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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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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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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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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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


15/20


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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