BMJ  2003;327:1385 (13 December), doi:10.1136/bmj.327.7428.1385

Primary care

Efficacy and tolerability of borage oil in adults and children with atopic eczema: randomised, double blind, placebo controlled, parallel group trial

¹ Department of Dermatology, George Eliot Hospital, Nuneaton CV10 7DJ, ² Department of Health Sciences, University of Leicester, Leicester LE1 6TP, ³ Essential Nutrition Ltd, Bank House, Saltgrounds Road, Brough, East Yorkshire HU15 1EF

Abstract

Objective To study the efficacy and tolerability of borage oil, which contains a high concentration of linolenic acid, in children and adults with atopic eczema.

Design Single centre, randomised, double blind, placebo controlled, parallel group trial.

Setting Acute district general hospital in Nuneaton, England.

Participants 151 patients, of whom 11 failed to return for assessment, leaving an evaluable population of 140 (including 69 children).

Intervention Adults received four capsules of borage oil twice daily (920 mg linolenic acid), and children received two capsules twice daily, for 12 weeks.

Main outcome measures Change in total sign score at 12 weeks measured with the six area, six sign, atopic dermatitis (SASSAD) score (primary endpoint); symptom scores, assessed on visual analogue scales; topical corticosteroid requirement, assessed on a five point scale; global assessment of response by participants; adverse events and tolerability.

Results The mean SASSAD score fell from 30 to 27 in the borage oil group and from 28 to 23 in the placebo group. The difference between the mean improvements in the two groups was 1.4 (95% confidence interval -2.2 to 5.0) points in favour of placebo (P = 0.45). No significant differences occurred between treatment groups in the other assessments. Subset analysis of adults and children did not indicate any difference in response. The treatments were well tolerated.

Conclusion linolenic acid is not beneficial in atopic dermatitis.

Introduction

Essential fatty acids are long chain fatty acids that are needed for normal cutaneous function and cannot be synthesised by human metabolism. Most important are the n6 series fatty acids, which include linolenic acid, and the n3 series, which include eicosapentaenoic acid. Many mechanisms have been proposed whereby supplementation with essential fatty acids might prove effective in treating atopic dermatitis.¹ For example, atopic eczema has been suggested to result partly from defective conversion of linoleic acid to metabolites such as the anti-inflammatory prostaglandin E₁.^{1 2} This disease might therefore respond to fatty acid supplementation, which would bypass this metabolic step.

The most investigated form of supplementation has been with linolenic acid.^3-8 Although this treatment has consistently proved safe and well tolerated, efficacy has been inconsistent.⁹ One possible explanation for the inconsistent results may be that the dose used has been too low in some trials. Purified borage oil contains a minimum of 23% linolenic acid. Borage oil is used to fortify infant foodstuffs with essential fatty acid and is available over the counter in chemists and in health food shops, where it is sold as "starflower oil."

Only one large well reported randomised controlled trial of borage oil in atopic eczema has been published.¹⁰ A response to borage oil could not be confirmed for the overall population with the primary response criterion, the quantity of topical steroid required to achieve a 50% reduction in the Costa severity score. Four smaller studies have been reported, two suggesting an improvement and two suggesting none.¹¹ We report here a further trial investigating the efficacy and tolerability of borage oil in the treatment of atopic eczema in both adults and children.

Methods

Design
The study was a prospective, randomised, double blind, placebo controlled trial of parallel group design, done in a single centre. We assessed participants at baseline and at 2, 4, 8, and 12 weeks.

Participants and treatment
We recruited patients aged over 2 years attending our department for treatment of atopic dermatitis diagnosed by using conventional criteria.¹² Borage oil and placebo treatments were provided in matching capsules. Adults received four 500 mg capsules twice daily, providing 920 mg of linolenic acid for those receiving borage oil. Children received half this dose. We allowed patients to use conventional treatment for atopic eczema throughout the study. We permitted no changes in concomitant treatment for two weeks before the study or for the duration of the study, except in the quantity and frequency of topical steroid application, which could be adjusted as needed in relation to the severity of the disease.

Assessments
We assessed disease activity objectively at each visit by using the six area, six sign, atopic dermatitis (SASSAD) score.¹³ This scoring system involves assessment of six signs (erythema, exudation, excoriation, dryness, cracking, and lichenification) at six sites (hands, feet, arms, legs, head and neck, and trunk). Each sign is graded at each site on a four point scale (0-3, representing grades of none, mild, moderate, and severe). The maximum score theoretically possible is therefore 108.

To assess the severity of symptoms, patients used horizontal 10 cm visual analogue scales marked none at the left hand end and worst ever at the right. We assessed itching, sleep disturbance, and irritability in this way. Participants made an overall assessment of response to treatment at the end of the treatment relative to the baseline, on a five point scale: worse, same, improved, much improved, or cleared. These assessments were also done on discontinuation of treatment in patients who were withdrawn. We recorded the need for topical steroid at each visit by using a five point scale: none, occasionally, alternate days, once daily, twice daily. Participants assessed overall tolerability of the treatment on a four point scale: very good, good, fair, or poor.

Sample size
The study was designed to have 80% power to detect a treatment response of 20% (that is, above the response to placebo), with a standard deviation (derived from existing data) of 35%, at a significance level of 0.05. We estimated that 120 participants would be needed. We anticipated that around 20% of participants would be withdrawn and therefore aimed to recruit 152 participants, comprising 76 adults and 76 children.

Results

Demographics
We recruited 151 participants between February 1997 and July 2001. Only two patients (both in the placebo arm) were withdrawn owing to adverse events—one developed a blotchy erythematous rash; the other developed diarrhoea and vomiting, headache, fever, and worsening of asthma. Disease severity was comparable in the two groups at baseline (table 1).

View this table: [in this window] [in a new window]   Table 1 Mean (SD) SASSAD scores, symptom scores, and topical steroid requirement and differences between treatment groups at the end of treatment

 

Efficacy
Table 1 and figure 1 show mean SASSAD scores and symptom scores. The mean SASSAD score fell from 30 to 27 in the borage oil group and from 28 to 23 in the placebo group at the end of treatment. The difference between the mean improvements in the two groups was 1.4 (95% confidence interval -2.2 to 5.0) points, with a marginally greater improvement in the placebo group (P = 0.45).

View larger version (20K): [in this window] [in a new window]   Fig 1 Six area, six sign, atopic dermatitis (SASSAD) scores throughout the trial (n=140; error bars show SE)

 

Symptom scores all fell in both treatment groups during the study (table 1). Pruritus, sleep disturbance, and irritability all improved slightly more in the placebo group than in the borage oil group. These differences between the two groups were not significant for any of the symptoms. Table 2 shows patients' assessments of overall response to treatment. Table 1 and figure 2 show data on the frequency of application of topical corticosteroids at baseline and throughout the study. Subset analysis of adults and children yielded no suggestion of any difference between them in any of the parameters studied.

View this table: [in this window] [in a new window]   Table 2 Overall assessments of response. Values are numbers (percentages)

 

View larger version (21K): [in this window] [in a new window]   Fig 2 Use of topical steroids assessed at each visit on a five point scale (n=140)

 

Tolerability
Both treatments were generally well tolerated (tables 3 and 4).

View this table: [in this window] [in a new window]   Table 3 Patients' assessment of tolerability of treatment. Values are numbers (percentages)

 

View this table: [in this window] [in a new window]   Table 4 Adverse events reported by more than one participant: number (percentage) of participants reporting

 

Discussion
The greatest level of response to borage oil likely to be compatible with these data is a two point improvement in the SASSAD score. If a benefit of this magnitude occurred (approximately 7% of the baseline sign score), this would be of limited clinical value. A two point improvement might represent, for example, an improvement of a single sign by one grade in two areas or of two different signs in one out of the six areas assessed. However, the data do not exclude the possibility of such a small degree of benefit. The data do not suggest that a longer duration of treatment would have been more likely to have yielded a positive outcome. Indeed, figure 1 would suggest that, if anything, the difference in favour of placebo was widening.

The design and method of this trial worked well. The narrow confidence intervals for the improvement in sign score indicate that the sample size was correctly estimated and that the study was adequately powered.

These data are compatible with results from the largest studies in which evening primrose oil was used as a supplement of linolenic acid.^{7 8} The results are also compatible with the results of previous trials on supplementation with borage oil.^{10 11} The dose of linolenic acid administered in this study was the highest used in any trial to date. The results would therefore seem to refute any contention that the response is dose related or that the lack of response, or the inconsistent response, seen in some previous trials has resulted from the dose being too low in those trials.

What is already known on this topic The essential fatty acid linolenic acid has been investigated in many small trials as a supplementary treatment for atopic eczema Results have so far been conflicting and inconclusive, but some studies have suggested a dose related benefit What this study adds The dose of linolenic acid in this study was the highest so far investigated The symptoms and signs of atopic dermatitis improved to a similar degree in both groups, with the minimal difference being in favour of placebo This study was well powered and confidence intervals were narrow, so linolenic acid is unlikely to offer any useful benefit in treatment of atopic dermatitis

We found no evidence of a steroid sparing effect from borage oil treatment. The recording of topical steroid requirement has always been one of the most difficult aspects of trials on atopic dermatitis, but the five point scale used in this study proved useful and simple to apply. The result seems incompatible with the 60% reduction in steroid requirement reported in a previous small study on evening primrose oil.⁴

In conclusion, it seems unlikely that dietary supplementation with linolenic acid is beneficial in management of atopic dermatitis.

---

This is an abridged version; the full version is on bmj.com

Editorial by Williams

Contributors: See bmj.com

Funding: This study was sponsored by Essential Nutrition Ltd.

Competing interests: TC is a director of Essential Nutrition Ltd.

Ethical approval: Warwickshire Research Ethics Committee approved the protocol.

References

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2. Melnik BC, Plewig G. Are disturbances of omega-6-fatty acid metabolism involved in the pathogenesis of atopic dermatitis? Acta Derm Venereol 1992;suppl 176: 77-85.
3. Wright S, Burton JL. Oral evening primrose seed oil improves atopic eczema. Lancet 1982;2: 1120-3.[Web of Science][Medline]
4. Schalin-Karrila M, Mattila L, Jansen CT, Uotila P. Evening primrose oil in the treatment of atopic eczema: effects on clinical status, plasma phospholipid fatty acids and circulating blood prostaglandins. Br J Dermatol 1987;117: 11-9.[Medline]
5. Bordoni A, Biagi BL, Masi M, Ricci G, Fanelli C, Patrizi A, et al. Evening primrose oil (Efamol) in the treatment of children with atopic eczema. Drugs Exp Clin Res 1988;14: 291-7.[Web of Science][Medline]
6. Morse PF, Horrobin DF, Manku MS, Stewart JC, Allen R, Littlewood S, et al. Meta-analysis of placebo-controlled studies on the efficacy of Epogam in the treatment of atopic eczema: relationship between plasma essential fatty acid changes and clinical responses. Br J Dermatol 1989;121: 75-90.[Web of Science][Medline]
7. Berth-Jones J, Graham-Brown RAC. Placebo controlled trial of essential fatty acid supplementation in atopic dermatitis. Lancet 1993;341: 1557-60.[CrossRef][Web of Science][Medline]
8. Bamford JTM, Gibson RW, Reiner CM. Atopic eczema unresponsive to evening primrose oil (linoleic and gamma-linolenic acids). J Am Acad Dermatol 1985;13: 959-65.[Web of Science][Medline]
9. Berth-Jones J, Graham-Brown RAC. A review of the use of essential fatty acid supplementation in atopic dermatitis with emphasis on the methodology of trial design. In: Maibach HI, Schwindt DA, eds. Cutaneous biometrics. New York: Plenum Publishing Corporation, 2000;ch 9: 109-17.
10. Henz BM, Jablonska S, Van der Kerkhof PCM, Stingl G, Blaszczyk M, Vandervalk PG, et al. Double-blind, multicentre analysis of the efficacy of borage oil in patients with atopic eczema. Br J Dermatol 1999;140: 685-8.[Medline]
11. Hoare C, Li Wan Po A, Williams H. Systematic review of treatments for atopic eczema. Health Technol Assess 2000;4(37): 1-91.[Medline]
12. Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol 1980;92(suppl): 44-7.
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(Accepted October 10, 2003)

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