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BMJ Clin Evid. 2007; 2007: 0812.
Published online 2007 April 1.
PMCID: PMC2943772

Breast pain

Nigel J Bundred, Professor in Surgical Oncology

Abstract

Introduction

Breast pain may be cyclical (worse before a period) or non-cyclical, originating from the breast or the chest wall, and occurs at some time in 70% of women. Cyclical breast pain resolves spontaneously in 20-30% of women, but tends to recur in 60% of women. Non-cyclical pain responds poorly to treatment but tends to resolve spontaneously in half of women.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments for breast pain? We searched: Medline, Embase, The Cochrane Library and other important databases up to January 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 22 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: a low-fat diet, antibiotics, bromocriptine, danazol, diuretics, evening primrose oil, gestrinone, gonadorelin analogues, hormone replacement therapy, lisuride, progestogens, pyridoxine, tamoxifen, tibolone, topical non-steroidal anti-inflammatory drugs, toremifene, and vitamin E.

Key Points

Breast pain may be cyclical (worse before a period) or non-cyclical, originating from the breast or the chest wall, and occurs at some time in 70% of women.

  • Cyclical breast pain resolves spontaneously in 20-30% of women, but tends to recur in 60% of women.
  • Non-cyclical pain responds poorly to treatment but tends to resolve spontaneously in half of women.

There is a consensus that topical NSAIDs are effective and well tolerated in relieving breast pain.

Danazol, tamoxifen, toremifene, gonadorelin analogues, and gestrinone may reduce breast pain but can all cause adverse effects.

  • Danazol can cause weight gain, deepening of the voice, menorrhagia and muscle cramps, and has androgenic effects on the fetus.
  • Tamoxifen and toremifene may increase the risk of venous thromboembolism and are not licensed for breast pain in the UK or USA.
  • Bromocriptine reduces breast pain compared with placebo, but its licence for this indication has been withdrawn in the USA because of frequent and intolerable adverse effects.
  • Breast pain may be made worse by hormone replacement therapy, which is also associated with increased risks of breast cancer, venous thromboembolism, and gall bladder disease.

Evening primrose oil has not been shown to improve breast pain and has had its licence withdrawn for this indication in the UK owing to lack of efficacy.

About this condition

Definition

Breast pain can be differentiated into cyclical mastalgia (worse before a menstrual period) or non-cyclical mastalgia (unrelated to the menstrual cycle). Cyclical pain is often bilateral, usually most severe in the upper outer quadrants of the breast, and may be referred to the medial aspect of the upper arm. Non-cyclical pain may be caused by true breast pain or chest wall pain located over the costal cartilages. Specific breast pathology and referred pain unrelated to the breasts are not included in this review.

Incidence/ Prevalence

Up to 70% of women develop breast pain in their lifetime. Of 1171 US women attending a gynaecology clinic for any reason, 69% suffered regular discomfort, which was judged as severe in 11% of women, and 36% had consulted a doctor about breast pain.

Aetiology/ Risk factors

Breast pain is most common in women aged 30-50 years.

Prognosis

Cyclical breast pain resolves spontaneously within 3 months of onset in 20-30% of women. The pain tends to relapse and remit, and up to 60% of women develop recurrent symptoms 2 years after treatment. Non-cyclical pain responds poorly to treatment but may resolve spontaneously in about 50% of women.

Aims of intervention

To reduce breast pain and improve quality of life, with minimal adverse effects.

Outcomes

Breast pain score based on the number of days of severe (score 2) or moderate (score 1) pain experienced in each menstrual cycle; visual analogue score of breast pain, heaviness, or breast tenderness; questionnaires.

Methods

BMJ Clinical Evidence search and appraisal January 2006. We searched the following databases: Medline 1966 to January 2006, Embase 1980 to January 2006, and The Cochrane Database of Systematic Reviews 2005, Issue 4. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD), Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE) clinical guidelines. Abstracts of the studies retrieved were assessed independently by two information specialists using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this chapter were: published systematic reviews and RCTs in any language, at least single blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow up required to include studies. We excluded all studies described as ‘open’, ‘open label’, or not blinded. We also did a search for cohort studies on specific harms of named interventions. In addition we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are continually added to the chapter as required. Overall, the evidence was poor, and some studies with weaker methods were included when higher quality evidence was not found, as indicated in the text. We have translated non-English language articles where necessary and have included any trials of sufficient quality. Studies were included whatever the definition of breast pain, as indicated in the text. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table
GRADE evaluation of interventions for breast pain

Glossary

Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

Notes

Premenstrual syndrome

References

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2. Ader DN, Shriver CD. Cyclical mastalgia: prevalence and impact in an outpatient breast clinic sample. J Am Coll Surg 1997;185:466–470. [PubMed]
3. Harding C, Osundeko O, Tetlow L, et al. Hormonally-regulated proteins in breast secretions are markers of target organ sensitivity. Br J Cancer 2000;2:354–360. [PMC free article] [PubMed]
4. Maddox PR, Harrison BJ, Mansel RE, et al. Non-cyclical mastalgia: improved classification and treatment. Br J Surg 1989;76:901–904. [PubMed]
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6. Colak T, Ipek T, Kanik A, et al. Efficacy of topical nonsteroidal anti-inflammatory drugs in mastalgia treatment. J Am Coll Surg 2003;196:525–530. [PubMed]
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8. Maddox PR, Harrison BJ, Mansel RE. Low-dose danazol for mastalgia. Br J Clin Pract 1989;68:43–47. [PubMed]
9. Anonymous. Danazol. In: The ABPI compendium of data sheets and summaries of product characteristics. London: Datapharm Publications, 1999–2000:1395.
10. Peters F. Multicentre study of gestinone in cyclical breast pain. Lancet 1992;339:205–208. [PubMed]
11. Parfitt K, ed. Martindale. The complete drug reference, 32nd ed. London: Pharmaceutical Press, 1999:1447–1448.
12. Mansel RE, Goyal A, Preece P, et al. European randomized, multicenter study of goserelin (Zoladex) in the management of mastalgia. Am J Obstet Gynecol 2004;191:1942–1949 [PubMed]
13. Fentiman IS, Caleffi M, Brame K, et al. Double-blind controlled trial of tamoxifen therapy for mastalgia. Lancet 1986;1:287–288. [PubMed]
14. Grio R, Cellura A, Geranio R, et al. Clinical efficacy of tamoxifen in the treatment of premenstrual mastodynia. Minerva Ginecol 1998;50:101–103. [PubMed]
15. GEMB Group. Tamoxifen therapy for cyclical mastalgia: dose randomised trial. Breast 1997;5:212–213.
16. Fentiman IS, Hamed H, Caleffi M, et al. Dosage and duration of tamoxifen treatment for mastalgia: a controlled trial. Br J Surg 1988;75:845–846. [PubMed]
17. Cuzick J, Powles T, Veronesi U, et al. Overview of the main outcomes in breast cancer prevention trials. Lancet 2003;361:296–300. [PubMed]
18. Anonymous. Nolvadex. In: The ABPI compendium of data sheets and summaries of product characteristics. London: Datapharm Publications Ltd, 1999–2000:1799.
19. Gong C, Song E, Jia W, et al. A double-blind randomized controlled trial of toremifen therapy for mastalgia. Arch Surg 2006;141:43–47. [PubMed]
20. Boyd NF, McGuire V, Shannon P, et al. Effect of a low-fat high-carbohydrate diet on symptoms of cyclical mastopathy. Lancet 1988;2:128–132. [PubMed]
21. Kaleli S, Aydin Y, Erel CT, et al. Symptomatic treatment of premenstrual mastalgia in premenopausal women with lisuride maleate: a double-blind placebo-controlled randomized study. Fertil Steril 2001;75:718–723. [PubMed]
22. Maddox PR, Harrison BJ, Horobin JM, et al. A randomised controlled trial of medroxyprogesterone acetate in mastalgia. Ann R Coll Surg Engl 1990;72:71–76. [PMC free article] [PubMed]
23. McFadyen IJ, Raab GM, Macintyre CC, et al. Progesterone cream for cyclic breast pain. BMJ 1989;298:931. [PMC free article] [PubMed]
24. Palomba S, Di Carlo C, Morelli M, et al. Effect of tibolone on breast symptoms resulting from postmenopausal hormone replacement therapy. Maturitas 2003;45:267–273. [PubMed]
25. Mansel RE, Dogliotti L. European multicentre trial of bromocriptine in cyclical mastalgia. Lancet 1990;335:190–193. [PubMed]
26. Blichert-Toft M, Anderson AN, Henrikson OB, et al. Treatment of mastalgia with bromocriptine: a double blind crossover study. BMJ 1979;1:237. [PMC free article] [PubMed]
27. Arrowsmith-Lowe T. Bromocriptine indications withdrawn. FDA Med Bull 1994;24:2.
28. Colacurci N, Mele D, De Franciscis P, et al. Effects of tibolone on the breast. Eur J Obstet Gynecol Reprod Biol 1998;80:235–238. [PubMed]
29. Goyal A, Mansel RE, on behalf of the Efamast Study Group. A randomized multicenter study of gamolenic acid (Efamast) with and without antioxidant vitamins and minerals in the management of mastalgia. Breast J 2005;11:41–47. [PubMed]
30. Blommers J, de Lange-De Klerk ES, Kuik DJ, et al. Evening primrose oil and fish oil for severe chronic mastalgia: a randomized, double-blind, controlled trial. Am J Obstet Gynecol 2002;187:1389–1394. [PubMed]
31. Preece PE, Hanslip JI, Gilbert L, et al. Evening primrose oil (Efamol) for mastalgia. In: Horrobin D, ed. Clinical uses of essential fatty acids. Montreal: Eden Press, 1982:147–154.
2007; 2007: 0812.
Published online 2007 April 1.

Topical NSAIDs

Summary

BREAST PAIN Compared with placebo: Topical NSAIDs (diclofenac) reduce breast pain compared with placebo at 6 months ( moderate-quality evidence ).

Benefits

Topical NSAIDs versus placebo:

We found one RCT (108 women with cyclical or non-cyclical breast pain), which found that topical diclofenac significantly reduced breast pain compared with placebo at 6 months (reduction in pain measured on visual analogue scale from 0 = no pain to 10 = intolerable pain; cyclical: 5.87 with diclofenac v 1.30 with placebo; P = 0.0001; non-cyclical: 6.33 with diclofenac v 1.12 with placebo; P = 0.0001; proportion of women with no pain; cyclical: 14/30 [47%] with diclofenac v 0/30 [0%] with placebo; P = 0.0001; non-cyclical: 12/24 [50%] with diclofenac v 0/24 [0%] with placebo; P = 0.0001).

Harms

The RCT did not report data on adverse effects associated with topical diclofenac or placebo.

Comment

Clinical guide:

There is a consensus that topical NSAIDs and oral paracetamol are effective and well tolerated in relieving breast pain, and they are easily available without prescription.

Substantive changes

No new evidence

2007; 2007: 0812.
Published online 2007 April 1.

Danazol

Summary

BREAST PAIN Compared with placebo: Danazol reduces cyclical breast pain after 12 months compared with placebo ( moderate-quality evidence ). ADVERSE EFFECTS Danazol is associated with weight gain, deepening of the voice, menorrhagia, and muscle cramps, and has deleterious androgenic effects in the fetus.

Benefits

Danazol versus placebo:

We found no systematic review. We found one good quality outpatient based RCT in 93 women with severe cyclical mastalgia. The RCT compared three treatments over 6 months: danazol 200 mg daily, tamoxifen 10 mg daily, and placebo. It found that significantly more women achieved greater than 50% pain relief at the end of treatment with danazol compared with placebo (21/32 [66%] with danazol v 11/29 [38%] with placebo; P < 0.01). The difference between groups remained significant 12 months after treatment (pain relief after 1 year: 12/32 [38%] with danazol v 0/29 [0%] with placebo; P < 0.001).

Harms

Adverse effects were reported in more women taking danazol than placebo. These included an increase in weight gain (10/32 [31%] with danazol v 1/29 [3%] with placebo), deepening of the voice (4/32 [13%] with danazol v 0/29 [0%] with placebo), menorrhagia (4/32 [13%] with danazol v 0/29 [0%] with placebo), and muscle cramps (3/32 [9%] with danazol v 0/29 [0%] with placebo; P values not reported).

Comment

Clinical guide:

Although we found no direct evidence, there is consensus that once a response is achieved, adverse effects can be avoided by reducing the dose of danazol to 100 mg daily and confining treatment to the 2 weeks preceding menstruation. Non-hormonal contraception is essential with danazol because danazol has deleterious androgenic effects in the fetus.

Substantive changes

No new evidence

2007; 2007: 0812.
Published online 2007 April 1.

Gestrinone

Summary

BREAST PAIN Compared with placebo: Gestrinone reduces breast pain after 3 months compared with placebo ( moderate-quality evidence ). ADVERSE EFFECTS Gestrinone is associated with greasy skin, hirsutism, acne, reduction in breast size, headache, and depression.

Benefits

Gestrinone versus placebo:

We found no systematic review. We found one double blind, outpatient based RCT (145 premenopausal women with cyclical breast pain) comparing gestrinone 2.5 mg twice weekly versus placebo. It found that gestrinone reduced breast pain significantly more than placebo after 3 months (using visual analogue score where 0 = no pain and 100 = worst pain; mean pain score reduced from 59.5 to 11.7 with gestrinone v from 58.2 to 36.7 with placebo; P < 0.0001).

Harms

Gestrinone versus placebo:

The RCT found that adverse effects were significantly more common with gestrinone compared with placebo (at least 1 adverse effect: 41% with gestrinone v 14% with placebo). Adverse effects included greasy skin or hair (13/64 [21%] with gestrinone v 2/61 [4%] with placebo), hirsutism (10/64 [16%] with gestrinone v 3/61 [5%] with placebo), acne (9/64 [15%] with gestrinone v 2/61[4%] with placebo), intermenstrual bleeding (7/64 [11%] with gestrinone v 0/61 [0%] with placebo), voice change (5/64 [8%] with gestrinone v 1/61 [2%] with placebo), reduced libido (5/64 [8%] with gestrinone v 3/61 [5%] with placebo), reduction in breast size (3/64 [5%] with gestrinone v 0/61 [0%] with placebo), headache (4/64 [7%] with gestrinone v 0/61 [0%] with placebo), depression (2/64 [4%] with gestrinone v 0/61[0%] with placebo), and tiredness (2/64 [4%] with gestrinone v 0/61 [0%] with placebo; P values not reported).

Comment

Gestrinone is a synthetic steroid, reported to have androgenic, antioestrogenic, and antiprogestogenic properties.

Clinical guide:

Gestrinone is not used for breast pain in clinical practice and is not widely available.

Substantive changes

No new evidence

2007; 2007: 0812.
Published online 2007 April 1.

Gonadorelin analogues (luteinising hormone releasing hormone analogues)

Summary

BREAST PAIN Compared with placebo: Goserelin injection reduces breast pain compared with placebo ( moderate-quality evidence ). ADVERSE EFFECTS Goserelin injection is associated with vaginal dryness, hot flushes, decreased libido, oily skin or hair, decreased breast size, and irritability.

Benefits

Gonadorelin analogues (luteinising hormone releasing hormone analogues) versus placebo:

We found one RCT (147 premenopausal women with breast pain), which found that goserelin injection significantly reduced breast pain compared with placebo at 6 months (pain measured using Cardiff breast pain chart; mean days with severe pain per cycle reduced from 17.6 to 5.9 [67% reduction from baseline] with goserelin v from 18.4 to 12.0 [35% reduction from baseline] with placebo; P = 0.0001).

Harms

Gonadorelin analogues (luteinising hormone releasing hormone analogues) versus placebo:

The RCT found that more women having goserelin injection than placebo had vaginal dryness (22% with goserelin v 13% with placebo), hot flushes (58% with goserelin v 16% with placebo), decreased libido (28% with goserelin v 7% with placebo), oily hair or skin (18% with goserelin v 9% with placebo), breast size reduction (16% with goserelin v 9% with placebo), and irritability (24% with goserelin v 17% with placebo; significance not reported for any adverse effect) compared with placebo injection. It found that the incidence of depression (16% with goserelin v 18% with placebo), tension (18% with goserelin v 20% with placebo), headache (50% with goserelin v 52% with placebo), hirsutism (4% with goserelin v 0% with placebo), acne (14% with goserelin v 11% with placebo), and ankle oedema (14% with goserelin v 22% with placebo; significance not reported for any adverse effect) was similar or reduced with goserelin, compared with placebo.

Comment

Clinical guide:

There is widespread consensus that goserelin injections should be reserved for severe refractory mastalgia. Addback tibolone or hormone replacement therapy can be used to relieve many of the adverse effects.

Substantive changes

No new evidence

2007; 2007: 0812.
Published online 2007 April 1.

Tamoxifen

Summary

BREAST PAIN Compared with placebo: Tamoxifen may be more effective than placebo at reducing breast pain ( low-quality evidence ). Compared with danazol: Tamoxifen is more likely to lead to improved pain scores over 6–12 months compared with danazol ( moderate-quality evidence ). Tamoxifen 10 mg compared with 20 mg: Lower-dose tamoxifen (10 mg) is as effective as higher-dose tamoxifen (20 mg) at reducing breast pain (moderate-quality evidence). ADVERSE EFFECTS Adverse effects of tamoxifen (hot flushes and gastrointestinal disturbances) are more likely with higher doses (20 mg) compared with lower doses (10 mg). Long-term use of tamoxifen has been associated with an increased risk of venous thromboembolism. Tamoxifen is not licensed for the treatment of mastalgia in the UK or USA.

Benefits

We found no systematic review.

Tamoxifen versus placebo:

We found three RCTs. One double blind RCT (60 premenopausal women with cyclical breast pain) compared tamoxifen 20 mg daily versus placebo. It found that significantly more women experienced pain relief (measured by visual analogue scale over 3 months) with tamoxifen compared with placebo (> 50% reduction in mean pain score: 22/31 [71%] with tamoxifen v 11/29 [38%] with placebo; P < 0.025). The second RCT (93 women) compared tamoxifen, danazol, and placebo. It found that significantly more women taking tamoxifen achieved a good outcome (> 50% reduction in mean pain score) at the end of treatment, 6 months later, and 12 months later, compared with placebo (> 50% reduction in pain score after 6 months of treatment: 23/32 [72%] with tamoxifen v 11/29 [38%] with placebo; P = 0.035). The third RCT (88 women, aged 22–44 years) found that 8 months of tamoxifen increased the proportion of women who achieved complete recovery (outcome not clearly defined) compared with placebo (40/44 [90%] with tamoxifen v 0/44 [0%] with placebo; P value not reported).

Tamoxifen versus danazol:

See benefits of danazol versus tamoxifen.

Dose response:

One RCT (301 women with cyclical breast pain for > 6 months) compared 10 mg versus 20 mg daily doses of tamoxifen from days 15 to 25 in the menstrual cycle for 3 months. It found no significant difference in pain relief (reduction of 2 points on pain score: 127/155 [82%] with tamoxifen 10 mg v 107/142 [75%] with tamoxifen 20 mg; P value reported as not significant). Another RCT (60 women) compared 10 mg versus 20 mg daily doses of tamoxifen for 3 and 6 months in cyclical and non-cyclical mastalgia. It found no significant difference between groups in the 3 month or 6 month response rates (at 3 months: 12/14 [86%] with tamoxifen 10 mg v 11/13 [85%] with tamoxifen 20 mg; at 6 months 14/15 [93%] with tamoxifen 10 mg v 13/15 [87%] with tamoxifen 20 mg; P values not reported but stated to be not significant).

Harms

Tamoxifen versus placebo:

The first two RCTs found that hot flushes and vaginal discharge were more common with tamoxifen 20 mg daily than with placebo. However, differences were not significant. The first RCT found more hot flushes (8/31 [26%] with tamoxifen v 3/29 [10%] with placebo) and vaginal discharge (5/31 [16%] with tamoxifen v 2/29 [7%] with placebo). The second RCT found higher rates of hot flushes and vaginal discharge with tamoxifen 20 mg daily compared with placebo, although the authors did not comment on whether the difference was significant (hot flushes: 8/32 [25%] with tamoxifen v 3/29 [10%] with placebo; vaginal discharge: 5/32 [16%] with tamoxifen v 2/29 [7%] with placebo, P values not reported). The third RCT did not report any significant adverse events. One meta-analysis of the four largest breast cancer prevention trials found that tamoxifen used long term at 20 mg daily was associated with an increased risk of venous thromboembolism (venous thromboembolic event: RR 1.9, 95% CI 1.4 to 2.6; P = 0.0001). See adverse effects of tamoxifen under treatment of non-metastatic breast cancer.

Dose response:

Adverse effects occurred more frequently with tamoxifen 20 mg than with tamoxifen 10 mg between days 15 and 25 of the menstrual cycle. The largest RCT found that adverse effects were reported significantly more frequently with tamoxifen 20 mg than with the tamoxifen 10 mg (94/142 [66%] with tamoxifen 20 mg v 80/155 [52%] with tamoxifen 10 mg; P = 0.01). Adverse effects were primarily hot flushes (54/142 [38%] with tamoxifen 20 mg v 33/155 [21%] with tamoxifen 10 mg; P = 0.015) and gastrointestinal disturbances (48/142 [34%] with tamoxifen 20 mg v 30/155 [19%] with tamoxifen 10 mg; P = 0.004).

Comment

Clinical guide:

Tamoxifen is not licensed for mastalgia in the UK or USA. There is consensus to limit its use to no more than 6 months at a time under expert supervision, and with appropriate non-hormonal contraception, because of the high incidence of adverse effects. There is no long term data on thromboembolic adverse effects with a dose of 10 mg given from days 10 to 25, which is the standard dose for treatment of mastalgia and lower than the dose used for breast cancer. Tamoxifen is contraindicated in pregnancy because of potential teratogenicity.

Substantive changes

No new evidence

2007; 2007: 0812.
Published online 2007 April 1.

Toremifene

Summary

BREAST PAIN Compared with placebo: Toremifene decreases breast pain compared with placebo ( moderate-quality evidence ). ADVERSE EFFECTS Toremifene has been associated with hot flushes, sweats, deep vein thrombosis, and visual disturbances, and is potentially teratogenic.

Benefits

We found one RCT which compared toremifene 30 mg daily versus placebo for three menstrual cycles in women who continued to experience moderate to severe breast pain during a placebo run-in cycle. All women recorded breast pain daily on a visual analogue scale chart, with 0 representing no pain and 10 representing the worst pain. The RCT found that more women reported a reduction of 50% or more in pain scores with toremifene compared with placebo (72/104 [69%] with toremifene v 29/91 [32%] with placebo; P < 0.001).

Harms

The RCT found that women in each group reported menses disturbances, dizziness, vaginal discharge, and nausea, with no significant difference between toremifene and placebo (all adverse effects: 53/104 [51%] with toremifene v 39/91 [43%] with placebo; P = 0.45).

Drug safety alert

MHRA issues drug safety alert on the risk of QT prolongation, which carries a risk of serious cardiac arrhythmia, associated with toremifene (03 February 09).

A drug safety alert has been issued on the risk of QT prolongation, which carries a risk of serious cardiac arrhythmia, associated with toremifene (http://www.mhra.gov.uk).

Comment

Toremifene, a metabolite of tamoxifen, is not licensed for mastalgia in the UK or USA. Although there is emerging evidence of its efficacy, there is no evidence that it is superior to tamoxifen which is a more widely used and better understood drug. Other adverse effects reported with use of toremifene include hot flushes, sweats, deep vein thrombosis, and occasional visual problems. Toremifene is potentially teratogenic and should not be used in women who are at risk of becoming pregnant.

Substantive changes

2007; 2007: 0812.
Published online 2007 April 1.

Antibiotics

Summary

We found no clinically important results about the effects of antibiotics in women with breast pain.

Benefits

We found no systematic review or good quality RCTs.

Harms

We found no RCTs.

Comment

Clinical guide:

Some clinicians have considered that the condition of mastitis or breast pain reflects infection. However, there is no infection associated with mastalgia and therefore there is no value to the use of antibiotics.

Substantive changes

No new evidence

2007; 2007: 0812.
Published online 2007 April 1.

Diet (low fat, high carbohydrate)

Summary

BREAST PAIN Advice to eat a low-fat diet, high-carbohydrate diet compared with general dietary advice: Advice to follow a low-fat, high-carbohydrate diet may reduce self-reported premenstrual breast swelling and breast tenderness at 6 months compared with general dietary advice ( low-quality evidence ).

Benefits

We found no systematic review. We found one small RCT (21 women attending a clinic in Canada with severe cyclical mastalgia for at least 5 years), which compared instruction to reduce fat content of the diet (to 15% of total calorie intake, while increasing complex carbohydrates to maintain calorie intake) versus general dietary advice (the principles for a healthy diet based on Canada's Food Guide, but the women were not counselled to modify the fat content of their diet) for 6 months. One woman in each group withdrew and was excluded from the analysis. The RCT found that, over 6 months, self reported premenstrual breast swelling and tenderness were significantly reduced in women advised to eat a low fat, high carbohydrate diet compared with those given general dietary advice (at 6 months: swelling: 5/10 [50%] with low fat diet v 9/9 [100%] with general diet; P = 0.04; tenderness: 6/10 [60%] with low fat diet v 9/9 [100%] with general diet; P = 0.0001). However, it found no significant difference between groups in the combined outcome of breast swelling, tenderness, and nodularity on physical examination at 6 months (improvement in outcome: 6/10 [60%] with low fat diet v 2/9 [22%] with general diet; P = 0.08).

Harms

The RCT reported no adverse effects.

Comment

Diets can be difficult to sustain in the long term. Caffeine use has been associated with breast pain, but there is little evidence to support caffeine restriction in the management of this problem.

Clinical guide:

Women should be advised to lower the amount of processed fat that they eat and ensure a high fibre diet, as this reduces oestrogen levels and is good general health advice.

Substantive changes

No new evidence

2007; 2007: 0812.
Published online 2007 April 1.

Diuretics

Summary

We found no clinically important results about the effects of diuretics in women with breast pain.

Benefits

We found no systematic review or RCTs of adequate quality.

Harms

We found no RCTs.

Comment

Clinical guide:

Diuretics are not indicated for the treatment of breast pain.

Substantive changes

No new evidence

2007; 2007: 0812.
Published online 2007 April 1.

Lisuride

Summary

BREAST PAIN Compared with placebo: Lisuride maleate (a dopamine agonist) may reduce breast pain over 2 months compared with placebo ( very low-quality evidence ). ADVERSE EFFECTS Dopamine agonists have been associated with pathological gambling and hypersexuality.

Benefits

Lisuride versus placebo:

One double blind RCT (60 women with premenstrual breast pain) comparing lisuride maleate 200 µg daily versus placebo over 2 months found significant improvement in visual analogue scores for pain (> 50% improvement in scores: 17/30 [57%] with lisuride maleate v 2/30 [7%] with placebo; P < 0.001). However, there were methodological flaws with this study. Allocation was carried out in blocks of 10 consecutive women. Tablet coding for active treatments and placebo differed, potentially confounding any treatment effect. Response to treatment was defined as a reduction greater than 25% from the baseline score during the first month, or greater than 50% during the second month.

Harms

Lisuride versus placebo:

During the first month of treatment, nausea was more frequently reported by women taking lisuride maleate than placebo; however, the difference was not significant (5/30 [17%] with lisuride maleate v 3/30 [10%] with placebo). The Medicines and Healthcare products Regulatory Agency has issued a warning that pathological gambling, and increased libido, including hypersexuality, may be class effects of dopamine agonists including lisuride (see Medicines and Healthcare products Regulatory Agency website).

Comment

Clinical guide:

Lisuride is not widely used, and should be used with caution in view of the safety alerts from the Medicines and Healthcare products Regulatory Agency.

Substantive changes

No new evidence

2007; 2007: 0812.
Published online 2007 April 1.

Progestogens

Summary

BREAST PAIN Compared with placebo: Progesterone cream or medroxyprogesterone acetate tablets may be no more effective than placebo at reducing breast pain ( very low-quality evidence ).

Benefits

Progestogens versus placebo:

We found two RCTs. The first RCT (crossover, 26 women) studied women with cyclical breast pain of at least 6 months' duration who had persistent symptoms after a 2 month observation period with no hormonal treatment. These women were randomly allocated to oral medroxyprogesterone acetate 20 mg tablets or placebo, given from days 10 to 26 of the menstrual cycle for 3 months, and then switched group (crossover) for the remaining 3 months. The RCT found no significant difference in the visual analogue scale for pain at the end of each phase before and after the crossover (data presented graphically). The overall withdrawal rate was 15%. The second RCT (crossover, 32 women with breast pain of at least 2 months' duration) identified women who were able to keep an updated diary with visual analogue scales of pain for 1 month, and then randomised them to daily applications of cream with progesterone 1% or placebo, from the 10th day of the cycle to the beginning of the next cycle, for 3 months. The analysis before crossover found no significant difference in pain scores between progesterone and placebo cream but numerical results were not reported and insufficient details were provided about the analysis. Withdrawals involved 7/32 (22%) women. Both RCTs had small sample sizes, significant withdrawals, and a selection phase, which may restrict the generalisability of the evidence.

Harms

The first RCT found that five women reported adverse effects while on medroxyprogesterone acetate, five while on placebo, and one with both. Symptoms were mostly vague premenstrual symptoms. No further details were reported. The second RCT did not report on harms.

Comment

Clinical guide:

Despite claims from Europe that progestogens would prevent breast pain, the randomised data do not support this, and progestogens are not indicated as treatment for the condition.

Substantive changes

Progestogens Recategorised from Unlikely to be beneficial to Unknown effectiveness.

2007; 2007: 0812.
Published online 2007 April 1.

Pyridoxine

Summary

We found no clinically important results about the effects of pyridoxine in women with breast pain.

Benefits

We found no systematic review or good quality RCTs.

Harms

We found no RCTs.

Comment

Clinical guide:

There is no evidence to support the use of pyridoxine for breast pain.

Substantive changes

No new evidence

2007; 2007: 0812.
Published online 2007 April 1.

Tibolone

Summary

BREAST PAIN Compared with calcium carbonate 'placebo': Tibolone may be no more effective than a calcium carbonate 'placebo' at reducing breast pain ( very low-quality evidence ). Compared with hormone replacement therapy: Tibolone is less likely to lead to the development or worsening of breast pain after 12 months compared with hormone replacement therapy ( moderate-quality evidence ).

Benefits

Tibolone versus placebo:

We found no systematic review or RCTs.

Tibolone versus hormone replacement therapy:

See benefits of hormone replacement therapy.

Harms

Tibolone versus placebo:

We found no RCTs.

Tibolone versus hormone replacement therapy:

See harms of hormone replacement therapy.

Drug safety alert

MHRA issues drug safety alert on the increased risk of breast cancer recurrence associated with tibolone (03 February 2009).

A drug safety alert has been issued on the increased risk of breast cancer recurrence associated with tibolone (http://www.mhra.gov.uk).

Comment

Tibolone is a synthetic steroid reported to have oestrogenic, progestogenic, and weak androgenic properties, which can be used as a form of hormone replacement therapy. See comment on hormone replacement therapy. We found one non-randomised, placebo controlled study which compared tibolone versus calcium carbonate “placebo” in 64 women with breast pain secondary to use of hormone replacement therapy, allocated to treatment according to individual women's preference. It found no significant difference in breast tenderness or breast pain at 12 months (both symptoms measured on a visual analogue scale from 0 = no symptoms to 10 = greatest severity; mean breast tenderness score: from 7.9 at baseline to 4.1 at 12 months with tibolone v from 7.4 at baseline to 3.8 at 12 months with calcium carbonate; P value not reported; mean mastalgia score: from 6.1 at baseline to 2.9 at 12 months with tibolone v from 5.7 at baseline to 2.7 at 12 months with calcium carbonate; P value not reported). The study found that the risk of vaginal bleeding was similar with tibolone compared with calcium carbonate in the first 2 months (6/31 [19%] with tibolone v 4/30 [13%] with placebo; P value not reported). The study reported that there were no other adverse effects.

Clinical guide:

In women with hormone replacement therapy-induced breast pain (oestrogen only or combined hormone replacement therapy), swapping to tibolone seems to be as effective as swapping to placebo in reducing breast pain, but tibolone relieves hot flushes and other menopausal symptoms, which placebo does not.

Substantive changes

No new evidence

2007; 2007: 0812.
Published online 2007 April 1.

Vitamin E

Summary

We found no clinically important results about the effects of vitamin E in women with breast pain.

Benefits

We found no systematic review or RCTs of adequate quality.

Harms

We found no RCTs.

Comment

Clinical guide:

There is no evidence that vitamin E improves breast pain.

Substantive changes

No new evidence

2007; 2007: 0812.
Published online 2007 April 1.

Bromocriptine

Summary

BREAST PAIN Compared with placebo: Bromocriptine (a dopamine agonist) may reduce breast pain compared with placebo ( very low-quality evidence ). ADVERSE EVENTS Bromocriptine is associated with nausea, dizziness, postural hypotension, and constipation. Bromocriptine is now rarely used because of frequent and intolerable adverse effects, and the US Food and Drug Administration has withdrawn its licence for this indication.

Benefits

We found no systematic review but found two RCTs. The first outpatient based, European RCT (272 premenopausal women with diffuse fibrocystic disease of the breast) compared bromocriptine 2.5 mg twice daily versus placebo. After 3 and 6 months it found that bromocriptine significantly improved symptoms compared with placebo on self assessed visual analogue scoring of breast pain, tenderness, and heaviness (results presented graphically). The results must be interpreted with care because analysis was not by intention to treat, and overall withdrawal rates were high. The second RCT (10 women) used a crossover design, and also found that bromocriptine significantly reduced pain compared with placebo (results after crossover: P < 0.02; results before crossover not reported).

Harms

The larger RCT found that adverse effects were significantly more frequent with bromocriptine than with placebo (61/135 [45%] with bromocriptine v 41/137 [30%] with placebo). It found that withdrawals related to adverse effects were more frequent in women taking bromocriptine (15/135 [11%] with bromocriptine v 8/137 [6%] with placebo). Adverse reactions included nausea (32% with bromocriptine v 13% with placebo), dizziness (12% with bromocriptine v 7% with placebo), postural hypotension, and constipation. Overall, withdrawal rates were high (withdrawals: 49/135 [36%] with bromocriptine v 36/137 [26%] with placebo). The second RCT found that nausea and dizziness occurred in 8/10 (80%) women on bromocriptine compared with 0/10 (0%) on placebo. Strokes and death have been reported after use of bromocriptine to inhibit lactation, and the US Food and Drug Administration has withdrawn its licence for this indication. The Medicines and Healthcare products Regulatory Agency has issued a warning that pathological gambling, and increased libido, including hypersexuality, may be class effects of dopamine agonists including bromocriptine (see Medicines and Healthcare products Regulatory Agency website).

Comment

Clinical guide:

Bromocriptine is now used rarely because frequent and intolerable adverse effects at the therapeutic dose outweigh the benefits for this indication.

Substantive changes

No new evidence

2007; 2007: 0812.
Published online 2007 April 1.

Danazol compared with tamoxifen

Summary

BREAST PAIN Danazol compared with tamoxifen: Danazol is less likely to improve pain scores after 6 and 12 months compared with tamoxifen ( moderate-quality evidence ).

Benefits

Danazol versus tamoxifen:

We found no systematic review. We found one good quality outpatient based RCT in 93 women with severe cyclical mastalgia. The RCT compared three treatments over 6 months: danazol 200 mg daily, tamoxifen 10 mg daily, and placebo. The RCT found that tamoxifen was more effective than danazol, both at the end of treatment (50% pain relief: 21/32 [66%] with danazol v 23/32 [72%] with tamoxifen; P < 0.001) and 12 months after treatment (50% pain relief: 12/32 [37%] with danazol v 17/32 [53%] with tamoxifen; P < 0.001).

Harms

Four women taking tamoxifen withdrew from the study owing to adverse effects of treatment, compared with three of those taking danazol. Reported adverse effects included an increase in weight (10/32 [31%] with danazol v 0/32 [0%] with tamoxifen), deepening of the voice (4/32 [13%] with danazol v 0/32 [0%] with tamoxifen), menorrhagia (4/32 [13%] with danazol v 2/32 [6%] with tamoxifen), and muscle cramps (3/32 [9%] with danazol v 0/32 [0%] with tamoxifen), hot flushes (4/32 [12%] with danazol v 8/32 [25%] with tamoxifen), and vaginal discharge (3/32 [9%] with danazol v 5/32 [16%] with tamoxifen; P values not reported).

Comment

Clinical guide:

Some clinicians now use tamoxifen 10 mg daily from days 10 to 25 of the menstrual cycle, rather than danazol, because of the lower adverse effects profile and greater efficacy. Both drugs are contraindicated in women who have had a previous venous thromboembolism.

Substantive changes

No new evidence

2007; 2007: 0812.
Published online 2007 April 1.

Hormone replacement therapy (oestrogen)

Summary

BREAT PAIN Compared with tibolone: Hormone replacement therapy increases breast pain compared with tibolone ( moderate-quality evidence ). ADVERSE EFFECTS Hormone replacement therapy is associated with an increased risk of breast cancer, venous thromboembolism, and gall bladder disease. NOTE We found no direct information about whether hormone replacement therapy is better than no active treatment for breast pain.

Benefits

Hormone replacement therapy (oestrogen) versus placebo:

We found no systematic review or RCTs examining effects of hormone replacement therapy for treating breast pain.

Hormone replacement therapy (oestrogen) versus tibolone:

One RCT (44 postmenopausal women with or without breast pain) found that hormone replacement therapy (transdermal oestrogen patches 50 µg twice weekly for 3 weeks/month, plus progestogen 5 mg/day for 12 days/month/cycle) significantly increased the risk of developing breast pain compared with tibolone 2.5 mg daily within 1 year (increase in breast pain as assessed by questionnaire: 8/15 [53%] with hormone replacement therapy v 1/17 [6%] with tibolone; P < 0.02).

Harms

See harms of hormone replacement therapy under secondary prevention of ischaemic cardiac events.

Hormone replacement therapy (oestrogen) versus tibolone:

The RCT did not report details of adverse effects.

Comment

Clinical guide:

HRT is considered to increase the risk of breast pain. In women with HRT-induced breast pain (oestrogen or combined HRT), swapping to tibolone seems to be as effective as swapping to placebo in reducing breast pain, but tibolone relieves hot flushes and other menopausal symptoms which placebo does not.

Substantive changes

No new evidence

2007; 2007: 0812.
Published online 2007 April 1.

Evening primrose oil

Summary

BREAST PAIN Compared with placebo: Evening primrose oil is no more effective than placebo at reducing frequency or severity of pain at 6 months ( moderate-quality evidence ). In the UK, the Committee for Safety of Medicines has withdrawn the prescription licence from evening primrose oil because of lack of efficacy, but it is still available to purchase without prescription.

Benefits

Evening primrose oil versus placebo:

We found three RCTs. The first RCT compared evening primrose oil plus antioxidants, evening primrose oil plus placebo antioxidants, antioxidants plus placebo evening primrose oil, and placebo antioxidants plus placebo evening primrose oil over four menstrual cycles, after which all women received open label evening primrose oil but randomisation to antioxidants or placebo antioxidants continued, for a further eight cycles. Breast pain was recorded on a diary card and a linear analogue chart. The RCT found no difference in recorded pain scores at the end of the blinded phase of the study between women taking evening primrose oil compared with placebo (555 women; mean breast pain score at end of 4th blinded cycle: 15.2 with evening primrose oil plus multivitamins v 14.9 with placebo plus multivitamins; P = 0.3). The second RCT compared four treatments in a factorial design: evening primrose oil plus placebo oil; fish oil plus placebo oil; fish oil plus evening primrose oil; and two placebo oils alone. Women recorded pain scores on a diary card, ranging from 0 = no pain to 3 = severe pain. The RCT found no significant difference between evening primrose oil and placebo in frequency or severity of pain at 6 months (120 women with a minimum of 5 days of pain each month; decrease in percentage of days with pain from baseline: 12% with evening primrose oil v 14% with placebo; P = 0.73; mean decrease in pain score from baseline: 0.06 with evening primrose oil v 0.08 with placebo; P = 0.83). The third RCT, which was of poor methodological quality, assessed 72 women receiving evening primrose oil or placebo for 3 months followed by 3 months of evening primrose oil. The RCT reported that women's recorded scores for pain, tenderness, and lumpiness improved in cyclical but not non-cyclical breast pain. However, the methodology of the RCT included post hoc revision of the inclusion criteria, subgroup analysis, exclusion of withdrawals, and the use of baseline comparisons (with the best response seen in women who were symptomatically worse at baseline), which all cast doubt on the validity of its conclusions.

Harms

The first RCT found that most adverse effects were gastrointestinal, with no significant difference in rates between the four groups (gastrointestinal adverse effects: 36/140 [25.7%] with evening primrose oil plus multivitamins v 27/137 [19.7%] with placebo plus multivitamins; respiratory: 27/140 [19.3%] with evening primrose oil plus multivitamins v 22/137 [16.1%] with placebo plus multivitamins; reproductive system: 19/140 [13.6%] with evening primrose oil plus multivitamins v 11/137 [8%] with placebo plus multivitamins; general disorders: 25/140 [17.9%] with evening primrose oil plus multivitamins v 25/137 [18.2%] with placebo plus multivitamins; P > 0.05 for all comparisons). The second RCT found that adverse effects were similar with evening primrose oil and placebo (all adverse effects: 14/30 [47%] with evening primrose oil v 13/30 [43%] with placebo; gastric or abdominal adverse effects: 8/30 [27%] with evening primrose oil v 12/30 [40%] with placebo; P values not reported). One poor quality RCT and one survey of randomised and open studies found that adverse effects causing treatment discontinuation were similar with evening primrose oil and placebo (3%), and were largely caused by abdominal bloating.

Comment

We found one survey of randomised and open studies; however, data were reported as overall summary figures, which makes specific data extraction impossible.

Clinical guide:

In the UK, the Committee for Safety of Medicines has withdrawn the prescription licence from evening primrose oil because of lack of efficacy, but it is still available to purchase without prescription. Evening primrose oil can be considered to be an expensive placebo treatment.

Substantive changes

Evening primrose oil One large RCT found no reduction in breast pain from evening primrose oil plus multivitamins compared with placebo plus multivitamins; categorisation unchanged (Likely to be ineffective or harmful). For GRADE evaluation of interventions for breast pain, see table.


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