Evidence-Based Management of Mastalgia: a Meta-Analysis of Randomised Trials

ARTICLE IN PRESS

The Breast (2007) 16, 503–512

THE BREAST

www.elsevier.com/locate/breast ORIGINAL ARTICLE Evidence-based management of Mastalgia: A meta-analysis of randomised trials

A. Srivastavaa,1, R.E. Mansela, N. Arvinda, K. Prasadb, A. Dharc,Ã, A. Chabraa aUniversity Department of Surgery, Cardiff University, UK bClinical Epidemiology Unit, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India cDepartment of Surgery, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110029, India

Received 23 February 2007; accepted 19 March 2007

KEYWORDS Summary Several agents have been utilised for therapy of mastalgia based on Danazol; data from small trials. No meta-analysis of trials on mastalgia exists. We have Bromocriptine; conducted a meta-analysis on trials on mastalgia published in the English language. Tamoxifen; Study was restricted to randomised controlled trials comparing Bromocriptine, Mastalgia; Danazol, Evening primrose oil (EPO) and Tamoxifen with placebo. The analysis was Meta-analysis carried out on the REVMAN statistical package. Weighted mean difference in the pain score in favour of Bromocriptine was 16.31(95% CI 26.35 to 6.27). Danazol produced a significant benefit with a mean pain score difference 20.23(95% CI 28.12 to 12.34). EPO did not offer any advantage over placebo in pain relief, mean pain score difference being 2.78 (95% CI 7.97 to 2.40). Tamoxifen achieved a relative risk (RR) of pain relief of 1.92 (95% CI 1.42–2.58). Tamoxifen is associated with least side effects and should be the drug of first choice. & 2007 Elsevier Ltd. All rights reserved.

Introduction of cyclical and non-cyclical breast pain. This includes hormonal manipulation by Danazol, Bro- Mastalgia or breast pain is a very common symptom mocriptine, Tamoxifen and LH-RH analogue, goser- 1 among patients attending the breast clinic. A large elin. Non-hormonal agents used in mastalgia are number of agents have been tried in the treatment non-steroidal anti-inﬂammatory gels, iodides, plant derivatives like evening primrose oil (EPO) and Vitus Agnus Castus.2 There is considerable debate Ã Corresponding author. Tel.: +91 11 2658 8500x3206; about the choice of best agent for initial manage- fax: +91 11 2658 8641. ment of mastalgia. So far no meta-analysis has E-mail address: [email protected] (A. Dhar). 1Present address: Clinical Epidemiology Unit, All India Institute been described to evaluate the effects of these of Medical Sciences, Ansari Nagar, New Delhi, 110029, India. agent. We therefore performed a meta-analysis on

504 A. Srivastava et al. published randomised trials of 4 common agents independently first on the baseline characteristics used in the therapy. from a photocopied portion of the paper where the result section was masked. Similarly data on the Objective results were extracted from a photocopy where the baselines features were masked. Following extrac- This investigation was carried out to generate Level tion by 2 persons a consensus was arrived by I evidence regarding the effectiveness of Bromo- discussion wherever a discordance occurred. Since criptine, Danazol, EPO and Tamoxifen in the cyclical mastalgia is more common in most breast therapy of mastalgia. clinics, the data on only cyclical mastalgia was extracted from the published reports. In some papers the actual data on mean pain score was not Search strategy and inclusion criteria reported in numerical form. In such cases, the pain score value was derived from the graph. In cross- Articles on randomised trials on treatment of over trials the result on initial phase (i.e. before mastalgia were searched using the electronic data- cross-over) was used for analysis wherever this was bases, viz. Medline, Google and Embase. Articles reported. were also hand searched from text books of breast diseases, benign breast diseases and surgery. The Statistical analysis search was performed with the following key words: mastalgia, mastodynia, breast pain, benign breast The outcome of interest is reported as the mean disease, therapy & treatment. The search was pain score with the active drug and with placebo in confined to articles published in the English language. some studies while other studies have described The search was restricted to randomised clinical trials the number of cases achieving clinical response where an active drug was compared with placebo or (usually greater than 50% reduction in the mean another drug along with the placebo. We have pain score measured on a visual analogue scale or conducted this meta-analysis for four agents, which Cardiff breast pain scale). The pooled estimates of are commonly used in the therapy of breast standardised difference of mean pain score be- pain—Bromocriptine, Danazol, EPO and Tamoxifen. tween active drug and placebo has been calculated for those studies reporting the outcome as mean pain score. We calculated the pooled relative risk Exclusion criteria (RR) for studies reporting outcome as dichotomous data on a 2 2 table. The point estimates and 95% Trials without randomisation or without a placebo confidence limits have been computed for fixed or arm were excluded. Trials on agents other than random effect model as appropriate. The random above 4 agents were excluded. effect model is more appropriate where there is significant heterogeneity among the trials whereas a fixed effect model is employed in situation of no Method of quality assessment significant heterogeneity among the trial results. The meta-analysis has been performed by two The following criteria were employed to assess the investigator (KP and AS) on ‘‘REVMAN’’ Meta- quality of individual trials: method of randomisa- analysis statistical package (version 4.2.8) obtained tion, concealment in randomisation, blinding in from Cochrane Collaboration through the world assessment of response, and reporting of dropouts/ wide web. In some trials the standard deviation loss to follow-up. Two investigators (AS and NA) (SD) of the mean pain score was not given, assessed the quality of studies independently and therefore we have taken the SD from the trial coded each study as: excellent, good and poor. No which has used the same drug and assumed the study was excluded because of poor quality. same SD across the studies. A funnel plot to evaluate the publication bias was not drawn because of very small number of studies available. Data extraction

The data on the important trial characteristics, Results patient population, dosage of drug with duration, response measure at 3 months and side-effects of We came across 34 studies on Bromocriptine with drugs were extracted by 2 investigators (AS and NA) 12 clinical trials. Of these 7 were RCTs and were ARTICLE IN PRESS

Evidence-based management of Mastalgia 505 included in the meta-analysis. For Tamoxifen, 34 Kontostolis et al.14 (Table 3). Of these the data studies with 14 clinical trials (4 RCTs) were found. was presented as mean pain score in the first 4 Three of these 4 RCTs are included in our analysis. trials and are included in the meta-analysis. The excluded trial of Fentiman et al.3 compared 2 Kontostolis et al. reported binary outcome of different dosage schedules of Tamoxifen without responders and failures, without any pain score, any placebo arm. For EPO—total studies 20, hence their data is not included in the analysis. clinical trials 6, RCTs-3. All 3 trials were included There is insignificant heterogeneity amongst the in the analysis along with the trial of Goyal and trials (heterogeneity Chi-square ¼ 5.11, df ¼ 3, Mansel on Gamolenic acid. Regarding Danazol—total p ¼ 0.16) hence a fixed effect model is employed. studies 35, clinical trials 8 and RCTs-4. All 4 RCT The overall weighted mean score difference of were included in the meta-analysis. 20.23 is statistically significant (Z ¼ 5.02, The quality of RCTs was assessed on the above- po0.00001) demonstrating the effectiveness of mentioned criteria. It was judged to be excellent in Danazol in amelioration of breast pain. The forest 2 trials, good in 2 trials and poor in 2 trials of plot is shown in Fig. 3. Bromocriptine. Regarding Tamoxifen trials 2 trials were good and one trial was found to be of poor Evening primrose oil (EPO) quality. For trials on Danazol the quality was as follows—1 excellent, 1 good and 2 poor. Of 4 trials Three trials with outcome presented as mean pain of EPO, 1 was excellent, 1 good and 2 of poor score were found. These are the trials of Pashby quality. No trial was excluded from the meta- et al.,15 Blommers et al.16 and Preece et al.17 analysis on grounds of poor quality. (Table 4). The multicentre European trial of Goyal and Mansel18 has evaluated the role of Gamolenic Bromocriptine acid (GLA) in controlling mastalgia. Since GLA is considered to be the active ingredient of EPO, we Seven trials were analysed—those of Mansel et al.,4 have included this trial data in the meta-analysis of Mansel et al.,5 Hinton et al.,6 Nazli et al.,7 Parlati EPO trials. The results are presented in Fig. 4. The et al.,8 Durning and Sellwood9 and that of Blichert- overall weighted mean difference of 2.78 was not toft et al.10 The outcome in the first six trials is significant (test for overall effect Z ¼ 1.05; recorded as mean pain score, whereas the last p ¼ 0.29) indicating the ineffectiveness of EPO trial reported outcome only as dichotomous data compared to placebo. There is significant hetero- (Table 1). Hence meta-analysis has been carried out geneity amongst the trials (heterogeneity Chi- on the first six trials using mean pain score. For square ¼ 15.08, df ¼ 3, p ¼ 0.002) hence a random trials of Nazli et al., Mansel et al. and Blichert-toft effect model is more appropriate. et al. we have estimated the overall RR based on binary data (Table 2). Bromocriptine offered a RR of Tamoxifen pain relief of 5.29 with a 95% CI 2.56–10.89; Z ¼ 4.51 and po0.00001. Six trials on Bromocrip- Three trials with data presented as number of tine have also reported results as mean pain score. patients achieving pain relief were found, those of The SD was reported only in the trial of Nazli et al.7 Messinis et al.,19 Fentiman et al.20 and Kontostolis We assumed that all the studies had the same SD for et al.14 (Table 5). The analysis is presented in the calculation of overall effect. Meta-analysis of Table 6 with its forest plot in Fig. 5. The overall these trials is presented in Fig. 1. There is a relief of pain achieved with Tamoxifen had a RR of significant heterogeneity amongst the trials (het- 1.92 (95% CI 1.42–2.58) which is significant, p-value erogeneity Chi-square ¼ 795.59, df ¼ 5, po0.00001) being o0.0001. There is insignificant heterogeneity hence a random effect model is presented in Fig. 2. amongst the trials, hence a fixed effect model is An overall weighted mean score difference of used. 16.31 was obtained which is statistically significant (Z ¼ 3.18, p ¼ 0.001) indicating a significant relief of mastalgia with Bromocriptine. Discussion

Danazol This paper presents the ﬁrst meta-analysis on the randomised trials published on the treatment of Five trials on the use of Danazol were found in the mastalgia. Since cyclical mastalgia is the more literature—those of Doberi et al.,11 Hinton et al.,6 common form of breast pain, we have included the Mansel et al.,12 O’Brian et al.13 and that of data of patients with cyclical mastalgia only. Most ARTICLE IN PRESS

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Table 1 Summary of trials on Bromocriptine vs. placebo.

Author Method intervention Outcome Outcome p-value Quality of Bromocriptine placebo trial

Nazli et al.7 2 arm RCT parallel, Mean pain score at 3 Mean pain po0.01 Good Bromocriptine month, VLA 0–100 score Wilcoxon sign 1.25–5 mg incremental rank Pre 86.2, SD 2 Pre 86.4 for 3 months Post 37, SD 0.4 SD 1.96 Binary outcome Post 73.3 15-CR,3-PR SD 4 5-No response 4-CR N ¼ 25, dropout 2 18-NR N ¼ 25 dropout 3 Mansel et al.5 2 arm parallel Mean score as Mean score p ¼ 0.007 Excellent multicentric in 13 percentage of VAS at Man–Whitney Europe centers end of therapy test Bromocriptine 2.5 mg Pre 65% Pre 65% bd for 3–6 months Post 14% Post 25% N ¼ 135 at 3 months, N ¼ 137 at dropouts 49 3 months dropouts 36 Hinton et al.6 Doubleblind 3 arm RCT- Mean score VAS 0–100 Mean score po0.05 on Good Bromocriptine-1.25 mg paired t-test Pre 53 Pre 60 od to 2.5 mg bd vs. Post 53.9 Post 45 Danazol vs. placebo for N ¼ 13 N ¼ 6 3 months Withdrawn 7 Withdrawn 3 Mansel et al.4 Doubleblind crossover Mean score VLA 0–100 Mean score po0.05 Good Bromocriptine at 3 months Wilcoxan 1.25–5 mg incremental matched pair Pre 65 Pre 65 vs. placebo, cyclical rank test Post 30. Post 55 mastalgia 29 for 3 Response 14/29, Response 2/29, months N ¼ 29 N ¼ 29 Blichert-toft Doubleblind crossover Resonse complete or Response 1/8 po0.02 Koch’s Poor et al.10 RCT Bromocriptine appreciably reduced N ¼ 8 test 2.5–5 mg incremental 8/8 N ¼ 8 cyclical for 2 months then mastalgia crossover to placebo

Parlati et al.8 Doubleblind placebo Pain score 0–4, Placebo po0.01 on Poor controlled 0-nil,1-mild, two-way two Bromocriptine 2 moderate, factor ANOVA incremental dosage 3-severe, for repeated 1.25 mgbd for 3 days 4 intolerable, Mean measures increasing to 2.5 mgtds mastodynia score for 3 months, Bromocriptine Pre 2.7 Mean score Post 0.14 Pre 2.5 N ¼ 13 Post 1.5 N ¼ 13 Durning and Double blind crossover Median pain score on Median score po0.01 on Good Sellwood9 Bromocriptine 1.25 mg VLA 0–100 41 Friedman od incremental to Pre 40 N ¼ 38 ranksum test 2.5 mg bd, placebo for Post 34 8 weeks then crossover N ¼ 38 Dropouts-7 between 2nd &3rd and 4th & 5th cycles ARTICLE IN PRESS

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Table 2 The meta-analysis on trials of Bromocriptine vs. placebo—outcome proportion of response.

Study Events/Total RR 95% conﬁdence limits Z-value p-value

Bromocriptine Placebo Lower Upper

Mansel et al.4 14/29 2/29 7 1.74 28.08 Blichert-toft et al.10 8/8 1/8 8 1.28 50.04 Nazli et al.7 15/25 4/25 3.75 1.45 9.73 Fixed model 5.29 2.56 10.89 4.51 o0.00001

Heterogeneity test chi-square ¼ 0.85; df ¼ 2; p ¼ 0.65.

Figure 1 Meta-analysis on trials of Bromocriptine vs. placebo, outcome mean pain score.

Figure 2 Meta-analysis on trials of Bromocriptine vs. placebo, outcome proportion pain relieved.

RCTs have been conducted on Bromocriptine, of 3 months the women were crossed over to the Danazol, Tamoxifen and EPO, hence only these 4 other group following an interval of a wash out drugs have been evaluated. time of 1 week. However, the drugs used for We encountered many problems in this meta- treating mastalgia such as danazol and bromo- analysis. The main issues were: criptine have shown a prolonged ‘carry over effect’ lasting up to 3 months or more.12,15 Thus 1. Poor quality of RCT—The overall quality of most the response recorded in women who received published trials on mastalgia is poor. The sample the active drug for ﬁrst 3 months and placebo size of most trials is very small. The process of later, would actually be residual activity of the randomisation is not reported in most trials. The ﬁrst drug. Moreover the natural history of data is very poorly presented in most papers. mastalgia is such that some women after 2. Cross-over RCTs—Many trials have utilised the achieving a good control of pain will remain cross-over design offering the active drug in remission for a long time regardless of initially for 3 months to half of the patients whether they receive any medication or not. and the placebo to the other half. After a period Such patients in remission will be counted as ARTICLE IN PRESS

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Table 3 Summary of trials on Danazol vs. placebo.

Author Method Outcome Outcome p-value Quality of trial intervention Danazol Mean, placebo Mean, SD SD

Doberi Doubleblind Mean intensity Mean score p ¼ 0.01 on Good et al.11 placebo controlled pain score per Pre 35.7 paired t-test with recurrent cycle on 0–100 cyclical VAS. Pre 42.3. mastodynia who Mean pain Mean score previously score difference at received Danazol difference at 3 months & relapsed 3 months 3.4, SE 6.2 Danazol 100 mg bd 24.2,SE 4.5 for 1 month, then N ¼ 13 100 mg od for 3 Dropout 1 months Hinton et al.6 Doubleblind 3arm Mean score Mean score po0.05 Good RCT Danazol VAS 0–100 100 mg tds Pre-mean 52.2 Pre-mean 60 Student t-test 3months vs Post-mean 4.3 Post-mean 45 placebo vs N ¼ 15 N ¼ 6 Bromocriptine Withdrawl 4 Withdrawl 3 Mansel Doubleblind Mean score Mean score po0.001 Poor et al.12 crossover Danazol VAS 0–100 200 mg bd for first Pre-mean 65 Pre-mean 80 On Wilcoxan 6 cases, 100 mg bd Post-mean 15 Post-mean 50 sign rank test for others for 3 In Danazol first In placebo first months then cases N ¼ 8 cases N ¼ 13 crossover O’Brian Doubleblind RCT Mean score on Mean score p ¼ 0.01 Excellent et al.13 Danazol 200 mg od VAS 0–100 ANOVA for in luteal phase for repeated Pre-mean Pre-mean 3 months vs. measures 49.4, SD 35 43.9, SD 32.4, placebo Post-mean Post-mean 14.6, 28.2, SD 29.6 SD 25.6 N ¼ 50 N ¼ 50 Kontostolis 3 arm RCT tam vs Response on Placebo po0.011 Poor et al.14 Danazol 100 mg bd scale 0–3, 0-no success ¼ 11 for 6 cycles vs pain, 1-mild, placebo tam 10 mg 2-moderate, day 5 to 24 of each 3-severe, cycle for 6 cycles response as 450% reduction in mean pain score Success ¼ 21, Failure ¼ 18 On failure ¼ 11 Mann–Whitney N ¼ 32 N ¼ 29 test

responders to whatever therapy they receive therapy. While most authors have used the visual (active drug or placebo). Thus crossover study analogue score to measure the pain objectively and design is not well suited to trials on mastalgia. report the mean pain score before and at the end of 3 months of therapy, others have simply reported Reporting of outcome: Different authors have the number of patients achieving good control of used different outcomes to report the result of pain. Various breast pain scoring systems, viz. ARTICLE IN PRESS

Evidence-based management of Mastalgia 509

Figure 3 Meta-analysis on trials of Danazol vs. placebo, outcome proportion of response.

Table 4 Summary of trials on EPO vs. placebo.

Author Method Outcome drug Outcome p-value Quality of trial intervention Mean, SD placebo Mean, SD

Blommers Double-blind Pin score on Mean score 0.83 Good, Scores et al.16 EPO vs Fish oil scale were vs corn and of 0–3,0-no multiplied with wheatgerm oil pain, 25 to make it for 6 months 4 1-mild, equivalent to arm parallel 2 moderate, 0–100 factorial block 3-severe. Mean randomized score design differnce. 0.06, SE 0.07, 0.08, SD 0.38 SE 0.07, SD 0.38 N ¼ 30 N ¼ 30, Result of cyclical cases not given separately Pashby Double-blind Mean score on Mean score po0.05 Poor et al.15 crossover EPO 3 VLA 0–100 months then Pre-mean 50, Pre-mean 45, crossover SD 26 SD 23 Post-mean 32, Post-mean 42, SD 30 SD 38 N ¼ 16, N ¼ N ¼ 16 dropout 3 dropout 16 Goyal and Double-blind Mean Cardiff Mean Nominal p ¼ 0.348 Excellent, Mansel18 placebo Nominal Breast Breast pain Scores were controlled pain score on score on scale multiplied with parallel 4 arm 0–56 of 0–56 1.78 to make it multicentre equivalent to Pre-mean 21.5, Pre-mean 22.2, On ANACOVA 555 women in 0–100 SD 10.76 SD 11.16 44 centres Post-mean Post-mean 14.8, 13.6, SD 10.88 SD 11.28 N ¼ 140 N ¼ 138 Preece Doubleblind pain score Pain score (po.05) Poor et al.17 placebo- (LAS) at 3 controlled months 0–100 crossover study Pre 36 Pre 24 (N ¼ 72) Post 22 Post 32 ARTICLE IN PRESS

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Figure 4 Meta-analysis on trials of EPO vs. placebo, outcome mean pain score.

Table 5 Summary of trials on Tamoxifen vs. placebo.

Author Method intervention Outcome Drug Outcome p-value Quality Tamoxifen placebo of trial

Messinis 2 arm open RCT Tamoxifen Pain on scale 0–3, Complete po0.001 chi Good and Lolis19 10 mg 6 cycles complete response 16 response 0, square test Partial response 2 at end Partial of therapy response 6 N ¼ 18 N ¼ 18 2 women did not take palcebo Fentiman Double-blind placebo Number of responders Responders po0.05 Good et al.20 Controlled tam 20 mg 3 with 450% reduction in 11 non- months Response on VLA VLA 22 non-responders 9 responders 18 N ¼ 31 (28 cyclical, 3 N ¼ 29(20 On Chi-square non-cyclical) cyclical,9 test non-cyclical) Kontostolis 3 arm RCT tam vs danazol Response on scale 0–3, Placebo po0.035 Poor et al.14 100 mg bd for 6 cycles vs 0-no pain, 1-mild, success ¼ 11, placebo tam 10 mg day 2-moderate, 3-severe, Failure ¼ 18 5–24 of each cycle for 6 response as 450% cycles reduction in mean pain score Success ¼ 23, failure ¼ 9 N ¼ 32 N ¼ 29 On Mann–Whitney test

Cardiff Breast Pain Score, VAS of 0–100, score of without the values of SD or standard error making it 0–4 mastodynia score, etc. have been employed by difﬁcult to compute a pooled estimate. Although in different authors. This makes the inter-trial com- case of missing values of SD, the method of parison and pooling of data for meta-analysis imputing it from other studies has been found difﬁcult. Many authors have not reported the useful in obtaining a precise estimate of effect in outcome data in a numerical form. They have meta-analysis21. simply depicted the mean pain score outcome on a The quality of trials on mastalgia should improve graph. While such graphs are useful in demonstrat- with appropriate sample size and better reporting ing the trend of pain score change with time and in (CONSORT) of outcome both in table and graph, comparing the scores of two treatment modalities, giving the mean and SD of the pain score. data extraction from graphs for meta-analysis is Preferably the experts should enter data in a fraught with error. The mean pain score is reported prospective meta-analysis similar to the ‘‘Early ARTICLE IN PRESS

Evidence-based management of Mastalgia 511

Table 6 The meta-analysis on trials of Tamoxifen vs. placebo. Outcome—proportion of response.

Study Pain relief with Pain relief with RR 95% CI 95% CI Z- p-value Tamoxifen events/total placebo events/total Lower Upper value limit limit

Messinis 18/18 6/18 3 1.56 5.77 and Lolis19 Fentiman 22/28 11/20 1.43 0.92 2.22 et al.20 Kontostolis 23/32 11/29 1.89 1.13 3.17 et al.14 Fixed 1.92 1.42 2.58 4.26 o0.0001 model

Heterogeneity test chi-square ¼ 3.51; df ¼ 2; p ¼ 0.17.

Figure 5 Meta-analysis on trials of Tamoxifen vs. placebo, proportion of pain relief.

breast cancer trialist group’’ organised by Sir References Richard Peto’s group. 1. Mansel RE, Goyal A, Preece P, Leinster S, Maddox PR, Gateley C, et al. European randomised, multicentre study of goserelin (Zoladex) in the management of mastalgia. Am J Conclusion Obstet Gynecol 2004;191(6):1942–9. 2. Halaska M, Beles P, Gorkow C, Sieder C. Treatment of Bromocriptine, Danazol and Tamoxifen all offer cyclical mastalgia with a solution containing a Vitex agnus significant relief from mastalgia. No good data on castus extract: results of a placebo-controlled double-blind direct comparison of above drugs is available. Of study. Breast 1999;8(4):175–81. these Tamoxifen, associated with least side effects, 3. Fentiman IS, Caleffi M, Hamed H, Chaudary MA. Dosage and should be the drug of first choice. EPO is ineffective duration of tamoxifen treatment for mastalgia: a controlled trial. Br J Surg 1988;75(9):845–6. and should not be used. 4. Mansel RE, Preece PE, Hughes LE. A double blind trial of the prolactin inhibitor bromocriptine in painful benign breast disease. Br J Surg 1978;65(10):724–7. Conflict of interests 5. Mansel RE, Dogliotti L. European multicentre trial of bromocriptine in cyclical mastalgia. Lancet 1990;335(8683): 190–3. All the authors declare that there is no conflict of 6. Hinton CP, Bishop HM, Holliday HW, Doyle PJ, Blamey R. A interest. double-blind controlled trial of danazol and bromocriptine in the management of severe cyclical breast pain. Br J Clin Pract 1986;40(8):326–30. 7. Nazli K, Syed S, Mahmood MR, Ansari F. Controlled trial of Funding the prolactin inhibitor bromocriptine (Parlodel) in the treatment of severe cyclical mastalgia. Br J Clin Pract No funds received. 1989;43(9):322–7. ARTICLE IN PRESS

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