Editorials

Evening primrose oil

Many of the studies have been crossover trials, which is a pity for two reasons. Firstly, crossover trials are really suitable only for assessing drugs whose effects fade rapidly after treatment has been stopped. Any ersistent effects will disappear provided there is a "washout" period before the crossover. Secondly, if the explanation given to patients before their informed consent is obtained includes the timing of the crossover their expectations may become a major source of bias. The treatment, the natural course of the disease, and placebo effects will induce changes that the patient may or may not have expected. For example, patients who receive active treatment in the first period and who notice improvements will have low expectations for the next period; and patients who notice no improvement in the first period will assume that they were taking placebo. These expectations would result in a bias, increasing the measured difference. Evening primrose oil is claimed to have effects that are both sustained and subjective, and so parallel trials should be used to assess its effects.

Turning to the published work, for atopic dermatitis Wright and Burton reported positive effects from a double blind crossover trial of evening primrose oil in 99 patients (60 adults and 39 children).² Bamford et al found negative effects in a double blind crossover trial in 123 patients.³ A meta-analysis of nine trials (five crossover trials) including the trial of Wright and Burton but excluding that of Bamford et al reported positive results, and, more recently, negative results were reported from a parallel trial in 123 patients.^4,5

For rheumatoid arthritis Joe and Hart discussed three randomised trials with parallel groups and Leventhal et al reported another one.^6,7 These trials were small - the largest group was of 19 patients, and the results were mixed. The investigators concluded that further trials were warranted.

For the premenstrual syndrome four trials (three crossover trials) have reported positive results,⁸ but more recently Khoo et al found no differences between evening primrose oil and placebo in a crossover trial in 38 women.⁹ The effects of evening primrose oil on mastalgia, one of the symptoms of the premenstrual syndrome, have been investigated in three small randomised trials, with favourable results.¹⁰

After a preliminary trial in 22 diabetic patients reported favourable results the Ggamma Linolenic Acid Multicenter Trial Group reported positive effects on many neurological and neurophysiological end points in a well performed parallel double blind trial in 111 patients with mild diabetic neuropathy.¹¹ These encouraging findings indicate that further investigations of evening primrose oil in diabetic neuropathy should be given priority.

Evening primrose oil seems to be safe. Its reported side effects include nausea, softening of the stools, and headache. One recent comment warned of a potential risk of inflammation, thrombosis, and immunosuppression to slow accumulation of tissue arachidonate after prolonged use of (gamma) linolenic acid for more than one year.¹²

The optimal dose and duration of treatment with evening primrose oil seem not to be known. Trials that have tried to establish a dose-response effect have shown varying results. In trials the daily dose has ranged from two to 16 capsules of 500 mg. One capsule contains about 320 mg linoleic acid, 40 mg (gamma) linolenic acid, and 10 IU of vitamin E. In the prescribing information a dose of three to six capsules twice daily is recommended. The clinical response is said to occur after three to four months and to last for several months.

Most trials have used placebo capsules containing paraffin and matching the capsules of evening primrose oil by colour and shape.¹³ The taste is different, but the capsules should be swallowed unbroken. In doses of 12 capsules daily the amount of vitamin E is a megadose (10 times the recommended daily allowance). Although there are valid arguments for using an inert placebo, one containing linoleic acid and vitamin E would make it possible to isolate the effect of linolenic acid.

The conclusion that I draw from the published research is that evening primrose oil has not been proved to be efficacious in rigorous clinical trials. Many of the trials to date have been crossover studies in small numbers of patients. Publication bias cannot be ruled out (practically all trials have been sponsored by the same company), and for most conditions for which evidence exists from several trials both positive and negative outcomes have been reported. Questions remain about the dose and duration of the treatment, and evening primrose oil should be compared with and shown to be more effective than linoleic acid and vitamin E. Nevertheless, evening primrose oil is an interesting substance, and for some indications it is a promising treatment - especially for diabetic neuropathy and atopic dermatitis, but also for rheumatoid arthritis and the premenstrual syndrome. Further rigorous trials of both evening primrose oil and (gamma) linolenic acid are warranted.

J Kleijnen 

1. Kleijnen J, Riet ter G, Knipschild P. Teunisbloemolie. Een overzicht van gecontroleerd onderzoek. [Evening primrose oil. Review of controlled trials.] Pharm Weekbl 1989;124:418-23. (English translation available from first author.)
2. Wright S, Burton JL. Oral evening-primrose-seed oil improves atopic eczema. Lancet 1982;ii:120-2.
3. Bamford JT, Gibson RW, Renier CM. Atopic eczema unresponsive to evening primrose oil (linoleic and (gamma)-linolenic acids). J Am Acad Dermatol 1985;13:959-65. [Medline]
4. Morse PF, Horrobin DF, Manku MS, Stewart JCM, Allen R, Littlewood S, et al. Meta-analysis of placebo-controlled studies of the efficacy of Epogam in the treatment of atopic eczema. Relationship between plasma essential fatty acid changes and clinical response. Br J Dermatol 1989; 121:75-90.
5. Berth-Jones J, Graham-Brown RAC. Placebo-controlled trial of essential fatty acid supplementation in atopic dermatitis [correction appears in Lancet 1993;342:564] Lancet 1993;341:1557-60.
6. Joe LA, Hart LL. Evening primrose oil in rheumatoid arthritis. Annals of Pharmacotherapy 1993;27:1475-7. [Medline]
7. Leventhal LJ, Boyce EG, Zurier RB. Treatment of rheumatoid arthritis with gammalinolenic acid. Ann Intern Med 1993;119:867-73. [Abstract/Free Full Text]
8. O'Brien PMS, Massil H. Premenstrual syndrome: clinical studies on essential fatty acids. In: Horrobin DF, ed. Omega-6 essential fatty acids. Pathophysiology and roles in clinical medicine. New York: Wiley-Liss, 1990:523-45.
9. Khoo SK, Munro C, Battistutta D. Evening primrose oil and treatment of premenstrual syndrome. Med J Austr 1990;153:189-92.
10. Mansel RE, Pye JK, Hughes LE. Effects of essential fatty acids on cyclical mastalgia and noncyclical breast disorders. In: Horrobin DF, ed. Omega-6 essential fatty acids. Pathophysiology and roles in clinical medicine. New York: Wiley-Liss, 1990:557-66.
11. Gamma-Linolenic Acid Multicenter Trial Group. Treatment of diabetic neuropathy with gamma-linolenic acid. Diabetes Care 1993;16:8-15. [Abstract]
12. Phinney S. Potential risk of prolonged gamma-linolenic acid use. Ann Intern Med 1994;120:692. [Free Full Text]
13. Horrobin DF, Ells KM, Morse-Fisher N, Manku MS. The effects of evening primrose oil, safflower oil and paraffin on plasma fatty acid levels in humans: choice of an appropriate placebo for clinical studies on primrose oil. Prostaglandins Leukotr Essent Fatty Acids 1991;42:245-9