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Evaluation and Management of Breast Pain

      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 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.
      Mastalgia, or breast pain, was described in the medical literature as early as 1829
      • Cooper A
      and was likely known to medical practitioners much earlier.
      • Grimm K
      • Fritsche E
      Reduction of breasts: Hans Schaller and the first mammaplasty in 1561 [in German].
      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.
      • BRIDGE Study Group
      The presentation and management of breast symptoms in general practice in South Wales.
      • Mansel RE
      ABC of breast disease: breast pain.
      • Roberts MM
      • Elton RA
      • Robinson SE
      • French K
      Consultations for breast disease in general practice and hospital referral patterns.
      • Nichols S
      • Waters WE
      • Wheeler MJ
      Management of female breast disease by Southampton general practitioners.
      • Bywaters JL
      The incidence and management of female breast disease in a general practice.
      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.
      • Barton MB
      • Elmore JG
      • Fletcher SW
      Breast symptoms among women enrolled in a health maintenance organization: frequency, evaluation, and outcome.
      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.
      • Ader DN
      • Browne MW
      Prevalence and impact of cyclic mastalgia in a United States clinic-based sample.
      Although increased awareness and overestimation of breast cancer risk
      • Black WC
      • Nease Jr, RF
      • Tosteson AN
      Perceptions of breast cancer risk and screening effectiveness in women younger than 50 years of age.
      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 severe breast pain, but fewer than half of the women with severe pain had reported this symptom to a physician.
      • Maddox PR
      • Mansel RE
      Management of breast pain and nodularity.
      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.
      • Braunstein GD
      Gynecomastia.
      • Pitt B
      • Zannad F
      • Remme WJ
      • Randomized Aldactone Evaluation Study Investigators
      • et al.
      The effect of spironolactone on morbidity and mortality in patients with severe heart failure.
      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.
      • Mansel RE
      ABC of breast disease: breast pain.
      • Maddox PR
      • Mansel RE
      Management of breast pain and nodularity.
      • BeLieu RM
      Mastodynia.
      • Dixon JM
      Managing breast pain.
      • Morrow M
      The evaluation of common breast problems.
      • Klimberg VS
      Etiology and management of breast pain.
      • Gateley CA
      • Mansel RE
      Management of cyclical breast pain.
      • Steinbrunn BS
      • Zera RT
      • Rodriguez JL
      Mastalgia: tailoring treatment to type of breast pain.
      • Faiz O
      • Fentiman IS
      Management of breast pain.
      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.
      • Davies EL
      • Gateley CA
      • Miers M
      • Mansel RE
      The long-term course of mastalgia.
      The distinctions are important because the evaluation and the likelihood of response to intervention vary among the different types of breast pain.
      • Gateley CA
      • Mansel RE
      Management of cyclical breast pain.
      • Gateley CA
      • Miers M
      • Mansel RE
      • Hughes LE
      Drug treatments for mastalgia: 17 years experience in the Cardiff Mastalgia Clinic.
      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.
      • Ader DN
      • Browne MW
      Prevalence and impact of cyclic mastalgia in a United States clinic-based sample.
      Outcome can be successful in most patients with reassurance, nonpharmacological measures, and in some instances, one of several effective medications.
      • BeLieu RM
      Mastodynia.
      • Klimberg VS
      Etiology and management of breast pain.
      • Gateley CA
      • Miers M
      • Mansel RE
      • Hughes LE
      Drug treatments for mastalgia: 17 years experience in the Cardiff Mastalgia Clinic.
      Breast pain: mastalgia is common but often manageable.
      • McFayden IJ
      • Forrest AP
      • Chetty U
      • Raab G
      Cyclical breast pain—some observations and the difficulties in treatment.
      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, 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.
      • Ader DN
      • Browne MW
      Prevalence and impact of cyclic mastalgia in a United States clinic-based sample.
      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.
      • Ader DN
      • Browne MW
      Prevalence and impact of cyclic mastalgia in a United States clinic-based sample.
      This information is most accurate when obtained from a patient's prospective breast pain record.
      • Gateley CA
      • Miers M
      • Mansel RE
      • Hughes LE
      Drug treatments for mastalgia: 17 years experience in the Cardiff Mastalgia Clinic.
      Breast pain: mastalgia is common but often manageable.
      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.
      • Ader DN
      • Browne MW
      Prevalence and impact of cyclic mastalgia in a United States clinic-based sample.

      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.
      • Ader DN
      • Browne MW
      Prevalence and impact of cyclic mastalgia in a United States clinic-based sample.
      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.
      • Ader DN
      • Browne MW
      Prevalence and impact of cyclic mastalgia in a United States clinic-based sample.
      • Ader DN
      • South-Paul J
      • Adera T
      • Deuster PA
      Cyclical mastalgia: prevalence and associated health and behavioral factors.
      • Goodwin PJ
      • Miller A
      • Del Giudice ME
      • Ritchie K
      Breast health and associated premenstrual symptoms in women with severe cyclic mastopathy.
      • Ader DN
      • Shriver CD
      Cyclical mastalgia: prevalence and impact in an outpatient breast clinic sample.
      Cyclic mastalgia typically presents during the third or fourth decade of life.
      • Davies EL
      • Gateley CA
      • Miers M
      • Mansel RE
      The long-term course of mastalgia.
      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.
      • Davies EL
      • Gateley CA
      • Miers M
      • Mansel RE
      The long-term course of mastalgia.

      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.
      • Preece PE
      • Mansel RE
      • Bolton PM
      • Hughes LM
      • Baum M
      • Gravelle IH
      Clinical syndromes of mastalgia.
      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.
      • Watt-Boolsen S
      • Emus HC
      • Junge J
      Fibrocystic disease and mastalgia: a histological and enzyme-histochemical study.
      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.
      • Jorgensen J
      • Watt-Boolsen S
      Cyclical mastalgia and breast pathology.
      Additionally, 58% to 89% of autopsy breast specimens have shown varying degrees of fibrocystic histology.
      • Love SM
      • Gelman RS
      • Silen W
      Fibrocystic “disease” of the breast—a nondisease?.
      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,
      • Dupont WD
      • Page DL
      Risk factors for breast cancer in women with proliferative breast disease.
      these histological findings are considered part of the spectrum of normal involutional patterns in the breast
      • Hughes LE
      Benign breast disorders—introduction: fibrocystic disease? nondisease? or ANDI?.
      and a “nondisease.”
      • Love SM
      • Gelman RS
      • Silen W
      Fibrocystic “disease” of the breast—a nondisease?.
      This emphasis has been evolving in the literature, which contains several thoughtful perspectives.
      • Love SM
      • Gelman RS
      • Silen W
      Fibrocystic “disease” of the breast—a nondisease?.
      • Hughes LE
      Benign breast disorders—introduction: fibrocystic disease? nondisease? or ANDI?.
      • Marchant DJ
      Benign breast disease.
      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 α) in breast tissue specimens.
      • Ramakrishnan R
      • Werbeck J
      • Khurana KK
      • Khan SA
      Expression of interleukin-6 and tumor necrosis factor α and histopathologic findings in painful and nonpainful breast tissue.
      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.
      • Andrews WC
      Hormonal management of fibrocystic disease of the breast.
      • Dogliotti L
      • Orlandi F
      • Angeli A
      The endocrine basis of benign breast disorders.
      Nonetheless, consistent hormonal abnormalities have not been identified. Several hormonal imbalances with potential causative roles in cyclic mastalgia have been investigated, and each has findings in support and opposition (Table 1
      • Walsh PV
      • McDicken IW
      • Bulbrook RD
      • Moore JW
      • Taylor WH
      • George WD
      Serum oestradiol-17β and prolactin concentrations during the luteal phase in women with benign breast disease.
      • Sitruk-Ware LR
      • Sterkers N
      • Mowszowicz I
      • Mauvais-Jarvis P
      Inadequate corpus luteal function in women with benign breast diseases.
      • Watt-Boolsen S
      • Andersen AN
      • Blitchert-Toft M
      Serum prolactin and oestradiol levels in women with cyclical mastalgia.
      • Kumar S
      • Mansel RE
      • Scanlon MF
      • et al.
      Altered responses of prolactin, luteinizing hormone and follicle stimulating hormone secretion to thyrotropin releasing hormone/gonadotropin releasing hormone stimulation in cyclical mastalgia.
      • Boyd NF
      • McGuire V
      • Shannon P
      • et al.
      Effect of a low-fat high-carbohydrate diet on symptoms of cyclical mastopathy.
      • Ayers JW
      • Gidwani GP
      The “luteal breast”: hormonal and sonographic investigation of benign breast disease in patients with cyclic mastalgia.
      • England PC
      • Skinner LG
      • Cottrell KM
      • Sellwood RA
      Sex hormones in breast disease.
      • Gorins A
      • Cordray JP
      Hormonal profile of benign breast disease and premenstrual mastodynia.
      • Sitruk-Ware R
      • Sterkers N
      • Mauvais-Jarvis P
      Benign breast disease, I: hormonal investigation.
      • Walsh PV
      • Bulbrook RD
      • Stell PM
      • Wang DY
      • McDicken IW
      • George WD
      Serum progesterone concentration during the luteal phase in women with benign breast disease.
      • Kumar S
      • Mansel RE
      • Wilson DW
      • et al.
      Daily salivary progesterone levels in cyclical mastalgia patients and their controls.
      • Ecochard R
      • Marret H
      • Rabilloud M
      • Boehringer H
      • Mathieu C
      • Guerin JF
      Gonadotropin level abnormalities in women with cyclic mastalgia.
      • Cole EN
      • Sellwood RA
      • England PC
      • Griffiths K
      Serum prolactin concentrations in benign breast disease throughout the menstrual cycle.
      • Graziottin A
      • Sopracordevole F
      • Velasco M
      • Grella PV
      Plasma prolactin in women with mastodynia.
      • Kumar S
      • Mansel RE
      • Hughes LE
      • et al.
      Prolactin response to thyrotropin-releasing hormone stimulation and dopaminergic inhibition in benign breast disease.
      • Parlati E
      • Travaglini A
      • Liberale I
      • Menini E
      • Dell'Acqua S
      Hormonal profile in benign breast disease: endocrine status of cyclical mastalgia patients.
      • Watt-Boolsen S
      • Eskildsen PC
      • Blaehr H
      Release of prolactin, thyrotropin, and growth hormone in women with cyclical mastalgia and fibrocystic disease of the breast.
      • Horrobin DF
      The effects of gamma-linolenic acid on breast pain and diabetic neuropathy: possible non-eicosanoid mechanisms.
      • Sharma AK
      • Mishra SK
      • Salila M
      • Ramesh V
      • Bal S
      Cyclical mastalgia—is it a manifestation of aberration in lipid metabolism?.
      • Sprecher H
      Biochemistry of essential fatty acids.
      ). One hormonal abnormality frequently detected in mastalgia is increased thyrotropin-induced prolactin secretion.
      • Kumar S
      • Mansel RE
      • Scanlon MF
      • et al.
      Altered responses of prolactin, luteinizing hormone and follicle stimulating hormone secretion to thyrotropin releasing hormone/gonadotropin releasing hormone stimulation in cyclical mastalgia.
      • Ayers JW
      • Gidwani GP
      The “luteal breast”: hormonal and sonographic investigation of benign breast disease in patients with cyclic mastalgia.
      • Kumar S
      • Mansel RE
      • Hughes LE
      • et al.
      Prolactin response to thyrotropin-releasing hormone stimulation and dopaminergic inhibition in benign breast disease.
      • Parlati E
      • Travaglini A
      • Liberale I
      • Menini E
      • Dell'Acqua S
      Hormonal profile in benign breast disease: endocrine status of cyclical mastalgia patients.
      Table 1Theories Regarding Hormonal Etiology of Cyclic Mastalgia
      References
      Proposed hormonal imbalanceSupportOppose
      Estrogen excess (luteal phase)
      Excess and deficiency refer to luteal-phase hormone levels in subjects with cyclic mastalgia compared with asymptomatic controls.
      • Walsh PV
      • McDicken IW
      • Bulbrook RD
      • Moore JW
      • Taylor WH
      • George WD
      Serum oestradiol-17β and prolactin concentrations during the luteal phase in women with benign breast disease.
      • Sitruk-Ware LR
      • Sterkers N
      • Mowszowicz I
      • Mauvais-Jarvis P
      Inadequate corpus luteal function in women with benign breast diseases.
      ,
      • Watt-Boolsen S
      • Andersen AN
      • Blitchert-Toft M
      Serum prolactin and oestradiol levels in women with cyclical mastalgia.
      ,
      • Kumar S
      • Mansel RE
      • Scanlon MF
      • et al.
      Altered responses of prolactin, luteinizing hormone and follicle stimulating hormone secretion to thyrotropin releasing hormone/gonadotropin releasing hormone stimulation in cyclical mastalgia.
      ,
      • Boyd NF
      • McGuire V
      • Shannon P
      • et al.
      Effect of a low-fat high-carbohydrate diet on symptoms of cyclical mastopathy.
      ,
      • Ayers JW
      • Gidwani GP
      The “luteal breast”: hormonal and sonographic investigation of benign breast disease in patients with cyclic mastalgia.
      ,
      • England PC
      • Skinner LG
      • Cottrell KM
      • Sellwood RA
      Sex hormones in breast disease.
      ,
      • Gorins A
      • Cordray JP
      Hormonal profile of benign breast disease and premenstrual mastodynia.
      Progesterone deficiency (luteal phase)
      Excess and deficiency refer to luteal-phase hormone levels in subjects with cyclic mastalgia compared with asymptomatic controls.
      • Sitruk-Ware LR
      • Sterkers N
      • Mowszowicz I
      • Mauvais-Jarvis P
      Inadequate corpus luteal function in women with benign breast diseases.
      ,
      • Ayers JW
      • Gidwani GP
      The “luteal breast”: hormonal and sonographic investigation of benign breast disease in patients with cyclic mastalgia.
      ,
      • Sitruk-Ware R
      • Sterkers N
      • Mauvais-Jarvis P
      Benign breast disease, I: hormonal investigation.
      • Kumar S
      • Mansel RE
      • Scanlon MF
      • et al.
      Altered responses of prolactin, luteinizing hormone and follicle stimulating hormone secretion to thyrotropin releasing hormone/gonadotropin releasing hormone stimulation in cyclical mastalgia.
      ,
      • Boyd NF
      • McGuire V
      • Shannon P
      • et al.
      Effect of a low-fat high-carbohydrate diet on symptoms of cyclical mastopathy.
      ,
      • England PC
      • Skinner LG
      • Cottrell KM
      • Sellwood RA
      Sex hormones in breast disease.
      ,
      • Gorins A
      • Cordray JP
      Hormonal profile of benign breast disease and premenstrual mastodynia.
      ,
      • Walsh PV
      • Bulbrook RD
      • Stell PM
      • Wang DY
      • McDicken IW
      • George WD
      Serum progesterone concentration during the luteal phase in women with benign breast disease.
      ,
      • Kumar S
      • Mansel RE
      • Wilson DW
      • et al.
      Daily salivary progesterone levels in cyclical mastalgia patients and their controls.
      Progesterone-estrogen ratio decreased (luteal phase)
      • Sitruk-Ware LR
      • Sterkers N
      • Mowszowicz I
      • Mauvais-Jarvis P
      Inadequate corpus luteal function in women with benign breast diseases.
      ,
      • Sitruk-Ware R
      • Sterkers N
      • Mauvais-Jarvis P
      Benign breast disease, I: hormonal investigation.
      • Gorins A
      • Cordray JP
      Hormonal profile of benign breast disease and premenstrual mastodynia.
      ,
      • Parlati E
      • Travaglini A
      • Liberale I
      • Menini E
      • Dell'Acqua S
      Hormonal profile in benign breast disease: endocrine status of cyclical mastalgia patients.
      Increased levels or dynamic release of FSH and LH
      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.
      • Kumar S
      • Mansel RE
      • Scanlon MF
      • et al.
      Altered responses of prolactin, luteinizing hormone and follicle stimulating hormone secretion to thyrotropin releasing hormone/gonadotropin releasing hormone stimulation in cyclical mastalgia.
      ,
      • Ecochard R
      • Marret H
      • Rabilloud M
      • Boehringer H
      • Mathieu C
      • Guerin JF
      Gonadotropin level abnormalities in women with cyclic mastalgia.
      Prolactin excess (luteal phase)
      Excess and deficiency refer to luteal-phase hormone levels in subjects with cyclic mastalgia compared with asymptomatic controls.
      • Walsh PV
      • McDicken IW
      • Bulbrook RD
      • Moore JW
      • Taylor WH
      • George WD
      Serum oestradiol-17β and prolactin concentrations during the luteal phase in women with benign breast disease.
      ,
      • Watt-Boolsen S
      • Andersen AN
      • Blitchert-Toft M
      Serum prolactin and oestradiol levels in women with cyclical mastalgia.
      ,
      • Cole EN
      • Sellwood RA
      • England PC
      • Griffiths K
      Serum prolactin concentrations in benign breast disease throughout the menstrual cycle.
      ,
      • Watt-Boolsen S
      • Eskildsen PC
      • Blaehr H
      Release of prolactin, thyrotropin, and growth hormone in women with cyclical mastalgia and fibrocystic disease of the breast.
      • Kumar S
      • Mansel RE
      • Scanlon MF
      • et al.
      Altered responses of prolactin, luteinizing hormone and follicle stimulating hormone secretion to thyrotropin releasing hormone/gonadotropin releasing hormone stimulation in cyclical mastalgia.
      ,
      • Boyd NF
      • McGuire V
      • Shannon P
      • et al.
      Effect of a low-fat high-carbohydrate diet on symptoms of cyclical mastopathy.
      ,
      • Gorins A
      • Cordray JP
      Hormonal profile of benign breast disease and premenstrual mastodynia.
      ,
      • Sitruk-Ware R
      • Sterkers N
      • Mauvais-Jarvis P
      Benign breast disease, I: hormonal investigation.
      ,
      • Graziottin A
      • Sopracordevole F
      • Velasco M
      • Grella PV
      Plasma prolactin in women with mastodynia.
      ,
      • Parlati E
      • Travaglini A
      • Liberale I
      • Menini E
      • Dell'Acqua S
      Hormonal profile in benign breast disease: endocrine status of cyclical mastalgia patients.
      Increased dynamic release of prolactin
      Increased release of prolactin during stimulation with thyrotropin and gonadotropin-releasing hormones in subjects with cyclic mastalgia compared with asymptomatic controls.
      • Kumar S
      • Mansel RE
      • Scanlon MF
      • et al.
      Altered responses of prolactin, luteinizing hormone and follicle stimulating hormone secretion to thyrotropin releasing hormone/gonadotropin releasing hormone stimulation in cyclical mastalgia.
      ,
      • Ayers JW
      • Gidwani GP
      The “luteal breast”: hormonal and sonographic investigation of benign breast disease in patients with cyclic mastalgia.
      ,
      • Kumar S
      • Mansel RE
      • Hughes LE
      • et al.
      Prolactin response to thyrotropin-releasing hormone stimulation and dopaminergic inhibition in benign breast disease.
      ,
      • Parlati E
      • Travaglini A
      • Liberale I
      • Menini E
      • Dell'Acqua S
      Hormonal profile in benign breast disease: endocrine status of cyclical mastalgia patients.
      • Gorins A
      • Cordray JP
      Hormonal profile of benign breast disease and premenstrual mastodynia.
      ,
      • Watt-Boolsen S
      • Eskildsen PC
      • Blaehr H
      Release of prolactin, thyrotropin, and growth hormone in women with cyclical mastalgia and fibrocystic disease of the breast.
      Thyroid hormone abnormality
      • Kumar S
      • Mansel RE
      • Hughes LE
      • et al.
      Prolactin response to thyrotropin-releasing hormone stimulation and dopaminergic inhibition in benign breast disease.
      Altered lipid metabolism
      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
      • Boyd NF
      • McGuire V
      • Shannon P
      • et al.
      Effect of a low-fat high-carbohydrate diet on symptoms of cyclical mastopathy.
      ,
      • Horrobin DF
      The effects of gamma-linolenic acid on breast pain and diabetic neuropathy: possible non-eicosanoid mechanisms.
      ,
      • Sharma AK
      • Mishra SK
      • Salila M
      • Ramesh V
      • Bal S
      Cyclical mastalgia—is it a manifestation of aberration in lipid metabolism?.
      * 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.
      • Horrobin DF
      The effects of gamma-linolenic acid on breast pain and diabetic neuropathy: possible non-eicosanoid mechanisms.
      • Sprecher H
      Biochemistry of essential fatty acids.
      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 water-electrolyte balance in nonlactating breasts related to prolactin lead to cyclic painful swelling of breast microcysts.
      • Cole EN
      • Sellwood RA
      • England PC
      • Griffiths K
      Serum prolactin concentrations in benign breast disease throughout the menstrual cycle.
      In fact, breast volume may increase by more than 100 mL during the luteal phase of the menstrual cycle.
      • Milligan D
      • Drife JO
      • Short RV
      Changes in breast volume during normal menstrual cycle and after oral contraceptives.
      However, measurements of body weight and total body water are not increased in women with cyclic mastalgia,
      • Preece PE
      • Richards AR
      • Owen GM
      • Hughes LE
      Mastalgia and total body water.
      and most investigators do not recommend diuretics for its treatment.
      • Maddox PR
      • Mansel RE
      Management of breast pain and nodularity.
      • BeLieu RM
      Mastodynia.
      • Klimberg VS
      Etiology and management of breast pain.
      • Gateley CA
      • Mansel RE
      Management of cyclical breast pain.
      A relationship between mastalgia and dietary factors has been considered, including aberrant lipid metabolism
      • Horrobin DF
      The effects of gamma-linolenic acid on breast pain and diabetic neuropathy: possible non-eicosanoid mechanisms.
      • Sharma AK
      • Mishra SK
      • Salila M
      • Ramesh V
      • Bal S
      Cyclical mastalgia—is it a manifestation of aberration in lipid metabolism?.
      • Sprecher H
      Biochemistry of essential fatty acids.
      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 Cooper
      • Cooper A
      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.
      • Atkins HJB
      Chronic mastitis.
      In 1978, the opinion that breast pain was primarily an “expression of psychoneurosis” was challenged by a study
      • Preece PE
      • Mansel RE
      • Hughes LE
      Mastalgia: psychoneurosis or organic disease?.
      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).
      • Preece PE
      • Mansel RE
      • Hughes LE
      Mastalgia: psychoneurosis or organic disease?.
      Subsequent studies have identified increased anxiety
      • Ramirez AJ
      • Jarrett SR
      • Hamed H
      • Smith P
      • Fentiman IS
      Psychosocial adjustment of women with mastalgia.
      • Fox H
      • Walker LG
      • Heys SD
      • Ah-See AK
      • Eremin O
      Are patients with mastalgia anxious, and does relaxation therapy help?.
      • Jenkins PL
      • Jamil N
      • Gateley C
      • Mansel RE
      Psychiatric illness in patients with severe treatment-resistant mastalgia.
      and depression
      • Ramirez AJ
      • Jarrett SR
      • Hamed H
      • Smith P
      • Fentiman IS
      Psychosocial adjustment of women with mastalgia.
      • Jenkins PL
      • Jamil N
      • Gateley C
      • Mansel RE
      Psychiatric illness in patients with severe treatment-resistant mastalgia.
      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.
      • Ramirez AJ
      • Jarrett SR
      • Hamed H
      • Smith P
      • Fentiman IS
      Psychosocial adjustment of women with mastalgia.
      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.
      • Colegrave S
      • Holcombe C
      • Salmon P
      Psychological characteristics of women presenting with breast pain.
      Breast pain was noted to be distinct from other conditions with persistent pain because rates of physical and sexual abuse were relatively low.
      • Colegrave S
      • Holcombe C
      • Salmon P
      Psychological characteristics of women presenting with breast pain.
      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.
      • Downey HM
      • Deadman JM
      • Davis C
      • Leinster SJ
      Psychological characteristics of women with cyclical mastalgia.
      Perceived stress was also associated with cyclic mastalgia in a population-based study.
      • Ader DN
      • South-Paul J
      • Adera T
      • Deuster PA
      Cyclical mastalgia: prevalence and associated health and behavioral factors.
      The extent to which psychological distress has a causal or consequential relationship to breast pain is unclear; however, substantial improvements in depression and social impairment were noted in women whose pain was treated successfully.
      • Ramirez AJ
      • Jarrett SR
      • Hamed H
      • Smith P
      • Fentiman IS
      Psychosocial adjustment of women with mastalgia.

      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.
      • Klock SC
      Psychological aspects of women's reproductive health.
      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.
      • Goodwin PJ
      • Miller A
      • Del Giudice ME
      • Ritchie K
      Breast health and associated premenstrual symptoms in women with severe cyclic mastopathy.
      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.
      • Tavaf-Motamen H
      • Ader DN
      • Browne MW
      • Shriver CD
      Clinical evaluation of mastalgia.
      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.
      • Ader DN
      • Shriver CD
      • Browne MW
      Cyclical mastalgia: premenstrual syndrome or recurrent pain disorder?.
      Figure thumbnail gr1
      Figure 1Timeline 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,
      • Tavaf-Motamen H
      • Ader DN
      • Browne MW
      • Shriver CD
      Clinical evaluation of mastalgia.
      with permission. Copyrighted 1998, American Medical Association.

      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.
      • Goodwin PJ
      • DeBoer G
      • Clark RM
      • et al.
      Cyclical mastopathy and premenopausal breast cancer risk: results of a case-control study.
      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.
      • Plu-Bureau G
      • Thalabard JC
      • Sitruk-Ware R
      • Asselain B
      • Mauvais-Jarvis P
      Cyclical mastalgia as a marker of breast cancer susceptibility: results of a case-control study among French women.
      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.
      • Goodwin PJ
      • DeBoer G
      • Clark RM
      • et al.
      Cyclical mastopathy and premenopausal breast cancer risk: results of a case-control study.
      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.
      • Davies EL
      • Gateley CA
      • Miers M
      • Mansel RE
      The long-term course of mastalgia.

      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.
      • Mansel RE
      ABC of breast disease: breast pain.
      • BeLieu RM
      Mastodynia.
      Adjectives patients use to describe the pain are “drawing,” “burning,” “achy,” and “sore.”
      • Mansel RE
      ABC of breast disease: breast pain.
      • BeLieu RM
      Mastodynia.
      Typically, noncyclic mastalgia presents at a later age; most women are in the fourth or fifth decade of life at diagnosis.
      • Mansel RE
      ABC of breast disease: breast pain.
      • BeLieu RM
      Mastodynia.
      • Klimberg VS
      Etiology and management of breast pain.
      • Davies EL
      • Gateley CA
      • Miers M
      • Mansel RE
      The long-term course of mastalgia.
      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).
      Table 2Medications Associated With Breast Pain in Women
      Information obtained from MEDLINE, MICROMEDEX, and discussion with breast specialists and pharmacists.
      • 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
          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.
        • Doxepin
          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.
        • Haloperidol (and other antipsychotic agents)
      • Antihypertensive and cardiac medications
        • Spironolactone
          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.
        • Methyldopa
        • Minoxidil
        • Digoxin
          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.
        • Reserpine
          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.
      • Antimicrobial agents
        • Ketoconazole
          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.
        • Metronidazole
          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.
      • Miscellaneous agents
        • Cimetidine
          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.
        • Cyclosporine
        • Domperidone
        • Penicillamine
        • Methadone
          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.
        • 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.
      Approximately 16% and 32% of women report breast pain as an adverse effect of estrogen and combined hormonal therapies, respectively.
      • Davies GC
      • Huster WJ
      • Lu Y
      • Plouffe Jr, L
      • Lakshmanan M
      Adverse events reported by postmenopausal women in controlled trials with raloxifene.
      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).
      • McNicholas MM
      • Heneghan JP
      • Milner MH
      • Tunney T
      • Hourihane JB
      • MacErlaine DP
      Pain and increased mammographic density in women receiving hormone replacement therapy: a prospective study.
      Other researchers have identified increased breast density during hormonal therapy
      • Lundstrom E
      • Wilczek B
      • von Palffy Z
      • Soderqvist G
      • von Schoultz B
      Mammographic breast density during hormone replacement therapy: differences according to treatment.
      ; 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.
      • Davies GC
      • Huster WJ
      • Lu Y
      • Plouffe Jr, L
      • Lakshmanan M
      Adverse events reported by postmenopausal women in controlled trials with raloxifene.
      • Colacurci N
      • Mele D
      • De Franciscis P
      • Costa V
      • Fortunato N
      • De Seta L
      Effects of tibolone on the breast.
      The frequency of breast pain associated with raloxifene is not different from placebo in postmenopausal women.
      • Davies GC
      • Huster WJ
      • Lu Y
      • Plouffe Jr, L
      • Lakshmanan M
      Adverse events reported by postmenopausal women in controlled trials with raloxifene.
      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, and 3.89 mm in women with noncyclic mastalgia (P<.001). Ductal width correlated with pain intensity.
      • Peters F
      • Diemer P
      • Mecks O
      • Behnken LJ
      Severity of mastalgia in relation to milk duct dilatation.
      This finding supports an approach taken by earlier researchers in dividing noncyclic mastalgia into subsets, one of which was ductal ectasia.
      • Preece PE
      • Mansel RE
      • Bolton PM
      • Hughes LM
      • Baum M
      • Gravelle IH
      Clinical syndromes of mastalgia.

      Relationship to Breast Cancer

      Classically, breast pain associated with cancer is unilateral, constant, and intense.
      • Conry C
      Evaluation of a breast complaint: is it cancer?.
      The occurrence of subclinical breast cancer in women with focal, noncyclic breast pain who present to breast or oncology clinics has been studied (Table 3
      • Barton MB
      • Elmore JG
      • Fletcher SW
      Breast symptoms among women enrolled in a health maintenance organization: frequency, evaluation, and outcome.
      • Preece PE
      • Baum M
      • Mansel RE
      • et al.
      Importance of mastalgia in operable breast cancer.
      • Smallwood JA
      • Kye DA
      • Taylor I
      Mastalgia: is this commonly associated with operable breast cancer?.
      • Fariselli G
      • Lepera P
      • Viganotti G
      • Martelli G
      • Bandieramonte G
      • Di Pietro S
      Localized mastalgia as presenting symptom in breast cancer.
      • Lumachi F
      • Ermani M
      • Brandes AA
      • et al.
      Breast complaints and risk of breast cancer: population-based study of 2,879 self-selected women and long-term follow-up.
      ). In these studies, breast cancer was found in 2% to 7% of patients presenting with pain as the primary symptom.
      • Preece PE
      • Baum M
      • Mansel RE
      • et al.
      Importance of mastalgia in operable breast cancer.
      • Smallwood JA
      • Kye DA
      • Taylor I
      Mastalgia: is this commonly associated with operable breast cancer?.
      • Fariselli G
      • Lepera P
      • Viganotti G
      • Martelli G
      • Bandieramonte G
      • Di Pietro S
      Localized mastalgia as presenting symptom in breast cancer.
      • Lumachi F
      • Ermani M
      • Brandes AA
      • et al.
      Breast complaints and risk of breast cancer: population-based study of 2,879 self-selected women and long-term follow-up.
      • Benson EA
      Mastalgia: is this commonly associated with operable breast cancer [letter].
      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.
      • Khan SA
      • Apkarian AV
      Mastalgia and breast cancer: a protective association? [published correction appears in Cancer Detect Prev. 2003;27:82].
      In a recent case-control study of women referred for diagnostic breast imaging to evaluate 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.
      • Duijm LE
      • Guit GL
      • Hendriks JH
      • Zaat JO
      • Mali WP
      Value of breast imaging in women with painful breasts: observational follow up study.
      Table 3Frequency of Cancer in Patients Presenting With Breast Pain
      StudyNo. of patients with breast painNo. (%) of patients with breast cancerComments
      Preece et al,
      • Preece PE
      • Baum M
      • Mansel RE
      • et al.
      Importance of mastalgia in operable breast cancer.
      1982
      53636 (6.7)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
      Smallwood et al,
      • Smallwood JA
      • Kye DA
      • Taylor I
      Mastalgia: is this commonly associated with operable breast cancer?.
      1986
      2098 (3.8)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
      Fariselli et al,
      • Fariselli G
      • Lepera P
      • Viganotti G
      • Martelli G
      • Bandieramonte G
      • Di Pietro S
      Localized mastalgia as presenting symptom in breast cancer.
      1988
      2205 (2.3)In a review of 220 patients presenting to an oncology clinic, focal breast pain was the only symptom
      Barton et al,
      • Barton MB
      • Elmore JG
      • Fletcher SW
      Breast symptoms among women enrolled in a health maintenance organization: frequency, evaluation, and outcome.
      1999
      1692 (1.2)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%
      Lumachi et al,
      • Lumachi F
      • Ermani M
      • Brandes AA
      • et al.
      Breast complaints and risk of breast cancer: population-based study of 2,879 self-selected women and long-term follow-up.
      2002
      114136 (3.2)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)

      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.
      • Wallace MS
      • Wallace AM
      • Lee J
      • Dobke MK
      Pain after breast surgery: a survey of 282 women.
      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.
      • Wallace MS
      • Wallace AM
      • Lee J
      • Dobke MK
      Pain after breast surgery: a survey of 282 women.
      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.
      • Wallace MS
      • Wallace AM
      • Lee J
      • Dobke MK
      Pain after breast surgery: a survey of 282 women.
      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.
      • Kwekkeboom K
      Postmastectomy pain syndromes.
      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.
      • Kroner K
      • Krebs B
      • Skov J
      • Jorgensen HS
      Immediate and long-term phantom breast syndrome after mastectomy: incidence, clinical characteristics and relationship to pre-mastectomy breast pain.
      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.
      • Kwekkeboom K
      Postmastectomy pain syndromes.
      • Kroner K
      • Krebs B
      • Skov J
      • Jorgensen HS
      Immediate and long-term phantom breast syndrome after mastectomy: incidence, clinical characteristics and relationship to pre-mastectomy breast pain.

      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.
      • Maddox PR
      • Mansel RE
      Management of breast pain and nodularity.
      • BeLieu RM
      Mastodynia.
      • Maddox PR
      • Harrison BJ
      • Mansel RE
      • Hughes LE
      Non-cyclical mastalgia: an improved classification and treatment.
      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.
      Table 4Differential 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)
      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.
      • Fam AG
      Approach to musculoskeletal chest wall pain.
      • Wise CM
      Chest wall syndromes [editorial].
      • Gregory PL
      • Biswas AC
      • Batt ME
      Musculoskeletal problems of the chest wall in athletes.
      • Disla E
      • Rhim HR
      • Reddy A
      • Karten I
      • Taranta A
      Costochondritis: a prospective analysis in an emergency department setting.
      The absence of a clear precipitating event increases the patient's concern regarding a sinister or malignant cause.
      • Fam AG
      Approach to musculoskeletal chest wall pain.
      An estimated 12% to 30% of patients evaluated in emergency departments for suspected cardiac chest pain have pain due to a musculoskeletal syndrome.
      • Wise CM
      Chest wall syndromes [editorial].
      • Disla E
      • Rhim HR
      • Reddy A
      • Karten I
      • Taranta A
      Costochondritis: a prospective analysis in an emergency department setting.
      Similarly, chest wall pain frequently accounts for the symptom of breast pain.
      • Mansel RE
      ABC of breast disease: breast pain.
      • Maddox PR
      • Mansel RE
      Management of breast pain and nodularity.
      • BeLieu RM
      Mastodynia.
      • Dixon JM
      Managing breast pain.
      • Steinbrunn BS
      • Zera RT
      • Rodriguez JL
      Mastalgia: tailoring treatment to type of breast pain.
      • Goodwin PJ
      • Miller A
      • Del Giudice ME
      • Ritchie K
      Breast health and associated premenstrual symptoms in women with severe cyclic mastopathy.
      • Maddox PR
      • Harrison BJ
      • Mansel RE
      • Hughes LE
      Non-cyclical mastalgia: an improved classification and treatment.
      Costochondritis is characterized by pain and tenderness of the costochondral or chondrosternal joints, with involvement of the second through fifth costal cartilages.
      • Fam AG
      Approach to musculoskeletal chest wall pain.
      • Wise CM
      Chest wall syndromes [editorial].
      • Gregory PL
      • Biswas AC
      • Batt ME
      Musculoskeletal problems of the chest wall in athletes.
      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.
      • Fam AG
      Approach to musculoskeletal chest wall pain.
      • Wise CM
      Chest wall syndromes [editorial].
      • Gregory PL
      • Biswas AC
      • Batt ME
      Musculoskeletal problems of the chest wall in athletes.
      Management of these conditions involves rest, nonsteroidal anti-inflammatory agents, and reassurance.
      • Fam AG
      Approach to musculoskeletal chest wall pain.
      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.
      • Mansel RE
      ABC of breast disease: breast pain.
      • Peters F
      • Diemer P
      • Mecks O
      • Behnken LJ
      Severity of mastalgia in relation to milk duct dilatation.
      • Fam AG
      Approach to musculoskeletal chest wall pain.
      • Gregory PL
      • Biswas AC
      • Batt ME
      Musculoskeletal problems of the chest wall in athletes.
      Although symptoms tend to recur, most individuals improve within 1 year.
      • Gregory PL
      • Biswas AC
      • Batt ME
      Musculoskeletal problems of the chest wall in athletes.
      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 patient's 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 patient's 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 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.
      • Dixon JM
      Managing breast pain.
      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.
      • Preece PE
      • Baum M
      • Mansel RE
      • et al.
      Importance of mastalgia in operable breast cancer.
      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%).
      • Duijm LE
      • Guit GL
      • Hendriks JH
      • Zaat JO
      • Mali WP
      Value of breast imaging in women with painful breasts: observational follow up study.
      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.
      • Morrow M
      The evaluation of common breast problems.
      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.
      • Conry C
      Evaluation of a breast complaint: is it cancer?.
      • Leung JW
      • Kornguth PJ
      • Gotway MB
      Utility of targeted sonography in the evaluation of focal breast pain.
      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.
      • Leung JW
      • Kornguth PJ
      • Gotway MB
      Utility of targeted sonography in the evaluation of focal breast pain.
      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.
      • Morrow M
      The evaluation of common breast problems.
      • Gateley CA
      • Miers M
      • Mansel RE
      • Hughes LE
      Drug treatments for mastalgia: 17 years experience in the Cardiff Mastalgia Clinic.
      Breast pain: mastalgia is common but often manageable.
      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.
      • Tavaf-Motamen H
      • Ader DN
      • Browne MW
      • Shriver CD
      Clinical evaluation of mastalgia.
      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-of-life questions.
      • Khan SA
      • Apkarian AV
      The characteristics of cyclical and non-cyclical mastalgia: a prospective study using a modified McGill Pain Questionnaire.
      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 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.
      • BeLieu RM
      Mastodynia.
      Breast pain: mastalgia is common but often manageable.
      • Preece PE
      • Richards AR
      • Owen GM
      • Hughes LE
      Mastalgia and total body water.
      • Leung JW
      • Kornguth PJ
      • Gotway MB
      Utility of targeted sonography in the evaluation of focal breast pain.
      • Fentiman IS
      • Caleffi M
      • Hamed H
      • Chaudary MA
      Dosage and duration of tamoxifen treatment for mastalgia: a controlled trial.
      • Fentiman IS
      Management of breast pain.
      • Millett AV
      • Dirbas FM
      Clinical management of breast pain: a review.
      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.
      • Klimberg VS
      Etiology and management of breast pain.
      • Jenkins PL
      • Jamil N
      • Gateley C
      • Mansel RE
      Psychiatric illness in patients with severe treatment-resistant mastalgia.
      • Preece PE
      • Baum M
      • Mansel RE
      • et al.
      Importance of mastalgia in operable breast cancer.
      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.
      • Klimberg VS
      Etiology and management of breast pain.
      • Millett AV
      • Dirbas FM
      Clinical management of breast pain: a review.
      Approximately 10% to 22% experience more severe pain and elect treatment to improve or relieve symptoms.
      • Maddox PR
      • Mansel RE
      Management of breast pain and nodularity.
      • Dixon JM
      Managing breast pain.
      • Gateley CA
      • Mansel RE
      Management of cyclical breast pain.
      Breast pain: mastalgia is common but often manageable.
      • Fentiman IS
      • Caleffi M
      • Hamed H
      • Chaudary MA
      Dosage and duration of tamoxifen treatment for mastalgia: a controlled trial.
      There is overlap between the initial therapeutic approaches for patients with cyclic and noncyclic mastalgia; however, response to intervention varies.
      • Millett AV
      • Dirbas FM
      Clinical management of breast pain: a review.
      Hormonally active medications are more effective for patients with cyclic mastalgia and are indicated only for patients with severe, prolonged symptoms.
      • Maddox PR
      • Mansel RE
      Management of breast pain and nodularity.
      • BeLieu RM
      Mastodynia.
      • Dixon JM
      Managing breast pain.
      • Klimberg VS
      Etiology and management of breast pain.
      • Faiz O
      • Fentiman IS
      Management of breast pain.
      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. Additionally, the definition of a therapeutic response differs between studies, and there is a placebo effect of at least 20% (range, 10%-40%).
      • Maddox PR
      • Mansel RE
      Management of breast pain and nodularity.
      • Gateley CA
      • Mansel RE
      Management of cyclical breast pain.
      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.
      • Maddox PR
      • Mansel RE
      Management of breast pain and nodularity.
      • BeLieu RM
      Mastodynia.
      • Ashley B
      Mastalgia.
      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.
      • BeLieu RM
      Mastodynia.
      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,
      • Mansel RE
      ABC of breast disease: breast pain.
      • BeLieu RM
      Mastodynia.
      • Dixon JM
      Managing breast pain.
      • Fentiman IS
      Management of breast pain.
      • Millett AV
      • Dirbas FM
      Clinical management of breast pain: a review.
      • Ashley B
      Mastalgia.
      • O'Grady LF
      The painful breast.
      • Vaidyanathan L
      • Barnard K
      • Elnicki DM
      Benign breast disease: when to treat, when to reassure, when to refer.
      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.
      • Wilson MC
      • Sellwood RA
      Therapeutic value of a supporting brassiere in mastodynia.
      Breast pain during exercise may occur in as many as 56% of women and is attributed to movement of breast tissue.
      • Mason BR
      • Page KA
      • Fallon K
      An analysis of movement and discomfort of the female breast during exercise and the effects of breast support in three cases.
      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.
      • Mason BR
      • Page KA
      • Fallon K
      An analysis of movement and discomfort of the female breast during exercise and the effects of breast support in three cases.
      Currently available sports bras were also analyzed with a view to improving design and performance.
      • Page KA
      • Steele JR
      Breast motion and sports brassiere design: implications for future research.
      Although there are numerous limitations in these uncontrolled studies, they lend credence 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, 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 pain
      • Proctor DS
      Ultrasound therapy in the treatment of persistent breast pain [letter].
      (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.
      • Fox H
      • Walker LG
      • Heys SD
      • Ah-See AK
      • Eremin O
      Are patients with mastalgia anxious, and does relaxation therapy help?.
      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.
      • Fox H
      • Walker LG
      • Heys SD
      • Ah-See AK
      • Eremin O
      Are patients with mastalgia anxious, and does relaxation therapy help?.
      Dietary Change, Methylxanthine Restriction, and Nutritional Supplements. Dietary Fat.—The effectiveness of dietary interventions to reduce breast pain remains to be established
      • Horner NK
      • Lampe JW
      Potential mechanisms of diet therapy for fibrocystic breast conditions show inadequate evidence of effectiveness.
      ; 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.
      • Boyd NF
      • McGuire V
      • Shannon P
      • et al.
      Effect of a low-fat high-carbohydrate diet on symptoms of cyclical mastopathy.
      Lower dietary fat intake also has been associated with less severe mastalgia symptoms in a case-control study
      • Goodwin PJ
      • Miller A
      • Del Giudice ME
      • Singer W
      • Connelly P
      • Ritchie JW
      Elevated high-density lipoprotein cholesterol and dietary fat intake in women with cyclic mastopathy.
      and in a prospective uncontrolled study.
      • Rose DP
      • Boyar A
      • Haley N
      • Cohen C
      • Lahti H
      • Strong LE
      Low fat diet in fibrocystic disease of the breast with cyclical mastalgia: a feasibility study [abstract].
      Other parameters that may be related to mastalgia are altered by reducing dietary fat, including circulating estrogen (estradiol, estrone) levels
      • Boyd NF
      • McGuire V
      • Shannon P
      • et al.
      Effect of a low-fat high-carbohydrate diet on symptoms of cyclical mastopathy.
      • Prentice R
      • Thompson D
      • Clifford C
      • Gorbach S
      • Goldin B
      • Byar D
      • Women's Health Trial Study Group
      Dietary fat reduction and plasma estradiol concentration in healthy postmenopausal women.
      • Boyar AP
      • Rose DP
      • Wynder EL
      Recommendations for the prevention of chronic disease: the application for breast disease.
      • Rose DP
      • Boyar AP
      • Cohen C
      • Strong LE
      Effect of a low-fat diet on hormone levels in women with cystic breast disease, I: serum steroids and gonadotropins.
      and mammographic breast density.
      • Boyd NF
      • Greenberg C
      • Lockwood G
      • Canadian Diet and Breast Cancer Prevention Study Group
      • et al.
      Effects at two years of a low-fat, high-carbohydrate diet on radiologic features of the breast: results from a randomized trial.
      The effect of decreased dietary fat intake on other fibrocystic changes of the breast is limited.
      • Horner NK
      • Lampe JW
      Potential mechanisms of diet therapy for fibrocystic breast conditions show inadequate evidence of effectiveness.
      To derive benefit from this approach, women must decrease fat intake to less than 20% of total daily caloric intake.
      • Rose DP
      • Boyar A
      • Haley N
      • Cohen C
      • Lahti H
      • Strong LE
      Low fat diet in fibrocystic disease of the breast with cyclical mastalgia: a feasibility study [abstract].
      • Boyar AP
      • Rose DP
      • Wynder EL
      Recommendations for the prevention of chronic disease: the application for breast disease.
      This diet may be difficult to sustain and may not be optimal in some women.
      • Hu FB
      • Willett WC
      Optimal diets for prevention of coronary heart disease.
      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.
      • Fentiman IS
      Management of breast pain.
      However, most 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.
      • Levinson W
      • Dunn PM
      Nonassociation of caffeine and fibrocystic breast disease.
      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.
      • Minton JP
      • Abou-Issa H
      • Reiches N
      • Roseman JM
      Clinical and biochemical studies on methylxanthine-related fibrocystic breast disease.
      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.
      • Ernster VL
      • Mason L
      • Goodson WH
      • et al.
      Effects of caffeine-free diet on benign breast disease: a randomized trial.
      An association between methylxanthines (caffeine or theophylline) and breast symptoms of pain, tenderness, nodularity,
      • Ader DN
      • South-Paul J
      • Adera T
      • Deuster PA
      Cyclical mastalgia: prevalence and associated health and behavioral factors.
      • Hindi-Alexander MC
      • Zielezny MA
      • Montes N
      • et al.
      Theophylline and fibrocystic breast disease.
      • Brooks PG
      • Gart S
      • Heldfond AJ
      • Margolin ML
      • Allen AS
      Measuring the effect of caffeine restriction on fibrocystic breast disease: the role of graphic stress telethermometry as an objective monitor of disease.
      and fibrocystic histology
      • La Vecchia C
      • Franceschi S
      • Parazzini F
      • et al.
      Benign breast disease and consumption of beverages containing methylxanthines.
      • Boyle CA
      • Berkowitz GS
      • LiVolsi VA
      • et al.
      Caffeine consumption and fibrocystic breast disease: a case-control epidemiologic study.
      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.
      • Allen SS
      • Froberg DG
      The effect of decreased caffeine consumption on benign proliferative breast disease: a randomized clinical trial.
      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.
      • Lubin R
      • Ron E
      • Wax Y
      • Black M
      • Funaro M
      • Shitrit A
      A case-control study of caffeine and methylxanthines in benign breast disease.
      • Marshall J
      • Graham S
      • Swanson M
      Caffeine consumption and benign breast disease: a case-control comparison.
      • Lawson DH
      • Jick H
      • Rothman KJ
      Coffee and tea consumption and breast disease.
      • Parazzini F
      • La Vecchia C
      • Riundi R
      • Pampallona S
      • Regallo M
      • Scanni A
      Methylxanthine, alcohol-free diet and fibrocystic breast disease: a factorial clinical trial.
      The nonendocrine mechanism by which methylxanthines are believed to influence fibrocystic change in the breast relates to their mediation of elevated 3',5'-cyclic adenosine monophosphate (cAMP) in fibrocystic tissue specimens and circulating catecholamines.
      • Minton JP
      • Abou-Issa H
      Nonendocrine theories of the etiology of benign breast disease.
      High caffeine intake also may be associated with altered hormone levels in postmenopausal women, with increased plasma estrone, sex hormone-binding globulin, and decreased testosterone.
      • Ferrini RL
      • Barrett-Connor E
      Caffeine intake and endogenous sex steroid levels in postmenopausal women: the Rancho Bernardo Study.
      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,
      • Ader DN
      • South-Paul J
      • Adera T
      • Deuster PA
      Cyclical mastalgia: prevalence and associated health and behavioral factors.
      • Minton JP
      • Abou-Issa H
      • Reiches N
      • Roseman JM
      Clinical and biochemical studies on methylxanthine-related fibrocystic breast disease.
      • Ernster VL
      • Mason L
      • Goodson WH
      • et al.
      Effects of caffeine-free diet on benign breast disease: a randomized trial.
      • Hindi-Alexander MC
      • Zielezny MA
      • Montes N
      • et al.
      Theophylline and fibrocystic breast disease.
      • Brooks PG
      • Gart S
      • Heldfond AJ
      • Margolin ML
      • Allen AS
      Measuring the effect of caffeine restriction on fibrocystic breast disease: the role of graphic stress telethermometry as an objective monitor of disease.
      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.
      • Pye JK
      • Mansel RE
      • Hughes LE
      Clinical experience of drug treatments for mastalgia.
      • Renwick S
      Modern management of benign mammary dysplasia.
      • Smallwood J
      • Ah-Kye D
      • Taylor I
      Vitamin B6 in the treatment of pre-menstrual mastalgia.
      • Santamaria LA
      • Santamaria AB
      Cancer chemoprevention by supplemental carotenoids and synergism with retinol in mastodynia treatment.
      • Abrams AA
      Use of vitamin E in chronic cystic mastitis [letter].
      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 (α-tocopherol) in fibrocystic breast disease.
      • Abrams AA
      Use of vitamin E in chronic cystic mastitis [letter].
      • Solomon D
      • Strummer D
      • Nair PP
      Relationship between vitamin E and urinary excretion of ketosteroid fractions in cystic mastitis.
      • Sundaram GS
      • London R
      • Manimekalai S
      • Nair PP
      • Goldstein P
      Alpha-tocopherol and serum lipoproteins.
      Proposed mechanisms include its potential to alter steroidal hormone production (dehydroepiandrosterone or progesterone), to correct abnormal serum cholesterol-lipoprotein distribution, and to function as an antioxidant.
      • Solomon D
      • Strummer D
      • Nair PP
      Relationship between vitamin E and urinary excretion of ketosteroid fractions in cystic mastitis.
      • Sundaram GS
      • London R
      • Manimekalai S
      • Nair PP
      • Goldstein P
      Alpha-tocopherol and serum lipoproteins.
      • Ernster VL
      • Goodson III, WH
      • Hunt TK
      • Petrakis NL
      • Sickles EA
      • Miike R
      Vitamin E and benign breast “disease”: a double-blind, randomized clinical trial.
      • Meyer EC
      • Sommers DK
      • Reitz CJ
      • Mentis H
      Vitamin E and benign breast disease.
      • London RS
      • Sundaram GS
      • Murphy L
      • Manimekalai S
      • Reynolds M
      • Goldstein PJ
      The effect of vitamin E on mammary dysplasia: a double-blind study.
      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.
      • Ernster VL
      • Goodson III, WH
      • Hunt TK
      • Petrakis NL
      • Sickles EA
      • Miike R
      Vitamin E and benign breast “disease”: a double-blind, randomized clinical trial.
      • Meyer EC
      • Sommers DK
      • Reitz CJ
      • Mentis H
      Vitamin E and benign breast disease.
      Additionally, mean serum concentrations of estradiol, progesterone, testosterone, and dehydroepiandrosterone did not differ between vitamin E- and placebotreated women.
      • London RS
      • Sundaram GS
      • Murphy L
      • Manimekalai S
      • Reynolds M
      • Goldstein PJ
      The effect of vitamin E on mammary dysplasia: a double-blind study.
      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.
      • Renwick S
      Modern management of benign mammary dysplasia.
      • Smallwood J
      • Ah-Kye D
      • Taylor I
      Vitamin B6 in the treatment of pre-menstrual mastalgia.
      At this time, evidence is insufficient to support routine use of vitamins for breast pain.
      • Pye JK
      • Mansel RE
      • Hughes LE
      Clinical experience of drug treatments for mastalgia.
      • Goodwin PJ
      • Neelam M
      • Boyd NF
      Cyclical mastopathy: a critical review of therapy.
      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.
      • Mansel RE
      ABC of breast disease: breast pain.
      • Maddox PR
      • Mansel RE
      Management of breast pain and nodularity.
      • BeLieu RM
      Mastodynia.
      • Dixon JM
      Managing breast pain.
      • Morrow M
      The evaluation of common breast problems.
      • Klimberg VS
      Etiology and management of breast pain.
      • Gateley CA
      • Mansel RE
      Management of cyclical breast pain.
      • Steinbrunn BS
      • Zera RT
      • Rodriguez JL
      Mastalgia: tailoring treatment to type of breast pain.
      • McFayden IJ
      • Forrest AP
      • Chetty U
      • Raab G
      Cyclical breast pain—some observations and the difficulties in treatment.
      • Pye JK
      • Mansel RE
      • Hughes LE
      Clinical experience of drug treatments for mastalgia.
      • Goodwin PJ
      • Neelam M
      • Boyd NF
      Cyclical mastopathy: a critical review of therapy.
      • Fentiman IS
      Mastalgia mostly merits masterly inactivity [editorial].
      • Holland PA
      • Gateley CA
      Drug therapy for mastalgia: what are the options?.
      • Norlock FE
      Benign breast pain in women: a practical approach to evaluation and treatment.
      Two small randomized, double-blind, placebo-controlled studies of evening primrose oil have shown efficacy in the treatment of breast pain.
      • Pashby NL
      • Mansel RE
      • Hughes LE
      • Hanslip J
      • Preece PE
      A clinical trial of evening primrose oil in mastalgia [abstract].
      • Preece PE
      • Hanslip JI
      • Gilbert L
      • et al.
      Evening primrose oil (efamol) for mastalgia.
      Also, several researchers have reported favorable response and adverse effect rates for evening primrose oil from sequential uncontrolled studies and clinical series.
      • Gateley CA
      • Miers M
      • Mansel RE
      • Hughes LE
      Drug treatments for mastalgia: 17 years experience in the Cardiff Mastalgia Clinic.
      • McFayden IJ
      • Forrest AP
      • Chetty U
      • Raab G
      Cyclical breast pain—some observations and the difficulties in treatment.
      • Pye JK
      • Mansel RE
      • Hughes LE
      Clinical experience of drug treatments for mastalgia.
      • Wetzig NR
      Mastalgia: a 3 year Australian study.
      • Cheung KL
      Management of cyclical mastalgia in oriental women: pioneer experience of using gamolenic acid (Efamast) in Asia.
      A recent trial
      • Blommers J
      • de Lange-De Klerk ES
      • Kuik DJ
      • Bezemer PD
      • Meijer S
      Evening primrose oil and fish oil for severe chronic mastalgia: a randomized, double-blind, controlled trial.
      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.
      • Blommers J
      • de Lange-De Klerk ES
      • Kuik DJ
      • Bezemer PD
      • Meijer S
      Evening primrose oil and fish oil for severe chronic mastalgia: a randomized, double-blind, controlled trial.
      Thus, results of studies and clinical series assessing evening primrose oil in the treatment of mastalgia are conflicting (Table 5). Evening primrose oil also has shown variable effectiveness for cyclic breast symptoms in studies of women with premenstrual syndrome.
      • Campbell EM
      • Peterkin D
      • O'Grady K
      • Sanson-Fisher R
      Premenstrual symptoms in general practice patients: prevalence and treatment.
      • Hardy ML
      Herbs of special interest to women.
      • Khoo SK
      • Munro C
      • Battistutta D
      Evening primrose oil and treatment of premenstrual syndrome.
      • Brush MG
      Efamol (evening primrose oil) in the treatment of the premenstrual syndrome.
      • Puolakka J
      • Makarainen L
      • Viinikka L
      • Ylikorkala O
      Biochemical and clinical effects of treating the premenstrual syndrome with prostaglandin synthesis precursors.
      Table 5Evening Primrose Oil in Studies of Women With Mastalgia
      Study
      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
      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.
      PlaceboAdverse effectsComments
      Pain score
      BeforeAfterBeforeAfter
      Pashby et al,
      • Pashby NL
      • Mansel RE
      • Hughes LE
      • Hanslip J
      • Preece PE
      A clinical trial of evening primrose oil in mastalgia [abstract].
      1981
       Cyclic mastalgia50324542NRRandomized, double-blind, placebo-controlled
       Noncyclic mastalgia54405660crossover study (N=73) at mastalgia clinic; pain score (LAS) at 3 mo (P<.05)
      Preece et al,
      • Preece PE
      • Hanslip JI
      • Gilbert L
      • et al.
      Evening primrose oil (efamol) for mastalgia.
      1982
       Cyclic mastalgia36222432In 4% of subjects (weight gain, rash), less than in placebo groupDouble-blind, placebo-controlled, crossover study
       Noncyclic mastalgia50424244(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,
      • Pye JK
      • Mansel RE
      • Hughes LE
      Clinical experience of drug treatments for mastalgia.
      1985
       Cyclic mastalgia47/92 (51)NR (19)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
       Noncyclic mastalgia9/33 (27)NR (9)
      McFayden et al,
      • McFayden IJ
      • Forrest AP
      • Chetty U
      • Raab G
      Cyclical breast pain—some observations and the difficulties in treatment.
      1992
       Cyclic mastalgia58/99 (59)NoneIn 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
      Wetzig,
      • Wetzig NR
      Mastalgia: a 3 year Australian study.
      1994
       Combined cyclic or noncylic mastalgia10/39 (26)NoneNRRetrospective review of clinical practice at mastalgia clinic; duration of treatment not specified
      Cheung,
      • Cheung KL
      Management of cyclical mastalgia in oriental women: pioneer experience of using gamolenic acid (Efamast) in Asia.
      1999
       Cyclic mastalgiaIn 12% of subjects (acne, rash, nausea, dizziness)Prospective, uncontrolled trial in surgical clinic (Hong Kong); response at 6 mo. No placebo comparison
        Improved or resolved33/34 (97)None
        Resolved17/34 (50)
      Days with pain
      Blommers et al,
      • Blommers J
      • de Lange-De Klerk ES
      • Kuik DJ
      • Bezemer PD
      • Meijer S
      Evening primrose oil and fish oil for severe chronic mastalgia: a randomized, double-blind, controlled trial.
      2002
       Combined cyclic and noncyclic mastalgia12.3% decrease13.8% decreaseEPO 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)
      Control oils = corn or corn and wheat germ oils.
      * 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 al
      • Pashby NL
      • Mansel RE
      • Hughes LE
      • Hanslip J
      • Preece PE
      A clinical trial of evening primrose oil in mastalgia [abstract].
      ; 2000-3000 mg/d in Wetzig
      • Wetzig NR
      Mastalgia: a 3 year Australian study.
      and McFayden et al
      • McFayden IJ
      • Forrest AP
      • Chetty U
      • Raab G
      Cyclical breast pain—some observations and the difficulties in treatment.
      ; and 3000 mg/d in the other studies.
      Control oils = corn or corn and wheat germ oils.
      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.
      • Horrobin DF
      The role of essential fatty acids and prostaglandins in the premenstrual syndrome.
      • Gateley CA
      • Maddox PR
      • Pritchard GA
      • et al.
      Plasma fatty acid profiles in benign breast disorders.
      Gamma-linolenic acid is believed to restore the saturated/unsaturated fatty acid balance and decrease sensitivity to steroidal hormones.
      • Horner NK
      • Lampe JW
      Potential mechanisms of diet therapy for fibrocystic breast conditions show inadequate evidence of effectiveness.
      • Horrobin DF
      The role of essential fatty acids and prostaglandins in the premenstrual syndrome.
      • Gateley CA
      • Maddox PR
      • Pritchard GA
      • et al.
      Plasma fatty acid profiles in benign breast disorders.
      Also, low levels of the gamma-linolenic acid metabolite, dihomogamma-linolenic acid, may affect breast sensitivity to prolactin via prostaglandins.
      • Horner NK
      • Lampe JW
      Potential mechanisms of diet therapy for fibrocystic breast conditions show inadequate evidence of effectiveness.
      • Puolakka J
      • Makarainen L
      • Viinikka L
      • Ylikorkala O
      Biochemical and clinical effects of treating the premenstrual syndrome with prostaglandin synthesis precursors.
      • Horrobin DF
      The role of essential fatty acids and prostaglandins in the premenstrual syndrome.
      • Gateley CA
      • Maddox PR
      • Pritchard GA
      • et al.
      Plasma fatty acid profiles in benign breast disorders.
      Some of these mechanisms relate to the effect of marked dietary fat restriction and support a role of lipid metabolism in cyclic mastalgia.
      • Goodwin PJ
      • Miller A
      • Del Giudice ME
      • Singer W
      • Connelly P
      • Ritchie JW
      Elevated high-density lipoprotein cholesterol and dietary fat intake in women with cyclic mastopathy.
      • Gateley CA
      • Maddox PR
      • Pritchard GA
      • et al.
      Plasma fatty acid profiles in benign breast disorders.
      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.
      • Cheung KL
      Management of cyclical mastalgia in oriental women: pioneer experience of using gamolenic acid (Efamast) in Asia.
      Physicians must be cognizant that herbal agents and nutritional supplements are not standardized or monitored for adulteration.
      • Miller LG
      Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions.
      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.
      • Miller LG
      Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions.
      The safety of evening primrose oil during pregnancy 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.
      • Fentiman IS
      Management of breast pain.
      • Horner NK
      • Lampe JW
      Potential mechanisms of diet therapy for fibrocystic breast conditions show inadequate evidence of effectiveness.
      • Campbell EM
      • Peterkin D
      • O'Grady K
      • Sanson-Fisher R
      Premenstrual symptoms in general practice patients: prevalence and treatment.
      • Khoo SK
      • Munro C
      • Battistutta D
      Evening primrose oil and treatment of premenstrual syndrome.
      Soy.—Soy is a rich source of the isoflavones genistein and daidzen, which exert their effect by binding to estrogen receptors (preferentially the β-receptor subtype).
      • Vincent A
      • Fitzpatrick LA
      Soy isoflavones: are they useful in menopause?.
      In premenopausal women, a diet rich in soy protein increases the duration of the follicular phase of the menstrual cycle and delays menstruation.
      • Cassidy A
      • Bingham S
      • Setchell KD
      Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women.
      Other hormonal effects may include decreased midcycle surges of luteinizing hormones and follicle-stimulating hormones
      • Cassidy A
      • Bingham S
      • Setchell KD
      Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women.
      and decreased estradiol levels.
      • Cassidy A
      • Bingham S
      • Setchell KD
      Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women.
      • Nagata C
      • Kabuto M
      • Kurisu Y
      • Shimizu H
      Decreased serum estradiol concentration associated with high dietary intake of soy products in premenopausal Japanese women.
      In a study of Japanese women, soy intake was inversely correlated with estradiol levels on days 11 and 22 of the menstrual cycle.
      • Nagata C
      • Kabuto M
      • Kurisu Y
      • Shimizu H
      Decreased serum estradiol concentration associated with high dietary intake of soy products in premenopausal Japanese women.
      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,
      • McMichael-Phillips DF
      • Harding C
      • et al.
      Effects of soy-protein supplementation on epithelial proliferation in the histologically normal human breast.
      • Petrakis NL
      • Barnes S
      • King EB
      • et al.
      Stimulatory influence of soy protein isolate on breast secretion in pre- and postmenopausal women.
      whereas others did not.
      • Hargreaves DF
      • Potten CS
      • Harding C
      • et al.
      Two-week dietary soy supplementation has an estrogenic effect on normal premenopausal breast.
      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.
      • Ferrini RL
      • Barrett-Connor E
      Caffeine intake and endogenous sex steroid levels in postmenopausal women: the Rancho Bernardo Study.
      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.
      • Loch EG
      • Selle H
      • Boblitz N
      Treatment of premenstrual syndrome with a phytopharmaceutical formulation containing Vitex agnus castus.
      Theoretical mechanisms are that Vitex agnus-castus binds to opioid, histamine, and estrogen receptors
      • Loch EG
      • Selle H
      • Boblitz N
      Treatment of premenstrual syndrome with a phytopharmaceutical formulation containing Vitex agnus castus.
      or acts via dopaminergic and prolactin-suppressant effects.
      • Wuttke W
      • Jarry H
      • Christoffel V
      • Spengler B
      • Seidlova-Wuttke D
      Chaste tree (Vitex agnus-castus)—pharmacology and clinical indications.
      Little is known about breast pain as a potential adverse effect of herbal remedies.
      • Palmer BV
      • Montgomery AC
      • Monteiro JC
      Gin Seng and mastalgia [letter].
      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.
      • Gabbrielli G
      • Binazzi P
      • Scaricabarozzi I
      • Massi GB
      Nimesulide in the treatment of mastalgia.
      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 scar-related breast pain.
      • Irving AD
      • Morrison SL
      Effectiveness of topical non-steroidal anti-inflammatory drugs in the management of breast pain.
      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.
      • Colak T
      • Ipek T
      • Kanik A
      • Ogetman Z
      • Aydin S
      Efficacy of topical nonsteroidal antiinflammatory drugs in mastalgia treatment.