February Issue.indd

Department of Surgery, Surgical Unit 11, Dow Medical College and Civil Hospital, Karachi, Pakistan

Correspondence to: S. Qureshi, Department of Surgery, Surgical Unit 11, Dow Medical College and Civil Hospital, Karachi, Pakistan email: sajida_q@hotmail.com

Introduction

Objective: To compare oil of evening primrose (OEP) and topical nonsteroidal anti-inflammatory (NSAIDs) with respect to safety, effectiveness, rapidity of response, cost effectiveness and acceptability in the treatment of breast pain. Study Design: An open, non-randomised, comparative study of topical (NSAI) gel versus OEP was carried out, over a period of one year. Patients and Methods: Fifty female patients attending the outpatient department with moderate to severe breast pain were given one of the two agents alternatively, after selection. Results: Results showed that out of 25 patients treated with OEP, 64% had a clinically significant response after three months of treatment, compared with 92% with topical NSAIDs. Only one patient (4%) had side effects with OEP, while no patient had side effects with topical NSAIDs. Twenty per cent and seventy per cent showed acceptability as far as costs were concerned and mode of administration respectively, with OEP. The acceptability rate was 68% and 96% respectively, with topical NSAIDs. Conclusion: This study has shown topical NSAIDs to be safe, effective, rapid and acceptable mode of treatment for cyclical and non-cyclical mastalgia

Keywords: Oil of evening primrose, topical NSAIDs, mastalgia, cyclical breast pain/mastalgia, noncyclical breast pain/mastalgia Surgeon, 1 February 2005, 7-10

Breast pain is a common clinical symptom affecting up to 70% of women at some stage of their life.^1,2 It is the commonest breast symptom in patients attending surgical outpatient departments.³ The reason underlying most of these presentations is the fear of an underlying carcinoma as the basis for the mastalgia, although only 7% of the patients with operable carcinoma have mastalgia as the sole presenting symptom.⁴ Most women develop minor premenstrual breast pain associated with or without nodularity which resolves with menstruation. This is considered to be physiological, hormonally driven and normal. Severe breast pain and nodularity that persists for most, if not all of the cycle and interferes with the daily activities by affecting the woman’s sleep and relationship with her children and/or partner is considered to be clinically relevant.

The most important factors in the evaluation and treatment of breast pain include taking a history, carrying out a physical examination and evaluation by imaging nodalities. These can be used to reassure the patient that she does not have breast cancer, and 85% of the patients will subsequently require no further treatment⁵; 15% who have significant pain affecting their quality of life will require treatment. Therapy may consist of a well-fitting bra, a decrease in dietary fat intake and discontinuance of oral contraceptives or hormone replacement therapy. These women may experience relief from OEP supplements, danazol, bromocriptine, tamoxifen, or a GnRH analogue. Predicting which treatment will be most useful for any particular women is challenging and bears no relationship with the reproductive history, presenting complaints, personal or family history of breast disease. Prescribing a drug requires taking into account the efficacy, cost and side-effects.

A range of non-hormonal and hormonal agents are available for symptom control, but many are ineffective. Only a small number of agents have been adequately assessed in randomised controlled trials and have been demonstrated to be more effective than placebo. Response to therapy and prognosis of mastalgia is unpredictable. It may follow a protracted course requiring long-term treatment. This study aims to assess the value of topical NSAIDs in comparison with OEP in the management of cyclical and non-cyclical breast pain.

The study conducted was a quasi-experimental study with a non-probability purposive sampling technique. Fifty female patients attending a general surgical outpatient department (OPD) at Civil Hospital Karachi, presenting with moderate to severe breast pain of two to three months duration over a period of one year, from January 2000 to January 2001, were included in the study. A thorough history was obtained and physical examination was carried out on each patient. Ultrasonography of the breast and mammography, where necessary, were done to exclude benign breast disease and to exclude occult carcinoma, particularly in cases having a strong family history of breast cancer. Patients presenting with a discrete lump, nipple discharge, lactation and obvious breast abscess were excluded. A proforma to collect data pertinent to the study was filled for each patient. In addition, a breast pain chart was provided, which each patient was required to fill each day for two months and then submit for classification of the type and severity of the breast pain (Table 1).

After taking informed consent about the respective treatments, patients were allocated to two groups alternatively (first patient to group 1 and second to group 2, third to group 1 and so on). Group 1 were given a topical NSAID in 0.5% Piroxicam gel (Feldene) for local application to the affected area twice a day for three months. Group 2 were given OEP capsules (Efamol) 500mg twice daily. Efamol is an extract from the primrose plant (5000 seeds = 500 gms of drug). Both groups were given the oral analgesic tablet Diclofenic twice daily for one week to alleviate the severity of the pain. Patients were advised not to take any analgesics after the initial one week and report if the pain became intolerable.

Response to treatment, side-effects and compliance of the patient was determined at four, eight and twelve weeks followup, respectively. Patients were required to fill the breast pain chart each day during treatment to monitor the pain. Each month, response to treatment was gauged according to the Cardiff breast pain score (Table 1). Patients were also asked at each follow-up regarding any side-effects, willingness to continue the treatment, the cost and mode of administration of the given drug.

No treatment was changed before three months of therapy, no matter what the response. If the patient did not respond to treatment for three months, the other medication used in this study was given for a further three months. This study focuses on the response to the two drugs over a period of three months only. After collecting the data, results were compared and data analysed by the student t test and chi-square test.

Fifty female patients aged 15 to 50 years were included in this study. Out of twenty-five patients who used OEP, none showed a grade I or II response at four weeks follow-up (Table 1). Fourteen patients (56%) had a grade III response at four weeks. Again no patient had a grade I response at the 12-week followup. Sixteen patients (64%) had a grade II response and eight (32%) had a grade III response at 12 weeks. Only one patient (4%) complained of nausea and altered taste, while twentyfour patients (96%) had no side-effects.

Of the twenty-five patients treated with topical NSAIDs, eight patients (32%) had a grade I response at four weeks and 14 (56%) had Grade-II response at four weeks. In the evaluation of overall effectiveness of topical NSAIDs at 12 weeks, 14 out of 25 patients (56%) had a grade I response, nine patients (36%) had a grade II response and two patients (8%) had a grade III response.

Only one patient (4%) showed side-effects with OEP, whereas none of the patients on NSAIDs had any side-effects. Five patients (20%) on OEP found the drug acceptable with regard to the cost of the treatment, while 20 patients (80%) found it costly. Seventeen patients (68%) on NSAIDs found the drug not costly and only eight patients (32%) found the medication expensive.

Regarding acceptability of mode of administration, 18 patients (72%) on OEP preferred the per-oral route of administration of the drug, while 24 patients (96%) on NSAIDs preferred the topical mode of administration.

The results were analysed using the student t test (p value 0.0001 for overall effectiveness and rapidity of response) and the chi-square test (p value 0.011 and 0.355 for acceptability to cost and mode of treatment of the two drugs, respectively).

Breast pain is an important clinical feature and common problem in women of all ages. Occasionally, it can be a distressing symptom, which may or may not be associated with nodularity. Reassurance following the exclusion of cancer is the keystone of management for the majority of patients. However, in spite of this, there remains a small group of patients with severe persistent mastalgia who will require therapy. Severe breast pain significantly impairs the quality of life of these women including work performance, sleep, personal and sexual relations, which are all indications for active treatment.

While prescribing any treatment, compliance of the patient should always be taken into consideration. Treatment should be initiated in consultation with the patient regarding the mode of treatment and different options available.

Breast pain with or without nodularity is a common and alarming feature to many patients attending the outpatients clinics in our country. Most females do not want to take hormonal therapy for their symptoms. This study was undertaken with the aim of evaluating a non-hormonal, rapid, efficient, less toxic and cost acceptable treatment option for patients with severe mastalgia.

The two agents used for comparison included OEP, which is used extensively in Britain as first line treatment for cyclical mastalgia. It is a natural product rather than a drug and is perceived as such and is thus more acceptable to the general public.⁶ It is rich in poly-unsaturated omega-6 essential fatty acids. It is thought to restore the abnormal essential fatty acid profile in the breast. Oil of evening primrose is considered useful for patients who require long-term therapy and is usually prescribed as a capsule in a dose of 500mg twice daily. Doses of the drug used in international studies have varied from 2gms to 3gms daily. The optimal dose and duration of treatment with OEP is not known.⁷ Use of OEP varies from countries and inhabitants and dietary habits. Women in our country have a smaller build, so less total body surface area, thereby decreasing the total requirement of the drug. There is also a difference with diet amongst Pakistanis and Western people.

The other medication used was a topical application of NSAIDs as a gel (Piroxicam) twice a day on the affected area for three months. Topical treatment for mastalgia has been suggested to be ideal.8 These agents are recommended for soft tissue injuries and muscle pain. Topical NSAIDs are established as having a local effect from transcutaneous absorption.9 They are rapidly effective in relieving pain.

Results of the study with regard to the over all effectiveness of the two drugs revealed topical NSAIDs to be highly effective (p<.0001) with standard deviation of 0.48. Out of the 25 patients on OEP, none had a grade I response (Cardiff breast score), compared with 14 patients (56%) having a grade I response with topical NSAIDs. By contrast, 16 patients (64%) had a grade I response, compared with nine patients (36%) with topical NSAIDs at 12 weeks. The overall effectiveness (grade I and II at 12 weeks) was 64% for OEP and 92% for topical NSAIDs.

In various studies, the overall response rate with OEP was 58% in cyclical mastalgia and 38% for non-cyclical pain respectively.¹⁰

In this study, the medications were given only for three months so that it was inadequate in determining if the response was maintained or not. However, the results showed topical NSAIDs to be significantly more effective than OEP supplementation. One factor limiting this judgement is that OEP, being a dietary supplement, produces its maximal effect usually after two to three months, whereas this study evaluated the results at the end of three months. To argue a more accurate assessment the study should have been of six months duration.

There are no national or international studies, to date, comparing the above two regimens in treatment of mastalgia. However, there are several studies, comparing dietary manipulation versus hormonal treatment in moderate to severe mastalgia. In one study, conducted in the UK, effectiveness of topical NSAIDs in the management of breast pain was evaluated and published.¹¹ Topical NSAIDs gel preparation was used on 26 women with severe breast pain. The results revealed a satisfactory relief of pain in 81% of cases.

Controversy has surrounded the introduction in recent years of transdermal NSAIDs.^12,13 Over the past 15 years, some six topical NSAIDs have been licensed for use in the UK, and a number of others are available in other countries or are under investigation.

The success of transdermal absorption lies in the enhanced topical delivery and local accumulation in target tissues by direct diffusion. The concentration of the drug in tissues adjacent to the skin, namely subcutaneous tissue and muscles, is substantially higher than in plasma after dermal application.⁹ Local reaction as a delayed type hypersensitivity dermatitis may occur at the site of application but this is uncommon.¹⁴ It should be avoided on skin that is either not intact or is unhealthy. These agents are contraindicated in subjects with known hypersensitivity to NSAIDs. Caution is also advised in their use in those cases with compromised renal function, as further depression of glomerular filtration may occur.¹⁵

None of the 25 patients on topical NSAIDs complained of any side-effects and only one patient complained of side-effects with OEP. Reported side-effects with OEP include abdominal bloating, nausea, weight gain, headache, depression, giddiness, rash and bad taste. One study reported side-effects in 4% of patients, significant enough in 2% to stop the treatment.¹⁶ The doses used in these latter studies were higher than those prescribed for our patients.

This study has shown topical NSAIDs to be safe, rapidly effective and a patient acceptable mode of treatment for cyclical and non-cyclical mastalgia. This compares favourably with established recommended first line treatments like OEP and other treatments which usually involve months of continous treatment, and not insignificant side-effects.

Further studies are required to investigate topical NSAIDs as a first line of treatment alone or as an adjuvant to other treatments in cyclical or non-cyclical breast pain.

We are grateful to Professor M. Saeed Quraishy for his help in the research work and writing of this article.

1. Gateley CA, Holland PA. Drug therapy of mastalgia.What are the options? Drugs 1994; 48 (5): 709-16.

2. Gateley CA, Mansel RE .Management of cyclical breast pain. Br J Hosp Med 1990; 43: 330-32.

3. Mansel RE. Clinical Assessment of mastalgia. Br J Clin Pract Suppl 1989; 43 :17-19.

4. Preece RE, Baumm M, Mansel RE, Webster DJ, Fortt RW, Gravelle IH et al. The importance of mastalgia in operable breast cancer. Br Med J 1982; 284:1299-330.

6. Fentiman IS, Caleffi M, Brame K, Chaudary MA, Hayward JL . Double-blind controlled trial of tamoxifen therapy for mastalgia. Lancet 1986;1: 287-88.

8. Mc Fadyen IJ, Raab GM, Macintyre CC, Forrest AP. Progesterone cream for cyclical mastalgia. BMJ 1989; 298:

9. Grahame R. Transdermal nonsteroidal anti-inflammatory agents. Br J Clinic Pract 1995; 49; 33-35.

10. Pye JK, Mansel RE, Hughes LE. Clinical experience of drug treatments for mastalgia. Lancet 1985; 2: 373-77.

11. Irving AD, Morrison SL. Effectiveness of topical nonsteriodal anti-inflammatory drugs in the management of breast pain . J R Coll Surg Edinb 1998; 43(3):158-59.

12. Anonymous. Topical nonsteroidal anti-inflammatory drugs (NSAIDs). Medicines Resource 1991; 4:13-16.

13. Anonymous. More topical NSAIDs: Worth the rub? Drug Ther Bull 1990;28:27-28.

14. Oh VM . Ketoprofen gel and delayed hypersensitivity dermatitis. BMJ 1994;309:512

15. O’Callaghan CA, Andrews A, Ogg CS. Renal Disease and use of topical nonsteroidal anti-inflammatory drugs . BMJ 1994; 308:110-11.

16. Gateley CA, Miers M, Mansel RE, Hughes LE . Drug treatments for mastlagia:17 years experience in Cardiff Mastalgia clinic. J R Soc Med 1992; 85:12-15.

TABLE 1. CARDIFF BREAST PAIN SCORE (CBS)
CBS 1	An excellent response with no residual pain
CBS 2	A substantial response but with some residual pain, considered by the patient to be bearable
CBS 3	A poor response with substantial residual pain
CBS 4	No beneficial response at all
Adapted from: Mansel RE, Fenn NJ, Davies EL. Benign breast disease and its management. In: Johnson CD, Taylor I, editors. Recent Advances in Surgery 21. Edinburgh: Churchill Livingstone; 1998. p. 71-83.

TABLE 2. COMPARISON OF DRUGS ACCORDING TO EFFECTIVENESS
	OEP		NSAIDs
	Patients (n=x)	%	Patients (n=x)	%	P value	Test used
Overall Effectiveness
Grade I+II at 12 weeks	16	64%	23	92%	0.0001	Student t test
Rapidity of response (grade I+II) at four weeks	0	0%	22	88%	0.0001	Student t test
Side-effects	1	4%	0	0%	-	-
Acceptability of cost	5	20%	17	68%	0.011	Chi-square test
Acceptability of mode of administration	18	72%	24	96%	0.355	Chi-square test
Cost of three months of treatment	$52		$21