may in-
clude decreased midcycle surges of luteinizing hormones
and follicle-stimulating hormones155 and decreased estra-
diol levels.155,156 In a study of Japanese women, soy intake
was inversely correlated with estradiol levels on days 11
and 22 of the menstrual cycle.156 These hormonal changes
provide a theoretical basis for the use of dietary soy or
supplements for treatment of cyclic mastalgia. However,
investigation into the effect of soy on breast epithelium has
yielded mixed results. Some studies revealed markers of
increased proliferation,157,158 whereas others did not.159 To
date, no well-designed studies of soy to ameliorate symp-
toms of mastalgia are known.
Other Nutritional Supplements and Herbal Agents.—
Interest is growing in herbal agents, nutritional supple-
ments, and alternative strategies for treatment of breast
pain.126 A few of these have undergone preliminary study
with regard to their effectiveness. In an open, uncontrolled
study of the fruit extract of Vitex agnus-castus (chaste tree
berry) in 1634 subjects for 3 menstrual cycles, 93% of the
subjects reported improvement in symptoms related to pre-menstrual syndrome. In subjects in whom breast pain was
the predominant symptom, the pain was less severe after
treatment. Few adverse effects were identified, and 81% of
subjects rated their status after treatment as much better or
very much better.160 Theoretical mechanisms are that Vitex
agnus-castus binds to opioid, histamine, and estrogen re-
ceptors160 or acts via dopaminergic and prolactin-suppres-
sant effects.161 Little is known about breast pain as a poten-
tial adverse effect of herbal remedies.162
In light of the frequency of breast pain, additional re-
search must clarify the therapeutic value of improved me-
chanical support, relaxation techniques, dietary adjust-
ments, nutritional supplements, herbal medicinals, andother nonpharmacological interventions.
Simple AnalgesicsSurprisingly, there has been little investigation into
simple analgesics, such as acetaminophen and nonsteroidal
anti-inflammatory agents, for breast pain. In one uncon-
trolled study of 60 women with mastalgia treated with the
oral nonsteroidal anti-inflammatory agent nimesulide (100
mg twice daily), breast pain decreased or resolved after 15
days.163 Topical application of the nonsteroidal anti-inflam-
matory agents diclofenac and piroxicam yielded satisfac-
tory relief in 21 (81%) of 26 women with severe cyclic,
noncyclic, and surgical scar–related breast pain.164 Re-
cently, a randomized blinded study of a topical nonsteroi-dal anti-inflammatory agent showed significant pain reduc-
tion in 60 subjects with cyclic mastalgia and 48 subjects
with noncyclic mastalgia compared with placebo. No ad-
verse effects occurred.165 Conversely, another study of topi-
cal ibuprofen used in clinical practice determined no
beneficial effect for breast pain.23 These medications often
are available without prescription and are likely used by
many women to alleviate mastalgia symptoms; however,
there are currently no prospective controlled studies to
assess the utility of oral acetaminophen or nonsteroidal
anti-inflammatory agents in the treatment of breast pain.
Both oral and topical agents are promising and merit addi-
tional investigation.
Hormonally Active M edicationsThe number of hormonal approaches and remedies pro-
moted to alleviate mastalgia attests to the lack of a single
effective agent with few adverse effects. There is no con-
sensus regarding the initial hormonal agent to use for
women who require intervention beyond the measures de-
scribed previously. Most researchers favor one of danazol,
bromocriptine, or tamoxifen.
Decisions regarding treatment of mastalgia require bal-
ancing the need for symptom relief against the likelihood
of medication adverse effects. Most of the hormonallyactive medications have been used for 2 to 6 months and
then tapered or discontinued. Relapse occurs in a fraction
of patients, and most respond to a second course of treat-
ment or another hormonal agent.166 Contraception is im-
portant during treatment and should be discussed with
patients.
Oral Contraceptives, Estrogen, and Progesterone .—
It is reasonable to adjust medications that may be contribut-
ing to breast pain, such as oral contraceptives or meno-
pausal hormone therapy. Eliminating or decreasing the
dose of estrogen in an oral contraceptive or hormone regi-
men is often effective in clinical practice, particularly if the
onset of symptoms is temporally related to initiation orchange in medication. Many oral contraceptives list breast
pain and tenderness as potential adverse effects. Studies of
low-dose oral contraceptives (20 µg ethinyl estradiol) havefound no increased breast symptoms compared with pla-
cebo.167 Many women report a reduction in severity and
duration of cyclic breast discomfort while taking oral con-
traceptives.168,169 There has been little investigation of ad-
justment in contraceptive medication as a therapeutic ap-
proach to alleviating breast pain.
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Topical, oral, and parenteral progestogens have been
studied for treatment of breast pain with variable results. A
multicenter case-control study was performed to assess
breast pain in women receiving medroxyprogesterone ac-
etate (Depo-Provera) for contraception compared with age-matched control women randomly selected without regard
to contraceptive method. Most controls had used oral con-
traceptives, and 10% had used medroxyprogesterone ac-
etate within the year before the study. Frequent breast pain
and medication use for breast pain were noted in 9% and
5%, respectively, of women using medroxyprogesterone
compared with 21% and 9% of women in the control group
(odds ratio, 0.220; P
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Table 6. Clinical Trials of Tamoxifen for Treatment of Mastalgia*
No. (%) of subjects responding to intervention
Bromo-Study 10 mg 20 mg Danazol criptine Placebo Comments
Fentiman NE 22/31 (71) NE NE 11/29 (38) Randomized double-blind trial of daily tamoxifenet al,206 1986 or placebo in 60 subjects with cyclic or
noncyclic pain; response (!50% decrease inmean pain score) at 3 mo. Significant differencebetween groups (P.10), but fewer adverseeffects were noted with tamoxifen (P
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in women after short-term (3 month) treatment with 10 or
20 mg/d of tamoxifen for mastalgia.214
Overall, tamoxifen compared favorably with danazol
and bromocriptine with regard to efficacy and adverse
effects.207,210,211 Use of tamoxifen in large numbers of pre-menopausal women in the breast cancer prevention trials
has increased familiarity with this medication in younger
women without breast cancer.215,216 Nonetheless, tamox-
ifen, like the other hormonal interventions, should be re-
served for women with severe mastalgia refractory to other
measures. Although not associated with increased pain in
clinical trials of postmenopausal women treated for os-
teoporosis,72 there are no known studies of raloxifene as a
therapeutic agent for breast pain.
Gonadotropin-Releasing Hormone Agonists .—Go-
nadotropin-releasing hormone agonists are synthetic ana-
logues of hypothalamic gonadotropin-releasing hormone.
Initial administration stimulates pituitary release of lutein-
izing hormone and follicle-stimulating hormone followed
by ovarian production of estrogen and progesterone; con-
tinuous administration results in suppression of pituitary
and ovarian hormone production.217 These agents reliably
decrease estrogen levels in women and have been used to
treat breast cancer, endometriosis, uterine leiomyoma,
polycystic ovarian syndrome, and precocious puberty, as
well as for in vitro fertilization. Also, extremely low levels
of progesterone, ovarian androgens, and prolactin result
from administration of gonadotropin-releasing hormone
agonists.217,218
Goserelin was evaluated in an uncontrolled study of 21premenopausal women with refractory cyclic or noncyclic
mastalgia with symptom relief achieved in 81% after 6
months of treatment. The efficacy of goserelin was 100%
in women with recurrent mastalgia and 56% in women
whose mastalgia was refractory to prior treatment with
tamoxifen, danazol, or bromocriptine.219 Buserelin im-
plants relieved breast pain in 6 patients with cyclic mastal-
gia.220 Other gonadotropin-releasing hormone agonists may
have similar effects in patients with breast pain.
Adverse effects related to the hypoestrogenic state pro-
duced by these medications are frequent and often severe,
including hot flashes, headache, nausea, fatigue, depres-
sion, anxiety, irritability, vaginal dryness, and decreasedlibido. Decline in trabecular bone mineral density is as high
as 6% within 6 months. Although usually reversible, treat-
ment duration is limited by this effect.221 In the treatment of
endometriosis, estrogen or progestin “add-back” therapies
and bisphosphonates are used to minimize vasomotor
symptoms and loss of bone mineral density.221
Although use of gonadotropin-releasing hormone ago-
nists is promising, few data are currently available to sup-
port their clinical use for treatment of mastalgia. As with
some other agents described, they have troublesome and
potentially serious adverse effects that must be considered
in future studies to define their therapeutic role for breast
pain.
Other Pharmacological Agents andSurgical Approaches
Over the years, numerous medications have been used
to treat breast pain, including diuretics, antibiotics, thyrox-
ine, iodine, and others. Diuretics are used widely but have
not been adequately examined to define their potential
benefit in the treatment of breast pain and swelling. Antibi-
otics should be reserved for treatment of patients with
breast infections. The other agents have been studied only
preliminarily or have been found to be ineffective.
Although there have been few investigations of the po-
tential causative role of breast size in cyclic mastalgia,
some women with symptomatic macromastia note im-
provement in breast pain as well as in neck, shoulder, and
back discomfort after reduction mammaplasty.222,223 In gen-
eral, however, breast surgery has an extremely limited role
in the treatment of breast pain.
CONCLUSIONS
Breast pain is rarely a sign of cancer; however, this concern
is the primary reason most women seek medical evaluation
and treatment for this symptom. A general approach to
patients presenting with breast pain is outlined in Table 7.
After an examination shows normal findings, most women
respond to reassurance, and few will require additionalintervention or medication. Those requesting treatment of-
ten will respond to a combination of nonpharmacological
measures. Consideration may be given to a trial of evening
primrose oil; although findings from controlled studies
conflict, the adverse effect rate for this treatment is consis-
tently low. Additional controlled clinical trials of this inter-
vention as well as other widely used herbal and nutritional
agents are needed to establish efficacy.
Women with severe, sustained breast pain that interferes
with their quality of life may benefit from treatment with
low-dose or luteal-phase medications such as danazol or
tamoxifen. These medications have proven effectiveness;
however, their benefit in ameliorating breast discomfortand pain must be balanced against their potential for ad-
verse effects. Selection of a specific agent is individual-
ized. In certain circumstances, bromocriptine or a gonado-
tropin-releasing hormone agonist may be needed; however,
approaches to decreased dosing to minimize adverse ef-
fects have not been established.
Additional research is needed to improve our under-
standing of breast pain and the care of women with moder-
ate to severe symptoms that affect activities of daily life.
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Future directions in mastalgia research need to include
continued efforts to identify etiologic factors and to assess
both existing and new therapeutic agents for mastalgia with
regard to the type, dosage, and duration of treatment that
optimizes therapeutic value and minimizes adverse effects.
Table 7. Principles for Management of Breast Pain
History and physical examinationCyclic mastalgia, noncyclic mastalgia, or extramammary painIdentify and evaluate any suspicious breast abnormalities
Breast imagingConsider ultrasonography for focal, persistent breast pain (any age)Consider mammography for women with breast pain, who
Are aged >30 years orHave a family history of early breast cancer, orHave other risk factors for breast cancer
Pain assessmentQuantitative pain assessment (with visual analog scale)Prospective documentation of pain (with pain diary)
Reassurance (may be all that is desired by most patients)Nonpharmacological interventions
Consider counseling onSupportive, well-fitting brassierePhysical measures for relief of painDietary interventionRelaxation training
Consider trial of well-tolerated supplements*
Pharmacological intervention (for patients with severe, sustained breastpain)Nonsteroidal anti-inflammatory agents (topical or oral)Danazol in low dose or during luteal phase (FDA approved)†Tamoxifen in low dose or during luteal phase (not FDA approved for
this indication)†Other agents (bromocriptine, gonadotropin-releasing hormone
agonists)†Follow-up
Recommend short-term follow-up for patients with focal, noncyclicbreast pain and patients with cyclic pain who may requireadditional intervention or pharmacological intervention
*Herbal therapies (eg, evening primrose oil) are favored by some patients.Some herbal therapies have been used extensively in mastalgia treat-ment. There is preliminary or mixed evidence of effectiveness and fewadverse effects.
†Hormonal therapies have shown effectiveness in controlled trials butwith adverse effects that limit their use to patients with severe, life-altering breast pain. FDA = Food and Drug Administration.
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