Breast pain
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% to 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 May 2010 (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 24 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: antibiotics, bromocriptine, combined oral contraceptive pill, danazol, diuretics, evening primrose oil, gestrinone, gonadorelin analogues, hormone replacement therapy (HRT), lisuride, low-fat diet, progestogens, pyridoxine, tamoxifen, tibolone, topical or oral non-steroidal anti-inflammatory drugs (NSAIDs), toremifene, and vitamin E.
Key Points
Breast pain (mastalgia) 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% to 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.
Diclofenac (a topical NSAID) seems effective at relieving symptoms of cyclical and non-cyclical breast pain but has been associated with adverse effects.
- There is consensus that topical NSAIDs are effective in relieving breast pain and should be considered as a first-line treatment, as the benefits are thought to outweigh the risk of adverse effects.
We found insufficient evidence to assess the effects of oral NSAIDs on breast pain.
Danazol, tamoxifen, toremifene, gonadorelin analogues, and gestrinone may reduce breast pain, but all can cause adverse effects.
- Danazol can cause weight gain, deepening of the voice, menorrhagia, and muscle cramps, and has androgenic effects on the fetus.
- Danazol is less effective than tamoxifen at reducing breast pain and has a less favourable adverse-effects profile compared with tamoxifen (10 mg daily).
- Tamoxifen (20 mg daily) and toremifene may increase the risk of venous thromboembolism, and neither drug is licensed for breast pain in the UK or USA.
- Tamoxifen (10 mg daily) under expert supervision, or danazol, may be considered when first-line treatments are ineffective.
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.
Hormone replacement therapy (HRT), which is associated with increased risks of breast cancer, venous thromboembolism, and gall bladder disease, may worsen breast pain. RCTs assessing the effects of HRT as a treatment for breast pain are unlikely to be conducted.
Evening primrose oil has not been shown to improve breast pain, and its licence has been withdrawn for this indication in the UK owing to lack of efficacy.
There is consensus that pyridoxine, diuretics, progestogens, tibolone, and antibiotics do not have a role in treating mastalgia.
- CAUTION: tibolone has been associated with increased risk of breast cancer recurrence.
We don't know whether the combined oral contraceptive pill reduces breast pain, as we found no RCTs.
We don't know whether a low-fat, high-carbohydrate diet, lisuride, or vitamin E reduce breast pain, as we found few studies.
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.
Prognosis
Cyclical breast pain resolves spontaneously within 3 months of onset in 20% to 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; quality of life; adverse effects.
Methods
Clinical Evidence search and appraisal May 2010. The following databases were used to identify studies for this systematic review: Medline 1966 to May 2010, Embase 1980 to May 2010, and The Cochrane Database of Systematic Reviews Issue 2, 2010 (1966 to date of issue). An additional search within The Cochrane Library was carried out for the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA). We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews of RCTs 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 unless blinding was impossible. We included systematic reviews of RCTs and RCTs where harms of an included intervention were studied, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews 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. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).
Table
GRADE Evaluation of interventions for Breast pain.
| Important outcomes | , Breast pain, Quality of life | ||||||||
| Studies (Participants) | Outcome | Comparison | Type of evidence | Quality | Consistency | Directness | Effect size | GRADE | Comment |
| What are the effects of treatments for breast pain? | |||||||||
| 1 (108) | Breast pain | Topical NSAIDs versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (40) | Breast pain | Oral NSAIDs versus placebo | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, no significance assessment of between-group difference, and unclear method of randomisation |
| 1 (93) | Breast pain | Danazol versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (145) | Breast pain | Gestrinone versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 1 (147) | Breast pain | Gonadorelin analogues (luteinising hormone-releasing hormone analogues) versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 3 (241) | Breast pain | Tamoxifen versus placebo | 4 | –1 | 0 | –1 | 0 | Low | Quality point deducted for incomplete reporting of results. Directness point deducted for uncertainty about definition of outcomes |
| 2 (361) | Breast pain | Different doses of tamoxifen versus each other | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for incomplete reporting of results |
| 2 (257) | Breast pain | Toremifene versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for lack of pre-crossover results in 1 RCT and for unclear follow-up methods in 1 RCT |
| 1 (62) | Quality of life | Toremifene versus placebo | 4 | –2 | 0 | 0 | 0 | Low | Quality points deducted for sparse data and lack of pre-crossover results |
| 1 (21) | Breast pain | Advice to eat a low-fat, high-carbohydrate diet versus general dietary advice | 4 | –1 | –1 | 0 | 0 | Low | Quality point deducted for sparse data. Consistency point deducted for different results for different outcomes |
| 1 (60) | Breast pain | Lisuride maleate versus placebo | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data and for randomisation and blinding flaws |
| 2 (58) | Breast pain | Progestogens versus placebo | 4 | –3 | 0 | 0 | 0 | Very low | Quality points deducted for sparse data, poor follow-up, and incomplete reporting of results |
| 2 (282) | Breast pain | Bromocriptine versus placebo | 4 | –3 | 0 | –1 | 0 | Very low | Quality points deducted for poor follow-up, no ITT analysis, and incomplete reporting of results. Directness point deducted for narrow inclusion criteria |
| 1 (93) | Breast pain | Danazol versus tamoxifen | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for sparse data |
| 3 (747) | Breast pain | Evening primrose oil (EPO) versus placebo | 4 | –1 | 0 | 0 | 0 | Moderate | Quality point deducted for poor methodology in one RCT |
We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.
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
NSAIDs (topical)
Summary
Diclofenac seems effective at relieving symptoms of cyclical and non-cyclical breast pain but has been associated with adverse effects.
There is consensus that topical NSAIDs are effective in relieving breast pain and should be considered as a first-line treatment, as the benefits are thought to outweigh the risk of adverse effects.
Benefits and harms
Topical NSAIDs versus placebo:
Breast pain
Topical NSAIDs (diclofenac) compared with placebo Diclofenac seems more effective at reducing breast pain (cyclical and non-cyclical) at 6 months (moderate-quality evidence).
Further information on studies
None.
Comment
Adverse effects
All products containing diclofenac sodium have been associated with the potential for elevation of liver function tests.
The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) recently conducted a scientific review on photosensitivity reactions associated with medicines containing topical ketoprofen. It concluded (July 2010) that the benefit–risk balance of these medicines continues to be positive. However, doctors should inform patients on appropriate use to prevent occurrence of serious skin photosensitivity reactions.
Substantive changes
Topical NSAIDs Evidence reassessed. Categorisation changed from Likely to be beneficial to Trade-off between benefits and harms.
NSAIDs (oral)
Summary
There is limited evidence that oral NSAIDs may reduce breast pain compared with placebo.
Benefits and harms
Oral NSAIDs versus placebo:
Breast pain
Oral NSAIDs compared with placebo Nimesulide may be more effective at reducing spontaneous breast pain at 15 days in women with non-cyclical breast pain (very low-quality evidence).
Further information on studies
None.
Comment
Nimesulide has been associated with a risk of serious damage to the liver and is not authorised in the UK and several European countries. The Committee for Medicinal Products for Human Use (CHMP) has restricted its use to 15 days.
Substantive changes
Oral NSAIDs Categorised as Unknown effectiveness as we found insufficient RCT evidence to assess their effects.
Danazol
Summary
Danazol may reduce breast pain but can cause adverse effects, including weight gain, deepening of the voice, menorrhagia, and muscle cramps, and has androgenic effects on the fetus.
Benefits and harms
Danazol versus placebo:
We found one good-quality outpatient-based RCT in 93 women.
Breast pain
Danazol compared with placebo Danazol reduces cyclical breast pain after 12 months (moderate-quality evidence).
Adverse effects
Further information on studies
None.
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
Gestrinone
Summary
Gestrinone may reduce breast pain but can cause adverse effects including greasy skin, hirsutism, acne, reduction in breast size, headache, and depression.
Benefits and harms
Gestrinone versus placebo:
We found one double-blind, outpatient-based RCT (145 women).
Breast pain
Gestrinone compared with placebo Gestrinone is more effective at reducing breast pain after 3 months (moderate-quality evidence).
Adverse effects
Further information on studies
None.
Comment
Gestrinone is a synthetic steroid, reported to have androgenic, anti-oestrogenic, and anti-progestogenic properties.
Clinical guide:
Gestrinone is not used for breast pain in clinical practice and is not widely available: it was discontinued in the UK in 2009. This medicine may be harmful to an unborn baby and is not recommended during pregnancy. For this reason, the first dose of this medicine should be taken on the first day of the menstrual period, to be certain that pregnancy is not a possibility.
Substantive changes
No new evidence
Gonadorelin analogues (luteinising hormone-releasing hormone analogues)
Summary
Gonadorelin analogues may reduce breast pain but can cause adverse effects. Goserelin injection is associated with vaginal dryness, hot flushes, decreased libido, oily skin or hair, decreased breast size, and irritability.
There is consensus that goserelin injections should be reserved for severe refractory mastalgia and that treatment should be limited to 6 months.
Benefits and harms
Gonadorelin analogues (luteinising hormone-releasing hormone analogues) versus placebo:
Breast pain
Goserelin injection compared with placebo Goserelin injection reduces breast pain (moderate-quality evidence).
Adverse effects
Further information on studies
None.
Comment
Clinical guide:
There is widespread consensus that goserelin injections should be reserved for severe refractory mastalgia and treatment should be limited to 6 months. Add-back tibolone or HRT can be used to relieve many of the adverse effects.
Substantive changes
No new evidence
Tamoxifen
Summary
Tamoxifen may reduce breast pain but can cause adverse effects. Adverse effects of tamoxifen (hot flushes and GI 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 and harms
Tamoxifen versus placebo:
Breast pain
Tamoxifen compared with placebo Tamoxifen may be more effective than placebo at reducing breast pain (low-quality evidence).
Adverse effects
Tamoxifen versus danazol:
See benefits of danazol versus tamoxifen.
Different doses of tamoxifen versus each other:
Breast pain
Different doses of tamoxifen compared with each other Lower-dose tamoxifen (10 mg) is as effective as higher-dose tamoxifen (20 mg) at reducing breast pain at 3 to 6 months (moderate-quality evidence).
Adverse effects
Further information on studies
None.
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. Tamoxifen 10 mg daily is initially prescribed for 3 months and may be continued for additional 3 months only if a response is observed. One meta-analysis of the 4 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. There are 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
Toremifene
Summary
Toremifene may reduce breast pain but can cause adverse effects; it has been associated with hot flushes, sweats, DVT, and visual disturbances, and is potentially teratogenic. Toremifene is not licensed for breast pain in the UK or USA.
Benefits and harms
Toremifene versus placebo:
Breast pain
Toremifene compared with placebo Toremifene may be more effective than placebo at decreasing breast pain (low-quality evidence).
Quality of life
Toremifene compared with placebo We don't know whether toremifene is more effective than placebo at increasing quality-of-life scores (low-quality evidence).
Adverse effects
Further information on studies
The RCT performed an intention-to-treat analysis. However, the withdrawal rate was high (72/195 women), and it is unclear how those women who withdrew were dealt with in the analysis.
Allocated treatments were given from day 15 of the menstrual cycle until menstruation for 3 consecutive cycles, followed by a no-treatment wash-out cycle before crossover to placebo or toremifene for a further 3 months.
Comment
Adverse effects
Toremifene has been associated with dose-dependent risk of QT prolongation, which carries a risk of serious cardiac arrhythmia.
Clinical guide:
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, a more widely used and better-understood drug. Other adverse effects reported with use of toremifene include hot flushes, sweats, DVT, and occasional visual problems. Toremifene is potentially teratogenic and should not be used in women who may become pregnant.
Substantive changes
Toremifene New evidence added. Categorisation unchanged (Trade-off between benefits and harms).
Antibiotics
Summary
Antibiotics have not been shown to have a role in treating mastalgia.
Benefits and harms
Antibiotics:
We found no systematic review or good-quality RCTs.
Further information on studies
None.
Comment
Clinical guide:
Some clinicians have considered that the condition of breast pain reflects infection. However, there is no infection associated with true mastalgia and therefore no value in the use of antibiotics (mastitis is not synonymous with true mastalgia). Conversely, infection caused by, for example, periductal mastitis, can cause breast pain and should therefore be ruled out as a cause of breast pain before diagnosing a patient with true mastalgia. Antibiotics are effective in resolving inflammation in, for example, periductal mastitis, but have no role in true mastalgia.
Substantive changes
Antibiotics Evidence reassessed. Recategorised from Unknown effectiveness to Unlikely to be beneficial, by consensus.
Diet (low-fat, high-carbohydrate)
Summary
We don't know whether a low-fat, high-carbohydrate diet reduces breast pain, as few RCTs have been found.
Benefits and harms
Advice to eat a low-fat, high-carbohydrate diet versus general dietary advice:
We found one small RCT (21 women).
Breast pain
Advice to eat a low-fat, 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).
Further information on studies
Low-fat, high-carbohydrate diet was defined as instruction to reduce fat content of the diet to 15% of total calorie intake while increasing complex carbohydrates to maintain calorie intake. General dietary advice was defined as principles for a healthy diet based on Canada's Food Guide, but no counselling to modify the fat content of the diet.
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
Diuretics
Summary
Diuretics have not been shown to have a role in treating mastalgia.
Benefits and harms
Diuretics:
We found no systematic review or RCTs of adequate quality.
Further information on studies
None.
Comment
Substantive changes
Diuretics Evidence reassessed. Categorisation changed from Unknown effectiveness to Unlikely to be beneficial, by consensus.
Lisuride
Summary
We don't know whether lisuride (a dopamine agonist) reduces breast pain, as few RCTs have been found. Dopamine agonists have been associated with pathological gambling and hypersexuality.
Benefits and harms
Lisuride maleate versus placebo:
Breast pain
Lisuride maleate compared with placebo Lisuride maleate (a dopamine agonist) may reduce breast pain over 2 months, compared with placebo (very low-quality evidence).
Adverse effects
Further information on studies
In this RCT, 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.
Comment
Adverse effects
Dopamine agonists including lisuride have been associated with pathological gambling, and with increased libido, including hypersexuality.
Clinical guide:
Lisuride is not widely used and has been discontinued in many countries, including the UK and USA. It should be used with caution in view of the safety alerts from the Medicines and Healthcare products Regulatory Agency.
Substantive changes
No new evidence
Contraceptive (combined oral)
Summary
We don't know whether the oral contraceptive pill reduces breast pain, as we found no RCTs.
Benefits and harms
Oral contraceptive pill:
We found no systematic review or RCTs.
Further information on studies
None.
Comment
None.
Substantive changes
Contraceptive (combined oral) New option. Categorised as Unknown effectiveness as we found no RCT evidence to assess its effects.
Progestogens
Summary
Progestogens have not been shown to have a role in treating mastalgia.
Benefits and harms
Progestogens versus placebo:
Breast pain
Progesterone cream or medroxyprogesterone acetate tablets compared with placebo Progesterone cream or medroxyprogesterone acetate tablets may be no more effective than placebo at reducing breast pain (very low-quality evidence).
Adverse effects
Further information on studies
In the active-treatment arm, cream containing progesterone 1% was applied daily from the 10th day of the cycle to the beginning of the next cycle, for 3 months. In the placebo arm, placebo cream was applied daily from the 10th day of the cycle to the beginning of the next cycle, for 3 months. The RCT had a small sample size, a significant level of withdrawals, and a selection phase, which may restrict the generalisability of the evidence.
In the active treatment-first arm, oral medroxyprogesterone acetate 20 mg tablets were given from days 10 to 26 of the menstrual cycle for 3 months, and then placebo for 3 months. In the placebo-first arm, placebo was given from days 10 to 26 of the menstrual cycle for 3 months, and then oral medroxyprogesterone acetate 20 mg tablets for 3 months. The RCT had a small sample size, a significant level of withdrawals, and a selection phase, which may restrict the generalisability of the evidence.
Comment
Clinical guide:
Despite claims from Europe that progestogens would prevent breast pain, the evidence does not support this, and progestogens are not indicated as treatment for the condition. Studies have failed to detect a significant difference in progestogen levels between women with and without mastalgia. Mastalgia is not associated with significant luteal-phase progestogen insufficiency.
Substantive changes
Progestogens Evidence reassessed. Categorisation changed from Unknown effectiveness to Unlikely to be beneficial.
Pyridoxine
Summary
Pyridoxine has not been shown to have a role in treating mastalgia.
Benefits and harms
Pyridoxine:
We found no systematic review or good-quality RCTs.
Further information on studies
None.
Comment
There is no evidence to support the use of pyridoxine for breast pain. One small, double-blind crossover RCT found no significant difference at 2 months between vitamin B6 (pyridoxine) and placebo for cyclical mastalgia (mean pain difference from baseline measured by linear analogue scale [parameters unclear]: –2.6 cm with B6 200 mg/day v –2.3 cm with placebo; reported as not significant). We chose not to report the study in detail because of poor methodology and reporting, but we mention it here because of a paucity of data.
Substantive changes
Pyridoxine Evidence reassessed. Recategorised from Unknown evidence to Unlikely to be beneficial, by consensus.
Tibolone
Summary
Tibolone has not been shown to have a role in treating mastalgia.
Benefits and harms
Tibolone:
We found no systematic review or RCTs.
Further information on studies
None.
Comment
We found one non-randomised, placebo-controlled study comparing tibolone versus calcium carbonate "placebo" in 64 women with breast pain secondary to use of HRT, allocated to treatment according to individual women's preferences. 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 no other adverse effects. See also comment on HRT.
Adverse effects
Tibolone has been associated with increased risk of breast cancer recurrence.
Clinical guide:
Tibolone is a synthetic steroid reported to have oestrogenic, progestogenic, and weak androgenic properties, which can be used as a form of HRT. See comment on HRT. Breast pain associated with hormone replacement treatment is less common with tibolone compared with oestrogen-only or combined HRT. Tibolone should not be considered an effective treatment of mastalgia. However, postmenopausal patients with breast pain secondary to use of HRT may benefit by swapping to tibolone.
Substantive changes
Tibolone Evidence reassessed. Categorisation changed from Unknown effectiveness to Unlikely to be beneficial, by consensus.
Vitamin E
Summary
We don't know whether vitamin E reduces breast pain, as few RCTs have been found. Vitamin E use has been associated with an increased risk of haemorrhagic stroke.
Benefits and harms
Vitamin E:
We found no systematic review or RCTs of adequate quality.
Further information on studies
None.
Comment
Clinical guide:
There is no evidence that vitamin E improves breast pain.
Substantive changes
No new evidence
Bromocriptine
Summary
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. Bromocriptine is associated with nausea, dizziness, postural hypotension, and constipation.
Benefits and harms
Bromocriptine versus placebo:
Breast pain
Bromocriptine compared with placebo Bromocriptine (a dopamine agonist) may be more effective at reducing breast pain (very low-quality evidence).
Adverse effects
Further information on studies
None.
Comment
Adverse effects
Strokes and death have been reported after use of bromocriptine to inhibit lactation, and the FDA has withdrawn its licence for this indication. Dopamine agonists including bromocriptine have been associated with pathological gambling, and with increased libido, including hypersexuality.
Clinical guide:
Bromocriptine is now rarely used, because frequent and intolerable adverse effects at the therapeutic dose outweigh the benefits for this indication.
Substantive changes
No new evidence
Danazol versus tamoxifen
Summary
Danazol may be less effective than tamoxifen for reducing pain. Adverse effects are common with both drugs (although less so with tamoxifen 10 mg), and both are contraindicated in women who have had a previous venous thromboembolism.
Benefits and harms
Danazol versus tamoxifen:
We found one good-quality outpatient-based RCT in 93 women.
Breast pain
Danazol compared with tamoxifen Danazol is less likely than tamoxifen to improve pain scores after 6 months' treatment, and 12 months after the end of 6 months' treatment (moderate-quality evidence).
Adverse effects
Further information on studies
None.
Comment
Clinical guide:
Some clinicians now use tamoxifen 10 mg daily rather than danazol, because of the more favourable adverse-effects profile and greater efficacy. Both drugs are contraindicated in women who have had a previous venous thromboembolism. Women with persistent symptoms after first-line treatment are started on tamoxifen 10 mg daily for 3 to 6 months under expert supervision. Women who do not respond to treatment with tamoxifen are started on danazol 200 mg daily (reduced to 100 mg/day after relief of symptoms) or only during the luteal phase of the menstrual cycle.
Substantive changes
No new evidence
HRT (oestrogen)
Summary
HRT may worsen breast pain, and is also associated with increased risks of breast cancer, venous thromboembolism, and gall bladder disease. RCTs assessing the effects of HRT as a treatment for breast pain are unlikely to be conducted.
HRT is associated with increased risk of breast pain in postmenopausal women, and studies in HRT as a treatment for breast pain are unlikely to be conducted.
Benefits and harms
HRT (oestrogen):
We found no systematic review or RCTs examining effects of HRT for treating breast pain.
Further information on studies
None.
Comment
HRT is associated with an increased risk of breast pain in postmenopausal women, and RCTs on HRT as a treatment for breast pain are unlikely to be conducted. We found one RCT (44 postmenopausal women with or without breast pain), which found that HRT increased the proportion of women who had breast pain at 1 year compared with tibolone (8/15 [53%] with HRT [transdermal oestrogen patches 50 micrograms twice weekly for 3 weeks/month, plus progestogen 5 mg/day for 12 days/month/cycle] v 1/17 [6%] with tibolone 2.5 mg/day; P 0.02). See harms of HRT in review on secondary prevention of ischaemic cardiac events.
Clinical guide:
HRT is considered to increase the risk of breast pain. In women with HRT-induced breast pain (oestrogen-only 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
HRT (oestrogen) Evidence reassessed. Categorisation changed from Unlikely to be beneficial to Unlikely to be beneficial, by consensus.
Evening primrose oil
Summary
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 (it is still available to purchase without prescription).
Benefits and harms
Evening primrose oil (EPO) versus placebo:
We found three RCTs comparing EPO versus placebo.
Breast pain
Evening primrose oil compared with placebo Evening primrose oil seems no more effective than placebo at reducing frequency or severity of pain at 6 months (moderate-quality evidence).
Adverse effects
Further information on studies
The methodology of this 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.
Comment
We found one survey of randomised and open studies; however, data were reported as overall summary figures, which makes specific data extraction impossible. The survey found that adverse effects causing treatment discontinuation were similar with evening primrose oil and placebo (3%), and were largely caused by abdominal bloating.
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
No new evidence