Breast Pain Management

Mayo Clin Proc, March 2004, Vol 79
Breast Pain
353
Review
Evaluation and Management of Breast Pain

ROBIN L. SMITH, MD; SANDHYA PRUTHI, MD; AND LORRAINE A. FITZPATRICK, MD
breast. The risk of cancer in a woman presenting with
breast pain as her only symptom is extremely low. After
appropriate clinical evaluation, most patients with breast
pain respond favorably to a combination of reassurance
and nonpharmacological measures. The medications
danazol, tamoxifen, and bromocriptine are effective;
however, the potentially serious adverse effects of these
medications limit their use to selected patients with severe, sustained breast pain. The status of other therapeutic strategies and directions for future research are
discussed.
Mayo Clin Proc. 2004;79:353-372
Pain is one of the most common breast symptoms experienced by women. It can be severe enough to interfere with
usual daily activities, but the etiology and optimal treatment remain undefined. Breast pain is typically approached according to its classification as cyclic mastalgia, noncyclic mastalgia, and extramammary (nonbreast)
pain. Cyclic mastalgia is breast pain that has a clear relationship to the menstrual cycle. Noncyclic mastalgia may
be constant or intermittent but is not associated with the
menstrual 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
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 tenderness may occur in men who develop gynecomastia secondary 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 (nonbreast) pain.4,11,14-20 Cyclic mastalgia, by definition, occurs
in premenopausal women and connotes breast pain that is
clearly 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 distinctions are important because the evaluation and the likelihood 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 usual
daily activities, and its effect on quality of life often is
underestimated.9 Outcome can be successful in most patients with reassurance, nonpharmacological measures, and
in some instances, one of several effective medications.14,17,22-24 We review the literature regarding the potential 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,
astalgia, or breast pain, was described in the medical

literature as early as 18291 and was likely known to
medical 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 consultation in specialty breast clinics.3-7 In a large cohort of
2400 women enrolled in a health maintenance organization in the United States during a 10-year period, pain was
the most common breast symptom, prompting medical
evaluation and accounting for 47% of breast-related visits.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 risk10 may prompt more women to seek medical 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
From the Breast Diagnostic Clinic, Division of General Internal

Medicine (R.L.S., S.P.) and Division of Endocrinology, Diabetes,
Metabolism, Nutrition and Internal Medicine (L.A.F.), Mayo Clinic
College of Medicine, Rochester, Minn.
This work was supported in part by grants NCRR K24 and
RR017593 from the Public Health Service, Mayo Foundation, and
an unrestricted educational grant from Solvay Pharmaceuticals for
the Womens 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.
Mayo Clin Proc. 2004;79:353-372
353
2004 Mayo Foundation for Medical Education and Research
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
354
Breast Pain
clinical trials, published clinical experience, and recent

reviews available in the English language.
CYCLIC MASTALGIA
Minor breast discomfort and swelling within the few days
before onset of menses is considered a normal physiological occurrence. In order of decreasing frequency, premenstrual 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 patients 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 experienced breast pain of severity greater than 4.0 cm on the
visual analog scale for 5 to 6 days per month.9
Clinical Features
Cyclic 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 but
may 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 interfered 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 symptoms 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 than
symptomatic 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 resolution; however, 42% experience resolution at menopause.21
Etiology
Despite extensive studies done to identify causative histopathological, hormonal, nutritional, or psychiatric abnormalities, few consistent findings have been uncovered, and
the etiology of cyclic mastalgia is unknown.
Histological Associations.For many years, the clinical manifestations of breast pain, tenderness, and nodularity were considered synonymous with fibrocystic histology
of the breast. Accordingly, clinical evaluation of breast
pain was directed toward identifying underlying histopathological diagnoses.28 However, the association between breast pain and fibrocystic histology has been inconsistent. In one study, the fibrocystic histological findings of
intraductal proliferation, adenosis, sclerosing adenosis,
papillomatosis, duct ectasia, intraductal debris, apocrine
metaplasia, microcysts, and proliferative periductal connective 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 histological 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 fibrocystic histology.31
Thus, fibrocystic changes of the breast comprise various
histological findings in both asymptomatic and symptomatic women. Except for proliferative change or atypia,
which confers an increased risk of breast cancer,32 these
histological findings are considered part of the spectrum
of normal involutional patterns in the breast33 and a
nondisease.31 This emphasis has been evolving in the
literature, which contains several thoughtful perspectives.31,33,34 The designation fibrocystic remains popular
because it encompasses the common clinical findings of
breast pain, tenderness, and nodularity; however, it emphasizes 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 inflammatory cytokines in mastalgia was studied. No differences
were found between 29 premenopausal women with breast
pain and 29 matched asymptomatic women regarding the
degree of inflammatory cell infiltration and cytokine expression (interleukin 6 and tumor necrosis factor ) 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 abnormalities have not been identified. Several hormonal
Breast Pain
355
Table 1. Theories Regarding Hormonal Etiology of Cyclic Mastalgia

References
Proposed hormonal imbalance
Support
Oppose
Estrogen excess (luteal phase)*

Progesterone deficiency (luteal phase)*
Progesterone-estrogen ratio decreased
(luteal phase)
Increased levels or dynamic release of FSH
and LH
Prolactin excess (luteal phase)*
Increased dynamic release of prolactin
Thyroid hormone abnormality
Altered lipid metabolism
38
39, 43, 46
39-45
41, 42, 44, 45, 47, 48
39, 46
45, 53
41, 49
38, 40, 50, 54
41, 43, 52, 53
41, 42, 45, 46, 51, 53

45, 54
52
42, 55, 56
*Excess and deficiency refer to luteal-phase hormone levels in subjects with cyclic mastalgia
compared with asymptomatic controls.
Increased release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) during
stimulation with thyrotropin and gonadotropin-releasing hormones in subjects with cyclic
mastalgia 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 in
subjects with cyclic mastalgia compared with asymptomatic controls, suggesting effects on
prostaglandins and receptor sensitivity to normal circulating hormones.55,57
imbalances with potential causative roles in cyclic mastalgia have been investigated, and each has findings in
support and opposition (Table 138-57). One hormonal abnormality frequently detected in mastalgia is increased
thyrotropin-induced prolactin secretion.41,43,52,53
Few recent investigations have examined hormonal causation 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 in
hormone levels. Thus, a definitive causal hormonal abnormality has not been identified.
Fluid-Electrolyte Balance and Nutritional Associations.Premenstrual breast swelling is associated with
mastalgia and has been considered a possible etiologic
factor. Some investigators posit that shifts in the waterelectrolyte balance in nonlactating breasts related to prolactin 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 treatment.11,14,17,18 A relationship between mastalgia and dietary
factors has been considered, including aberrant lipid metabolism55-57 and methylxanthine effects. Reductions in
dietary fat or caffeine consumption are frequently proposed
as therapeutic options for mastalgia.
Psychological Associations.The potential psychological 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 challenged 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 higher
scores for depression (P<.01) and hysteria (P<.001).61
Subsequent studies have identified increased anxiety62-64
and depression62,64 among women with breast pain compared with asymptomatic women. Comparable clinical levels of emotional distress have been reported in women with
severe mastalgia and women with breast cancer undergoing surgical treatment.62 In another recent study, women
with breast pain had increased anxiety, depression, somatization, and history of emotional abuse compared with
women with breast lumps alone.65 Breast pain was noted to
be distinct from other conditions with persistent pain because rates of physical and sexual abuse were relatively
low.65
Women with breast pain may experience greater cyclic
fluctuation in anxiety and depression. In a study of 20
women with cyclic breast pain, levels of anxiety and depression were higher and changes in anxiety and depression scores were greater between the follicular and luteal
phases than in 12 asymptomatic women.66 Perceived stress
was also associated with cyclic mastalgia in a populationbased study.25 The extent to which psychological distress
has a causal or consequential relationship to breast pain is
356
Breast Pain
unclear; however, substantial improvements in depression

and social impairment were noted in women whose pain
was treated successfully.62
Relationship to Other Premenstrual Symptoms
Cyclic breast pain and tenderness are part of the premenstrual syndrome and are among the constellation of
physical symptoms associated with the premenstrual dysphoric disorder.67 The relationship between cyclic mastalgia and other premenstrual symptoms has been studied.
Luteal-phase symptoms, including water retention, negative affect, impaired concentration, and behavior change,
were significantly greater in women with severe cyclic
mastopathy compared with women without breast symptoms. Also, women with severe cyclic mastalgia experienced more breast symptoms and negative affect in the
follicular phase of the menstrual cycle.26
Similarly, a study of 30 subjects showed that most
women whose symptoms meet the criteria for cyclic mastalgia experienced other premenstrual and somatic symptoms as measured by a menstrual symptom severity list
(Figure 1). However, 12% of these women had few other
premenstrual symptoms.68 In a follow-up study, investigators found that, although premenstrual symptoms were
common in women with cyclic breast pain, only 16% of
women had sufficient symptoms that met the criteria for
both cyclic mastalgia and premenstrual syndrome.69
Relationship to Breast Cancer
Although breast cancer is not considered a cause of
cyclic breast pain, a few studies have identified a potential association between cyclic mastalgia and breast cancer risk. In a case-control study, scores for premenstrual
tenderness involving the unaffected breast were higher in
192 premenopausal women with early-stage breast cancer
than in 192 age-matched premenopausal women without
breast cancer. After adjustment for other risk factors, the
odds ratio for breast cancer was 1.35 (95% confidence
interval, 1.01-1.83) for women with any cyclic pain and
3.32 for women with severe symptoms.70 This finding of
an association between cyclic mastalgia and breast cancer
risk is consistent with another study of retrospectively
reported cyclic breast symptoms in premenopausal
women with and without a history of breast cancer.71 It
has been hypothesized that increased tissue sensitivity to
estrogen, perhaps related to dietary fat intake and fatty
acid levels, has an etiologic role in both cyclic breast pain
and breast cancer risk and may account for the relationship.70 However, reporting of breast symptoms by premenopausal women with breast cancer may be amplified,
generating a bias and alternative explanation for these
observations.
NONCYCLIC MASTALGIA
Noncyclic mastalgia involves constant or intermittent pain
that is not associated with the menstrual cycle. Less common than cyclic mastalgia, it accounts for approximately
31% of women seen in mastalgia clinics.21
Clinical Features
Noncyclic mastalgia tends to be unilateral and localized
within a quadrant of the breast; however, diffusely distributed pain and radiation to the axilla also occur.4,14 Adjectives patients use to describe the pain are drawing, burning, achy, and sore.4,14 Typically, noncyclic mastalgia
presents at a later age; most women are in the fourth or fifth
decade of life at diagnosis.4,14,17,21 Many women are postmenopausal at onset of symptoms.
Etiology
Noncyclic breast pain may result from pregnancy, mastitis, trauma, thrombophlebitis, macrocysts, benign tumors,
or cancer; however, only a minority of breast pain is explained by these conditions. Most noncyclic breast pain
arises for unknown reasons, yet it is believed more likely to
have an anatomical, rather than hormonal, cause. An exception may be breast pain that is associated with medication use (Table 2).
Approximately 16% and 32% of women report breast
pain as an adverse effect of estrogen and combined hormonal therapies, respectively.72 Unilateral, noncyclic
breast pain may result from exogenous estrogen exposure.
Interestingly, in one study, 12 of 33 women developed breast
pain within 1 year of initiation of menopausal hormone
therapy. Of the 33 women, 7 women with moderate to severe
pain experienced an increase in mammographic breast density, 5 women with mild to moderate pain had no increase in
breast density, and 2 of 21 women without pain had an
increase in breast density (P=.005).73 Other researchers have
identified increased breast density during hormonal
therapy74; however, the association between breast pain or
tenderness and change in mammographic density during
different hormonal treatments requires confirmation.
Comparatively, the selective estrogen receptor modulators, tibolone and raloxifene, have much lower rates of
associated breast pain.72,75 The frequency of breast pain
associated with raloxifene is not different from placebo in
postmenopausal women.72
Recently, the possibility of a relationship between duct
ectasia (dilatation of the milk ducts) and noncyclic breast
pain was explored. Ultrasonographic measurement of ductal diameter differs between asymptomatic women and
women with cyclic and noncyclic breast pain. The maximum mean width of the milk ducts was 1.8 mm in asymptomatic women, 2.34 mm in women with cyclic mastalgia,
Breast Pain
Mastalgia
Other menstrual symptoms
10
357
100
80
Mastalgia
7
6
60
5
4
40
3
2
20
1
0
0
10
20
30
40
50
60
70
80
0
90 100 110 120 130 140 150
Days
Mastalgia
100
10
80
Mastalgia
7
6
60
5
4
40
3
20
1
0
0
0
10
20
30
40 50
60
70
80
90 100 110 120 130 140 150
Days
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. From
Tavaf-Motamen et al,68 with permission. Copyrighted 1998, American Medical Association.
and 3.89 mm in women with noncyclic mastalgia (P<.001).

Ductal width correlated with pain intensity.76 This finding
supports an approach taken by earlier researchers in dividing noncyclic mastalgia into subsets, one of which was
ductal ectasia.28
Relationship to Breast Cancer
Classically, breast pain associated with cancer is unilateral, constant, and intense.77 The occurrence of subclinical
breast cancer in women with focal, noncyclic breast pain
who present to breast or oncology clinics has been studied

(Table 38,78-81). In these studies, breast cancer was found in
2% to 7% of patients presenting with pain as the primary
symptom.78-82 Conversely, in a review of 1532 women
with breast pain incidental to presenting complaint, the
risk of breast cancer was decreased in women having
pain, with an adjusted odds ratio of 0.63 (95% confidence
interval, 0.49-0.79). Women with breast pain as a sole
complaint were excluded.83 In a recent case-control study
of women referred for diagnostic breast imaging to evalu-
358
Breast Pain
Table 2. Medications Associated With

Breast Pain in Women*
Hormonal medications
Estrogens
Progestogens
Combination medications
Oral contraceptives
Menopausal hormonal therapy
Diethylstilbestrol
Clomiphene
Cyproterone
Antidepressant, antipsychotic, and anxiolytic medications
Sertraline (and other serotonin reuptake inhibitors)
Venlafaxine
Mirtazapine
Chlordiazepoxide
Amitriptyline
Doxepin
Haloperidol (and other antipsychotic agents)
Antihypertensive and cardiac medications
Spironolactone
Methyldopa
Minoxidil
Digoxin
Reserpine
Antimicrobial agents
Ketoconazole
Metronidazole
Miscellaneous agents
Cimetidine
Cyclosporine
Domperidone
Penicillamine
Methadone
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 be
associated with breast pain. Other medications (not listed) also may be
associated with breast pain and should be considered according to clinical circumstances.
ate pain, there were no differences between the mammographic findings and frequency of malignancy in women
with pain compared with a matched control group undergoing 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 breast
pain after mastectomy, mastectomy with reconstruction,
augmentation, and reduction was 31%, 49%, 38%, and
22%, respectively. For analysis, women undergoing lumpectomy 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 regeneration, and focal nerve injury due to ischemia, radiation therapy, lymphedema, and implant capsule formation.85 Ipsilateral axillary and arm pain also may result from
injury to the intercostobrachial nerve (injured in 80%100% of patients undergoing axillary dissection), brachial
plexopathy secondary to radiation therapy, implant compression, 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 mastectomy), axillary dissection, and phantom symptoms.86 Phantom breast syndrome is a sensation of persistence of the
breast after mastectomy. Phantom breast pain can be distinguished 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 establishes a durable sensory pattern in the brain.86,87
EXTRAMAMMARY PAIN
Extramammary 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 costochondritis and other chest wall syndromes.11,14,88 Distinguishing between pain localized to the breast or chest wall
or radiating from elsewhere is usually straightforward, although diagnosis of patients with inconsistent findings or
more than 1 source of pain is more challenging. Establishing the diagnosis allows for appropriate, economical evaluation and management and minimizes unnecessary patient
concern.
Chest wall syndromes comprise a group of conditions
causing musculoskeletal chest pain, including costochondritis, Tietze syndrome, slipping and clicking ribs, and arthritis, which may be nontraumatic and insidious at onset.89-92
The absence of a clear precipitating event increases the
patients concern regarding a sinister or malignant cause.89
An estimated 12% to 30% of patients evaluated in emergency departments for suspected cardiac chest pain have
pain 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 symptoms but also has nonsuppurative swelling of the cartilaginous articulations and particular involvement of the second
and third costochondral junctions.89-91
Breast Pain
359
Table 3. Frequency of Cancer in Patients Presenting With Breast Pain

No. of
patients with
breast pain
No. (%) of
patients with
breast cancer
Preece et al, 1982
536
36 (6.7)
Smallwood et al,79 1986
209
8 (3.8)
Fariselli et al,80 1988
220
5 (2.3)
Barton et al,8 1999
169
2 (1.2)
1141
36 (3.2)
Study
78
Lumachi et al,81 2002
Management of these conditions involves rest, nonsteroidal anti-inflammatory agents, and reassurance.89 Many
researchers advocate use of a localized diagnostic and
therapeutic injection with an anesthetic and corticosteroid
to the affected site in selected patients, noting a favorable
response rate and few adverse effects.4,76,89,91 Although
symptoms tend to recur, most individuals improve within 1
year.91 Other causes of extramammary pain occur less frequently but should be considered when evaluating the patient presenting with breast pain.
CLINICAL EVALUATION
History
Obtaining a patients history should be directed toward
identifying and characterizing breast-related symptoms.
Historical features of breast pain to elicit include its quality
and location, relationship to physical activity, and severity as
manifested by interference with usual activities. Other breast
symptoms, such as associated mass, inflammation, or nipple
discharge, should be noted. Potential hormonal influences
should be assessed, including the relationship to the menstrual cycle, pregnancy, contraceptive use, and hormonal
therapies. Reviewing the patients medications to identify
any associated with breast pain may be helpful. The history
also allows additional symptoms or information to be obtained that would suggest a nonbreast source of pain. Risk
assessment for breast cancer should include obtaining the
appropriate reproductive, medical, and family history.
Physical Examination
Clinical breast examination requires careful inspection
and palpation of each breast, nipple-areolar complex, and
Comments
In a review of patients presenting to a breast clinic with focal
breast pain as primary symptom, pain was the only symptom
in 17 of 36 subjects with breast cancer
In a review of 460 patients presenting to a breast clinic, 209 had
focal pain as primary symptom; of 8 with breast cancer, pain
was the only symptom in 1, a mass was present in 7, and
nipple retraction was present in 3
In a review of 220 patients presenting to an oncology clinic,
focal breast pain was the only symptom
In a retrospective cohort study of 2400 women (aged 40-69 y)
presenting to health maintenance organizations over 10 years,
unilateral pain was reported by 91% and bilateral pain by 9%
In a review of 2879 patients with breast symptoms, 1141 had
breast pain as primary symptom; the relative risk of breast
cancer in patients aged 41 to 55 years with breast pain
compared with those presenting without breast symptoms
was 0.6 (95% confidence interval, 0.4-1.1)
regional lymph nodes. Detection of localized, generalized,

or bilateral breast tenderness may be helpful. Examination
with the patient seated, supine, or lateral decubitus with
the breast falling away from the chest wall may allow
breast and chest wall tenderness to be distinguished.15
Abnormalities detected during clinical breast examination
(including a mass, asymmetry, nipple discharge, or inflammatory change) should have precedence and merit
prompt evaluation. As appropriate, examination of the
cervical and thoracic spine, chest wall, shoulders, upper
extremities, heart, lungs, and abdomen may identify other
potential causes of the pain and provide direction for
diagnostic evaluation.
Diagnostic Studies
Mammography is often used to evaluate breast pain;
however, the yield is low in the setting of normal findings
on clinical examination. In one study, approximately 36 of
240 women with newly diagnosed breast cancer had localized breast pain as a presenting symptom. Of these, 10
women (28%) had normal mammographic findings and
were later diagnosed as having subclinical breast cancer at
the site of pain.78 Conversely, in a recent case-control
study, there were no differences in the incidence of malignancy among the painful breasts of women referred for
mammography to evaluate the pain (0.5%), the contralateral nonpainful breasts of the same women (0.5%), and the
breasts of women without pain referred for routine screening (0.7%).84 Accordingly, it has been questioned whether
breast pain is related to cancer or whether this symptom
prompts an evaluation in which an asymptomatic cancer is
identified.16
360
Breast Pain
Table 4. Differential Diagnosis of Mastalgia

Breast-related
Mastalgia
Mastitis
Breast trauma
Thrombophlebitis/Mondor disease
Breast cysts
Benign breast tumors
Breast cancer
Musculoskeletal
Chest wall pain
Costochondritis/Tietze syndrome
Chest wall trauma/rib fracture
Fibromyalgia
Cervical radiculopathy
Shoulder pain
Herpes zoster
Miscellaneous causes
Coronary artery disease/angina
Pericarditis
Pulmonary embolus
Pleurisy
Gastroesophageal reflux
Peptic ulcer disease
Cholelithiasis/cholecystitis
Sickle cell anemia
Psychological
Pregnancy
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 benign
finding 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 findings, 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. Ultrasonography 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 reproductive age if the history or examination suggests
pregnancy. Other hormone levels (such as estrogen, progesterone, 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-rating
instrument such as a visual analog scale may be helpful in
initially evaluating breast pain, for making decisions regarding 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 interference with lifestyle is helpful for women considering treatment. 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 painrating 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-oflife questions.94 At a minimum, the patients description of
her symptoms and their effect on usual activities, a simple
quantitative assessment of the pain, and decisions regarding any evaluation, follow-up, or therapeutic intervention should be documented during encounters for breast
pain.
BREAST PAIN MANAGEMENT
Breast pain prompts many women to seek medical attention 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 and
noncyclic 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 effectiveness of therapies for breast pain because the pain is
subjective, cyclic, or fluctuating in severity and is occasionally self-limited. These characteristics make assessment of response to an intervention challenging. Addition-
ally, the definition of a therapeutic response differs between studies, and there is a placebo effect of at least 20%
(range, 10%-40%).11,18 A wide variety of nonpharmacological measures are used to treat breast pain with little or
no scientific support. Although applying evidence-based
criteria 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 inclusive but have qualified the studies to guide clinicians and
define areas for future research.
Nonpharmacological Interventions
Nonpharmacological 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 interventions, 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 menstrual
cycle, 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 follow-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 medication 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 3
women 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 credence to the widely held clinical impression that a properly
Breast Pain
361
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, particularly when symptoms are cyclic or intermittent and of
short duration. Measures such as ultrasonography and acupuncture are used occasionally and are undergoing preliminary 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 progressive muscular relaxation experienced substantial or complete relief of breast pain compared with 25% of control subjects who did not use the audiocassettes (P<.05).
Subjects who performed relaxation techniques also had
substantially more pain-free days and less anxiety than
controls.63
Dietary Change, Methylxanthine Restriction, and
Nutritional Supplements. Dietary Fat.The effectiveness of dietary interventions to reduce breast pain remains
to be established105; however, several have shown promise.
A low-fat diet was associated with a substantial improvement in mastalgia symptoms when 21 patients with severe
mastopathy were randomized to a diet containing 15% fat
intake or a general diet containing 36% fat intake. The
subjects were monitored with symptom logs and breast
examinations for 6 months, at which time 9 of 10 subjects
(90%) who followed the low-fat diet and 2 of 9 controls
(22%) had decreased breast symptoms (P=.0023). In the
intervention group, body weight and cholesterol level were
reduced, the latter associated with the decrease in symptoms.42 Lower dietary fat intake also has been associated
with less severe mastalgia symptoms in a case-control
study106 and in a prospective uncontrolled study.107
Other parameters that may be related to mastalgia are
altered by reducing dietary fat, including circulating estrogen (estradiol, estrone) levels 42,108-110 and mammographic
breast density.111 The effect of decreased dietary fat intake
on other fibrocystic changes of the breast is limited.105 To
derive benefit from this approach, women must decrease
fat intake to less than 20% of total daily caloric intake.107,109
This diet may be difficult to sustain and may not be optimal
in some women.112
Methylxanthine Restriction.Although many women
report that caffeine reduction or elimination alleviates their
breast pain, clinical studies have not shown consistent findings. In an uncontrolled study, 61% of women with breast
pain who substantially decreased caffeine intake for 1 year
had decreased pain or complete relief.96 However, most
362
Breast Pain
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, improved, 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 fibrocystic nodularity of the breast. These authors observed,
but did not measure, an improvement in premenstrual
breast discomfort during the study.115 An association between 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 caffeine-free diet, a low-cholesterol diet, or an unrestricted
diet.120 Other investigators have found no association between caffeine and fibrocystic change of the breast, with
many of the studies assessing histological change, not
breast symptoms.121-124
The nonendocrine mechanism by which methylxanthines
are believed to influence fibrocystic change in the breast
relates to their mediation of elevated 3,5cyclic adenosine monophosphate (cAMP) in fibrocystic tissue specimens and circulating catecholamines.125 High caffeine
intake also may be associated with altered hormone levels in postmenopausal women, with increased plasma
estrone, sex hormonebinding globulin, and decreased
testosterone.126
Overall, no consistent evidence supports women restricting caffeine to improve physical examination, mammographic, or histological findings. Completely eliminating 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 consumption. 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 patients suggested a potential beneficial effect of vitamin E
(-tocopherol) in fibrocystic breast disease.131-133 Proposed
mechanisms include its potential to alter steroidal hormone
production (dehydroepiandrosterone or progesterone), to
correct abnormal serum cholesterollipoprotein distribution, 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 dehydroepiandrosterone did not differ between vitamin E- and placebotreated women.136 Many practitioners continue to recommend 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 B6 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 (gammalinolenic acid) has been widely advocated as an initial option.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 factorial 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% decrease 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 adverse 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 improving pain.145
Thus, results of studies and clinical series assessing
evening primrose oil in the treatment of mastalgia are
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363
Table 5. Evening Primrose Oil in Studies of Women With Mastalgia

Study*
EPO
Placebo
Adverse effects
Comments
Pain score
Before
After
Before
After
Pashby et al,141 1981

Cyclic mastalgia
Noncyclic mastalgia
50
54
32
40
45
56
42
60
Preece et al,142 1982

Cyclic mastalgia
Noncyclic mastalgia
36
50
22
42
24
42
32
44
NR
Randomized, double-blind, placebo-controlled

crossover study (N=73) at mastalgia clinic; pain
score (LAS) at 3 mo (P<.05)
In 4% of subjects (weight
gain, rash), less than in
placebo group
Double-blind, placebo-controlled, crossover study

(N=72) at mastalgia clinics; pain score (LAS) at
3 mo (P<.05). Not shown, tenderness and nodularity different from placebo at 3 and 6 mo (P<.05)
Subjects responding, No. (%)

Pye et al,127 1985
Cyclic mastalgia
Noncyclic mastalgia
47/92 (51)
9/33 (27)
NR (19)
NR (9)
In 2% of subjects
(bloating, mild nausea)
Retrospective review of sequential clinical trials and

practice at mastalgia clinic; response at 6 mo.
P values not reported
McFayden et al,24 1992

Cyclic mastalgia
58/99 (59)
None
In 2% of subjects (nausea,
headache)
Retrospective review of clinical practice at mastalgia

clinic; response at 2 mo; 17% of subjects did not
respond and 24% not available for follow up
10/39 (26)
None
NR
Retrospective review of clinical practice at mastalgia

clinic; duration of treatment not specified
33/34 (97)
None
In 12% of subjects (acne,

rash, nausea, dizziness)
Prospective, uncontrolled trial in surgical clinic

(Hong Kong); response at 6 mo. No placebo
comparison
EPO not different from

placebo (gastric, skin,
weight gain). FO and
FO + EPO adverse
effects increased from
placebo (gastric)
Randomized, double-blind trial with factorial design

(N=120) and 4 groups: (1) FO + control, (2) EPO
+ control, (3) FO + EPO, (4) both controls. All
groups showed decrease in pain severity and %
days with pain; neither EPO nor FO had benefit
over control oils (P=.73)
Wetzig,143 1994
Combined cyclic or
noncylic mastalgia
Cheung,144 1999
Cyclic mastalgia
Improved or
resolved
Resolved
17/34 (50)
Days with pain
Blommers et al,145 2002

Combined cyclic and
noncyclic mastalgia
12.3%
decrease
13.8%
decrease
*Studies involved subjects with disturbing, persistent breast pain. Studies that primarily evaluated premenstrual syndrome were not included. EPO =
evening primrose oil; FO = fish oil; LAS = linear analog scale (pain rating); NR = not reported.
EPO dosage was not specified in Pashby et al141; 2000-3000 mg/d in Wetzig143 and McFayden et al24; and 3000 mg/d in the other studies.
Control oils = corn or corn and wheat germ oils.
conflicting (Table 5). Evening primrose oil also has shown

variable effectiveness for cyclic breast symptoms in studies
of women with premenstrual syndrome.146-150
The proposed mechanism for evening primrose oil is
based on the finding that women with cyclic breast pain
have abnormal fatty acid profiles (increased saturated
fatty acid esters, palmitic acid, and stearic acid) that may
cause hypersensitivity of the breast epithelium to circulating hormones.151,152 Gamma-linolenic acid is believed to
restore the saturated/unsaturated fatty acid balance and
decrease sensitivity to steroidal hormones.105,151,152 Also,
low levels of the gamma-linolenic acid metabolite,
dihomogamma-linolenic acid, may affect breast sensitivity to prolactin via prostaglandins.105,150-152 Some of these
mechanisms relate to the effect of marked dietary fat
restriction and support a role of lipid metabolism in cyclic

mastalgia.106,152
Evening primrose oil is available as a nutritional supplement to women worldwide. Typically 9% gamma-linolenic
acid by weight, the dosage used for breast pain has been
3000 mg/d (in divided doses). Response to therapy is best
assessed at 6 months because patients may continue to
improve after 3 months of treatment.144 Physicians must be
cognizant that herbal agents and nutritional supplements are
not standardized or monitored for adulteration.153 Potential
interaction with medications and other herbal medicinals
also must be considered. Gamma-linolenic acid may affect
the seizure threshold; for this reason, some researchers advise against its use in patients requiring anticonvulsant
therapy.153 The safety of evening primrose oil during preg-
364
Breast Pain
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 genistein
and daidzen, which exert their effect by binding to estrogen
receptors (preferentially the -receptor subtype).154 In premenopausal 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 include decreased midcycle surges of luteinizing hormones
and follicle-stimulating hormones155 and decreased estradiol 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 symptoms of mastalgia are known.
Other Nutritional Supplements and Herbal Agents.
Interest is growing in herbal agents, nutritional supplements, 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 premenstrual 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 receptors160 or acts via dopaminergic and prolactin-suppressant effects.161 Little is known about breast pain as a potential adverse effect of herbal remedies.162
In light of the frequency of breast pain, additional research must clarify the therapeutic value of improved mechanical support, relaxation techniques, dietary adjustments, nutritional supplements, herbal medicinals, and
other nonpharmacological interventions.
Simple Analgesics
Surprisingly, there has been little investigation into
simple analgesics, such as acetaminophen and nonsteroidal
anti-inflammatory agents, for breast pain. In one uncontrolled 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-inflammatory agents diclofenac and piroxicam yielded satisfactory relief in 21 (81%) of 26 women with severe cyclic,
noncyclic, and surgical scarrelated breast pain.164 Recently, a randomized blinded study of a topical nonsteroidal anti-inflammatory agent showed significant pain reduction in 60 subjects with cyclic mastalgia and 48 subjects
with noncyclic mastalgia compared with placebo. No adverse effects occurred.165 Conversely, another study of topical 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 additional investigation.
Hormonally Active Medications
The number of hormonal approaches and remedies promoted to alleviate mastalgia attests to the lack of a single
effective agent with few adverse effects. There is no consensus regarding the initial hormonal agent to use for
women who require intervention beyond the measures described previously. Most researchers favor one of danazol,
bromocriptine, or tamoxifen.
Decisions regarding treatment of mastalgia require balancing the need for symptom relief against the likelihood
of medication adverse effects. Most of the hormonally
active 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 treatment or another hormonal agent.166 Contraception is important during treatment and should be discussed with
patients.
Oral Contraceptives, Estrogen, and Progesterone.
It is reasonable to adjust medications that may be contributing to breast pain, such as oral contraceptives or menopausal hormone therapy. Eliminating or decreasing the
dose of estrogen in an oral contraceptive or hormone regimen is often effective in clinical practice, particularly if the
onset of symptoms is temporally related to initiation or
change in medication. Many oral contraceptives list breast
pain and tenderness as potential adverse effects. Studies of
low-dose oral contraceptives (20 g ethinyl estradiol) have
found no increased breast symptoms compared with placebo.167 Many women report a reduction in severity and
duration of cyclic breast discomfort while taking oral contraceptives.168,169 There has been little investigation of adjustment in contraceptive medication as a therapeutic approach to alleviating breast pain.
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 acetate (Depo-Provera) for contraception compared with agematched control women randomly selected without regard
to contraceptive method. Most controls had used oral contraceptives, and 10% had used medroxyprogesterone acetate 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<.001 and P<.05, respectively).170
The oral progestogens lynestrenol and promegestone
administered during the luteal phase significantly improved
breast pain symptoms in 66% to 80% of women with benign
breast disease.171,172 Similarly, in a randomized double-blind
study of oral progestogens in 31 women with breast pain
and tenderness, 86% of women treated with medrogestone
and 75% of women treated with dydrogestone on days 14
to 25 of the menstrual cycle became pain free after 6
cycles.173 However, in another double-blind crossover
study of oral medroxyprogesterone acetate (20 mg/d) or
placebo given during the luteal phase in 26 women with
cyclic breast pain, no significant relief of symptoms was
noted.174
Micronized progesterone vaginal cream reduced breast
pain and tenderness in 65% of women in the active treatment group compared with 22% in the placebo group
(P<.01).175 Progesterone cream applied to the breast was
not better than placebo for cyclic breast pain in another
small randomized study.176
Danazol and Gestrinone.Danazol, the only medication approved by the Food and Drug Administration for
treatment of mastalgia, is a derivative of 17--ethinyl testosterone that suppresses gonadotropin secretion, prevents
luteinizing hormone surge, and inhibits ovarian steroid
formation. Danazol relieves breast pain and tenderness in
controlled clinical trials.177-183 Overall, 59% to 92% of
women treated with danazol experience relief of breast
pain.22,177-190 Typically, the initial dosage is 200 mg/d with
eventual tapering to lower-dose,177 alternate-day, or lutealphase administration.180,188,189 However, initial dosages of 50
to 400 mg/d have been described.177-187 Interestingly, danazol
was associated with decreased mammographic breast volume and density in 25 women with breast pain, 23 of whom
experienced complete resolution of symptoms.190
Unfortunately, adverse effects occur in 30% of patients
and result in discontinuation of treatment in 15% of patients, even when breast pain is improved.22 Adverse effects are dose related and primarily androgenic, including
acne, hair loss, decrease in voice pitch, weight gain, head-
Breast Pain
365
ache, nausea, rash, anxiety, and depression.22 Menstrual

irregularity or amenorrhea may occur in 50% to 85% of
women taking danazol (200-400 mg/d).177,187 Recently,
luteal-phase administration of danazol relieved premenstrual breast pain in women with premenstrual syndrome
without increased adverse effects compared with placebo.155 Low-dose, luteal-phase administration may maintain symptom relief with few adverse effects in women
with severe, relapsing cyclic mastalgia.188,189
Gestrinone, a synthetic 19-nor-testosterone derivative
originally developed as a contraceptive, has been studied as
a treatment for endometriosis and breast pain.191 Similar to
danazol, it has androgenic, antigonadotropic, antiprogestagenic, and antiestrogenic properties. Gestrinone reduces
ovarian hormone secretion, decreases follicular development, and suppresses the midcycle surge of follicle-stimulating hormone and luteinizing hormone.191 In a multicenter, double-blind, placebo-controlled study of women
with cyclic mastalgia, a significantly greater reduction in
breast pain and discomfort occurred with use of gestrinone
at a dosage of 2.5 mg/wk compared with placebo. Adverse
effects are primarily androgenic, occurring in 41% of patients treated with gestrinone and 14% of patients taking
placebo.192
Dopamine Agonists.One hormonal abnormality detected in women with mastalgia has been an increase in
thyrotropin-induced prolactin secretion.41,43,52 This finding
provides the rationale for dopamine agonists to treat breast
pain. Bromocriptine significantly decreased breast pain,
heaviness, and tenderness in several studies.193-201 In a
multicenter trial of 272 women with cyclic breast pain randomized to receive 2.5 mg twice daily of bromocriptine or
placebo for 6 months, breast pain, heaviness, and tenderness
and serum prolactin levels decreased in the bromocriptine
group compared with the placebo group. Despite a therapeutic response, 29% of women withdrew from the study because of adverse effects, mainly from the bromocriptine
group.193 Clinical improvement generally occurs in 47% to
88% of symptomatic women and is often sustained after
cessation of the medication.
Some researchers advocate using the prolactin response
to thyrotropin-releasing hormone to predict response to
bromocriptine.201,202 In one study, 74% of subjects with an
abnormal response experienced effective mastalgia treatment with bromocriptine compared with 24% of subjects
with a normal response.201 A randomized double-blind trial
of danazol, bromocriptine, and placebo in women with
severe breast pain found both therapeutic agents superior to
placebo, with danazol having the greatest pain reduction
measured by the visual analog scale.203
Adverse effects are common and dose related, including
nausea, vomiting, dizziness, headache, and fatigue.18,165
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Breast Pain
Table 6. Clinical Trials of Tamoxifen for Treatment of Mastalgia*

No. (%) of subjects responding to intervention
Tamoxifen
BromoStudy
10 mg
20 mg
Danazol
criptine
Placebo
Comments
Fentiman
et al,206 1986
NE
22/31 (71)
NE
NE
11/29 (38)
Powles et al,207
1987
NE
22/25 (88)
20/25 (80)
NE
NE
Randomized double-blind trial of daily tamoxifen

or placebo in 60 subjects with cyclic or
noncyclic pain; response (50% decrease in
mean pain score) at 3 mo. Significant difference
between groups (P<.025); 6 in each group
stopped study due to adverse effects
Randomized trial of tamoxifen, 20 mg/d and
danazol, 100 mg twice daily; agents were of
equal efficacy (P>.10), but fewer adverse
effects were noted with tamoxifen (P<.01)
Messinis &
Lolis,208 1988
16/18 (89)
NE
NE
NE
6/16 (38)
Fentiman
et al,95 1988
26/29 (90)
24/28 (86)
NE
NE
NE
127/155 (82)
107/142 (75)
NE
NE
NE
Sandrucci
et al,211 1990
18/20 (90)
NE
NE
16/18 (89)
NE
Kontostolis
et al,210 1997
23/32 (72)
NE
21/32 (66)
NE
11/29 (38)
GEMB,209 1997
Randomized trial of tamoxifen or placebo

administered from day 5 to 24 for 6 consecutive
menstrual cycles; significant difference between
groups (P<.0001)
Randomized double-blind trial of 10 or 20 mg of
tamoxifen daily for 3 or 6 mo. Each dosage and
duration equally effective; fewer adverse
effects in 10-mg compared with 20-mg group
(21% vs 64%; P<.0001)
Randomized trial of 10 or 20 mg of tamoxifen
from day 15 to 25 of menstrual cycle; doses
equally effective (P=NS) with fewer adverse
effects in 10-mg group (P<.05)
Randomized, blind trial of tamoxifen, 10 mg from
day 15 to 25 of menstrual cycle or bromocriptine,
7.5 mg/d; agents equally effective (P=NS);
adverse effects reported as mild and similar
Randomized trial of tamoxifen, 10 mg from day 5
to 24 of menstrual cycle; danazol, 100 mg twice
daily, or placebo for 6 mo. Tamoxifen was more
effective than danazol (P<.001), but both were
more effective than placebo (P<.035, P<.011,
respectively)
*GEMB = Grupo de Estudio de Mastopatias Benignas; NE = not evaluated in the study.

Relapse occurred in 48% and 39% of subjects in 10- and 20-mg group at 3 mo median time after treatment.
Hot flashes, gastrointestinal discomfort, vaginal discharge, ankle edema, and menorrhagia.
These may be minimized with use of an incremental dosing

regimen, with stepwise increases of 1.25 mg during a period of 2 weeks.18 Prolactin levels decline during therapy,
whereas estrogen, progesterone, testosterone, and gonadotropin-releasing hormone do not significantly change.
Other dopamine agonists, quinagolide and lisuride, have
shown promising results in the treatment of mastalgia.204,205
Selective Estrogen Receptor Modulators.The selective estrogen receptor modulator tamoxifen is used to
prevent and treat breast cancer. It is effective in reducing
pain in 71% to 96% of women with cyclic mastalgia and
56% of women with noncyclic mastalgia in controlled
trials (Table 695,206-211). Similar efficacy was reported in a
clinic-based survey of 165 patients treated for mastalgia,
17% of whom had been treated with tamoxifen.212 In studies comparing tamoxifen dosages and duration for breast
pain, the 10 mg/d dosage of tamoxifen was as effective as
the 20 mg/d dosage with fewer adverse effects,95,209 and

assessment at 3 months had the same number of subjects
responding to treatment as at 6 months.95
Tamoxifen has a risk of potentially serious adverse effects, with the principal concerns being deep venous
thrombosis and endometrial cancer. Also, hot flashes, nausea, menstrual irregularity, vaginal dryness or discharge,
and weight gain have been associated with tamoxifen treatment. As part of one of the clinical trials of tamoxifen for
breast pain, metabolic and hematologic variables were assessed without alteration in clotting function.213 Increases
in sex hormonebinding globulin, estradiol, free estradiol,
and high-density lipoprotein levels and decreases in the
percentage of biologically available free estradiol and lowdensity lipoprotein levels were seen without adverse
changes.213 Additionally, bone mineral density and markers
of bone turnover did not change from pretreatment values
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 premenopausal women in the breast cancer prevention trials
has increased familiarity with this medication in younger
women without breast cancer.215,216 Nonetheless, tamoxifen, like the other hormonal interventions, should be reserved for women with severe mastalgia refractory to other
measures. Although not associated with increased pain in
clinical trials of postmenopausal women treated for osteoporosis,72 there are no known studies of raloxifene as a
therapeutic agent for breast pain.
Gonadotropin-Releasing Hormone Agonists.Gonadotropin-releasing hormone agonists are synthetic analogues of hypothalamic gonadotropin-releasing hormone.
Initial administration stimulates pituitary release of luteinizing hormone and follicle-stimulating hormone followed
by ovarian production of estrogen and progesterone; continuous 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 21
premenopausal 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 implants relieved breast pain in 6 patients with cyclic mastalgia.220 Other gonadotropin-releasing hormone agonists may
have similar effects in patients with breast pain.
Adverse effects related to the hypoestrogenic state produced by these medications are frequent and often severe,
including hot flashes, headache, nausea, fatigue, depression, anxiety, irritability, vaginal dryness, and decreased
libido. Decline in trabecular bone mineral density is as high
as 6% within 6 months. Although usually reversible, treatment 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 agonists is promising, few data are currently available to support their clinical use for treatment of mastalgia. As with
Breast Pain
367
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 and
Surgical Approaches
Over the years, numerous medications have been used
to treat breast pain, including diuretics, antibiotics, thyroxine, 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. Antibiotics 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 potential causative role of breast size in cyclic mastalgia,
some women with symptomatic macromastia note improvement in breast pain as well as in neck, shoulder, and
back discomfort after reduction mammaplasty.222,223 In general, 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 additional
intervention or medication. Those requesting treatment often 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 consistently low. Additional controlled clinical trials of this intervention 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 discomfort
and pain must be balanced against their potential for adverse effects. Selection of a specific agent is individualized. In certain circumstances, bromocriptine or a gonadotropin-releasing hormone agonist may be needed; however,
approaches to decreased dosing to minimize adverse effects have not been established.
Additional research is needed to improve our understanding of breast pain and the care of women with moderate to severe symptoms that affect activities of daily life.
368
Breast Pain
Table 7. Principles for Management of Breast Pain

History and physical examination
Cyclic mastalgia, noncyclic mastalgia, or extramammary pain
Identify and evaluate any suspicious breast abnormalities
Breast imaging
Consider ultrasonography for focal, persistent breast pain (any age)
Consider mammography for women with breast pain, who
Are aged >30 years or
Have a family history of early breast cancer, or
Have other risk factors for breast cancer
Pain assessment
Quantitative 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 on
Supportive, well-fitting brassiere
Physical measures for relief of pain
Dietary intervention
Relaxation training
Consider trial of well-tolerated supplements*
Pharmacological intervention (for patients with severe, sustained breast
pain)
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, noncyclic
breast pain and patients with cyclic pain who may require
additional intervention or pharmacological intervention
*Herbal therapies (eg, evening primrose oil) are favored by some patients.
Some herbal therapies have been used extensively in mastalgia treatment. There is preliminary or mixed evidence of effectiveness and few
adverse effects.
Hormonal therapies have shown effectiveness in controlled trials but
with adverse effects that limit their use to patients with severe, lifealtering breast pain. FDA = Food and Drug Administration.
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.
7.
8.
9.
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12.
13.
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16.
17.
18.
19.
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21.
22.
23
24.
25.
26.
27.
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Mayo Clin Proc, March 2004, Vol 79

Evaluation and Management of Breast Pain

astalgia, or breast pain, was described in the medical

From the Breast Diagnostic Clinic, Division of General Internal

2004 Mayo Foundation for Medical Education and Research

clinical trials, published clinical experience, and recent

Mayo Clin Proc, March 2004, Vol 79

Mayo Clin Proc, March 2004, Vol 79

Table 1. Theories Regarding Hormonal Etiology of Cyclic Mastalgia

Estrogen excess (luteal phase)*

41, 42, 45, 46, 51, 53

nervous and irritable temperament. Although endocrine

unclear; however, substantial improvements in depression

Mayo Clin Proc, March 2004, Vol 79

Mayo Clin Proc, March 2004, Vol 79

Other menstrual symptoms

Other menstrual symptoms

90 100 110 120 130 140 150

and 3.89 mm in women with noncyclic mastalgia (P<.001).

who present to breast or oncology clinics has been studied

Table 2. Medications Associated With

Mayo Clin Proc, March 2004, Vol 79

Proposed causes for postsurgical breast pain vary with

Mayo Clin Proc, March 2004, Vol 79

Table 3. Frequency of Cancer in Patients Presenting With Breast Pain

Preece et al, 1982

Smallwood et al,79 1986

Fariselli et al,80 1988

Barton et al,8 1999

Lumachi et al,81 2002

regional lymph nodes. Detection of localized, generalized,

Table 4. Differential Diagnosis of Mastalgia

In many medical centers, ultrasonography is used alone

Mayo Clin Proc, March 2004, Vol 79

BREAST PAIN ASSESSMENT

Mayo Clin Proc, March 2004, Vol 79

fitted brassiere has therapeutic value for symptomatic

work in this area has focused on the relationship between

Mayo Clin Proc, March 2004, Vol 79

Vitamins.Several vitamins have been evaluated as

Mayo Clin Proc, March 2004, Vol 79

Table 5. Evening Primrose Oil in Studies of Women With Mastalgia

Pashby et al,141 1981

Preece et al,142 1982

Randomized, double-blind, placebo-controlled

Double-blind, placebo-controlled, crossover study

Subjects responding, No. (%)

Retrospective review of sequential clinical trials and

McFayden et al,24 1992

Retrospective review of clinical practice at mastalgia

Retrospective review of clinical practice at mastalgia

In 12% of subjects (acne,

Prospective, uncontrolled trial in surgical clinic

EPO not different from

Randomized, double-blind trial with factorial design

Blommers et al,145 2002

conflicting (Table 5). Evening primrose oil also has shown

restriction and support a role of lipid metabolism in cyclic

nancy or lactation has not been established. Although widely

Mayo Clin Proc, March 2004, Vol 79

Mayo Clin Proc, March 2004, Vol 79

Topical, oral, and parenteral progestogens have been

ache, nausea, rash, anxiety, and depression.22 Menstrual

Mayo Clin Proc, March 2004, Vol 79