Oenothera – Evening Primrose Oil (Oenotherae biennis oleum)
|Latin name of the genus:||Oenothera|
|Latin name of herbal substance:||Oenotherae biennis oleum|
|Botanical name of plant:||Oenothera biennis l.; oenothera lamarckiana l.|
|English common name of herbal substance:||Evening primrose oil|
Latin name of the genus: Oenothera
Latin name of herbal substance: Oenotherae biennis oleum
Botanical name of plant: Oenothera biennis L.; Oenothera lamarckiana L.
English common name of herbal substance: Evening Primrose Oil
- 1. Introduction
- 2. Historical data on medicinal use
- 3. Non-Clinical Data
- 3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- 3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
- 3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
- 3.4. Overall conclusions on non-clinical data
- 4. Clinical Data
- 4.1. Clinical Pharmacology
- 4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
- 4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
- 4.2 Clinical Efficacy
- 4.2.1. Dose response studies
- 4.2.2 Clinical studies (case studies and clinical trials)
- 4.2.3 Clinical studies in special populations (e.g. elderly and children)
- 4.3. Overall conclusions on clinical pharmacology and efficacy
- 5. Clinical Safety/Pharmacovigilance
- 6. Overall conclusions
1.1 Description of the herbal substance(s), herbal preparation(s) or combinations thereof
The HMPC has established a Community herbal monograph on the oil obtained from the seeds of Oenothera biennis L. or Oenothera lamarckiana L. The monograph does not cover the herbal substance itself, i.e. the seeds from the two species.
The fatty oil is obtained from seeds of Oenothera biennis L. or Oenothera lamarckiana L. by extraction and/or expression. It contains at least 65% (cis)linoleic acid,
The oil of Oenothera biennis and Oenothera lamarckiana is a fatty oil obtained by cold pressing of the seeds. This oil is more reactive and less stable than most other fatty oils. Besides oxidation after exposure to air and light, the oil is also sensitive to heat and humidity. Consequently, it should be stored in a cool, dark place (Price & Price 2007).
Combinations of herbal substance(s) and/or herbal preparation(s) including a description of vitamin(s) and/or mineral(s) as ingredients of traditional combination herbal medicinal products assessed, where applicable.
1.2Information about products on the market in the Member States
According to the Drogelist DK at least 5 g oil is accepted in food supplements. These products were very popular
Rare: hypersensitive reactions like exanthema, abdominal pain and very rare rise in temperature.
1 capsule contains 500 mg Oenotherae biennis oleum, minimum gamma linolenic acid content 9%.
On the market since 1992.
Oral use. For adults and adolescents above 12 years of age 3 times
Indications: atopic eczema, symptoms associated with menstruation, prevention of vascular diseases, as adjuvant treatment of rheumatic arthritic inflammation and multiple sclerosis.
Undesired effects: rarely nausea, diarrhoea, vomiting, bloating.
In case of adverse effects occur the dose should be reduced.
Apart from this licensed preparation, more than 5 combination products are on the market.
Oenothera fatty oil is used in a licensed cream with a full marketing authorisation. It is indicated as an occlusive, emollient cream, which restores hydration and improves skin smoothness in chronic dry skin conditions.
There are some food supplements on the Spanish market, usually soft gelatine caps of 500 mg
Undesirable effects: Mild and transient irritation to the site of application has been reported rarely. Contact dermatitis and urticaria has been reported in individual cases.
Regulatory status overview
MA: Marketing Authorisation TRAD: Traditional Use Registration
Other TRAD: Other national Traditional systems of registration Other: If known, it should be specified or otherwise add ’Not Known’
This regulatory overview is not legally binding and does not necessarily reflect the legal status of the products in the MSs concerned.
1.3Search and assessment methodology
The following basic sources were searched:
Herbal Medicines (Barnes et al. 2007)
Phytotherapy (Capasso et al. 2003)
European Pharmacopoeia (2008, 2010)
Hagers Handbuch der pharmazeutischer Praxis (Hänsel 1993)
Pubmed and Embase were searched from February 2009 to March 2011 on the following keywords (separate or combined):
Oenothera biennis or lamarckiana primrose fatty oil, skin, disorders, atopic, dermatitis, eczema, children, patient, premenstrual, syndrome, oral, topical, premenstrual syndrome = PMS, mastalgia, menopausal, menopause, hormonal, Sjögren, Raynaud, safety, quality, mutagenicity, mutagenic, side effects, adverse, event.
2. Historical data on medicinal use
2.1. Information on period of medicinal use in the Community
Oenothera biennis was first grown by North American Indians. They used the plant as treatment for swelling in the body and other health problems.
Before the arrival of the Pilgrim Fathers, Oenothera species oil was used by the Indians in poultices to relieve skin disorders. In 1614, botanists from Virginia brought it to Europe, in order to study it. English herbalist Nicholas Culpeper wrote in 1650: “It opens obstructions of the liver and spleen, provokes urine, is good for dropsy (oedema) if infused in common drink.”
It was introduced to Europe by the name ‘king’s
Since then it was ignored for centuries, even though old herbal text books described it as astringent and sedative, with its oil being ‘helpful in treating
The German scientist Unger discovered that the oil can be extracted from the seeds, which contain 15% oil, using light petroleum. In 1919, an unusual linolenic acid was found by Heiduschka and Lüft when they analysed the seed oil; they named it
Modern usage of Oenothera biennis oil
Interest in Oenothera biennis oil increased in the late 1970s when the oil was proposed to treat various ailments. Oenothera biennis oil products were marketed as a supplement for the treatment of PMS, alcoholism,
In 2002, the UK Medicines Agency withdrew all marketing authorisations for oral evening primrose oil capsules. This followed a review by the UK Medicines Agency of all the relevant information, including new studies and statistical analyses. The UK Medicines Agency concluded that the data did not support the current standards of efficacy required for authorisation of these products as medicines for the treatment of eczema and mastalgia (Anonymous 2002).
2.2. Information on traditional/current indications and specified substances/preparations
See 1.2. Information about products on the European market and 2.3. Relevant preparations and indications.
2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications
Based on the posology published in handbooks, the dosages for atopic eczema for adults and children are
Based on clinical trials, the dosages for atopic eczema for children and adults are
Duration of use
Three months of therapy is usually required before a full therapeutic effect is noticed (Bédard 2003). Results of clinical studies on atopic eczema demonstrated a clinical effect after
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
There was no significant difference in weight gain between the two diets. The average number of tumours and
(AA) levels were significantly higher, and oleic acid levels were significantly lower in rats who received an Oenothera feeding compared with a corn oil feeding.
De La Cruz et al. (1997) performed a study of 6 weeks. Animals used were forty male white New Zealand rabbits of 2 months and had a body weight of 2498 ±36 g. Four groups were made with each ten rabbits. The first group received a normal diet and was seen as controls. The second group received an atherogenic diet. The following group had to eat a normal diet with 15% Oenothera. The last group of rabbits received an atherogenic diet with 15% Oenothera. The rabbits received their meal periodically. Serum lipid profile, platelet aggregation in whole blood, tromboxane B2 production and platelet lipid peroxide were measured. Oenothera fatty oil reduced platelet production. The oil also inhibited the lipid peroxide production. The cholesterol was reduced by 25%, the triglyceride value by 51% and the
Al – Shabanah (1997) used Wistar albino rats of both sexes, approximately the same age and weighing
In the first study, pylorus
acidity output. Oenothera reduced the volume of gastric secretion, free acid and total acid output significantly, compared with controls.
The second study proceeded
30 mg/kg body weight (0.5 ml/100 g). The rats were killed after 6 hours administration of indomethacin. Each stomach was examined. Phenylbutazone induced gastric lesions. Two hundred mg/kg phenylbutazone was given intraperitoneal to rats who had fasted 24 hours. After 6 hours of administration, the rats were killed. The results are:
The third study proceeded hypothermic restraint
The last study consisted of gastric ulcers induced by necrotising agents (cytoprotective studies). After fasting 36 hours with access to water ad libitum, 1 ml of necrotising agent (0.6 M HCl, 0.2 M NaOH, 25% NaCl or 80% (v/v) aqueous ethanol) was given intragastrically. Oenothera or corn oil was administered 30 minutes before the necrotising agents. One hour after the administration of necrotising agents, the rats were killed and their stomachs were examined. The inhibitory action exerted by Oenothera on the ulcers induced by HCl and ethanol was
The results show that Oenothera oil prevents an increase in acid secretion in
Riaz Azra et al. (2009) assessed the effect of Oenothera on coagulation parameters in healthy rabbits. Oenothera fatty oil contained 73% linoleic acid, 9%
fibrinogen time (Fg) were measured to monitor the influence of Oenothera on the blood coagulation process.
After 30 days of treatment a significant increase was found in PT and TT at normal, moderate and high doses and at standard drug warfarin. Also a significant increase in aPTT was observed at normal, moderate and high dose of Oenothera and standard drug warfarin.
After 60 days significant increase in TT and in PT were found at all doses. Fibrinogen time was not significantly affected at any dose. This study concluded that Oenothera has anticoagulant properties and its anticoagulant activity is supported by its
Pellegrina et al. (2005): A phenolic fraction from Oenothera biennis showed potent and selective cytotoxic effects against bone
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
No data available.
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
Everett et al. (1988a) studied the toxic effects of Oenothera oil in a
Twenty male and 20 female beagle dogs received a daily dose of 5 ml/kg oil by oral gavage. A natural vitamin E was added to the oils. There were 4 groups with a different dose of Efamol® (0, 1, 3, 5 ml/kg) and corn oil. Food consumption was measured every week, body weight every 4 weeks and ophtalmoscopic examination was performed at 0, 25 and 52 weeks. Haematology analysis, clinical chemistry analysis and urinalysis were carried out at 0, 12, 26 and 50 weeks. After 52 weeks, the animals were killed and a post mortem examination was carried out. One dog died during the study, after administration of an intermediate dose of Efamol, was also examined. A histopathologic examination was performed on internal and external body parts. These data were analysed and the Efamol® treatment was compared with the control group. No significant differences were found in food consumption, clinical signs or body weight changes neither in haematology, urinalysis nor clinical chemistry. No differences were found in the necroscopical or histopathological examination.
Male and female
No important adverse effects were found in comparison with corn oil. Therefore, it is safe to use Efamol® as a nutritional supplement.
Everett et al. (1988b) performed a
No specific genotoxicity or mutagenicity testing was performed.
In animal studies, Oenothera oil was found not to be teratogenic (Barnes et al. 2007).
3.4. Overall conclusions on
The activity of Oenothera oil has been studied in experimental in vivo cancer models. It seems to protect the animals against development of
There was no chronic toxic, carcinogenic or teratogenic effect observed in the studies.
4. Clinical Data
4.1. Clinical Pharmacology
4.1.1. Overview of pharmacodynamic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
Linoleic acid (LA) is an essential fatty acid that is metabolised by
Figure 1: Metabolic pathway of linoleic acid.
There is a deficit of D6D enzyme in atopic eczema and PMS. This causes an increase of LA and a decrease of GLA and DGLA.
An increased sensitivity for prolactin and other hormones during the luteal phase in PMS might be caused by the abnormal fatty acid metabolism (Collins et al. 1993).
Because of this D6D deficit in atopic eczema, there is a lower concentration of PGE1 and PGE2. The decrease of PGE1 causes an increased IgE concentration which leads to a release of mediators including histamine from leukocytes, mast cells and basophils. A decrease of PGE2 results in less activation of T- suppressor lymphocytes (=
Assessor’s overall conclusions on pharmacodynamics
Patients with atopic eczema and premenstrual syndrome have a deficit in D6D, the enzyme that converts linoleic acid in
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
Table 1: Pharmacokinetic parameters of
( g ml–
aSignificantly higher than tmax PM (p < 0.05).
bSignificantly higher than AUC24h of the baseline concentration of
Assessor’s overall conclusions on pharmacokinetics
GLA, administered as Oenothera oil (Epogam®), is absorbed from the
4.2 Clinical Efficacy
4.2.1. Dose response studies
There are no dose response studies available.
4.2.2 Clinical studies (case studies and clinical trials)
Grade system for quality assessment
The GRADE system for randomised clinical trials, reviews and
*Consistency: refers to the similarity of estimates of effect across studies. If there is important unexplained inconsistency in the results, our confidence in the estimate of effect for that outcome decreases. Differences in the direction of effect, the size of the differences in effect, and the significance of the differences guide the (inevitably somewhat arbitrary) decision about whether important inconsistency exists.
**Directness: there are two types of indirectness of evidence. The first occurs when considering, for example, use of one of two active drugs. Although randomised comparisons of the drugs may be unavailable, randomised trials may have compared one drug with placebo and the other with placebo. Such trials allow indirect comparisons of the magnitude of effect of both drugs. Such evidence is of lower quality than would be provided by head to head comparisons of the drugs.
The second type of indirectness of evidence includes differences between the population, intervention, comparator to the intervention, and outcome of interest, and those included in the relevant studies.
***Imprecision: When studies include relatively few patients and few events and thus have wide confidence intervals, a guideline panel will judge the quality of the evidence to be lower.
For more information: http://www.gradeworkinggroup.org
‘Atopic eczema/dermatitis syndrome’ is the summarised term for ‘atopic dermatitis’, ‘atopic eczema’ and ‘prurigo Besnier’. This disease is a chronic inflammatory of the skin, which can appear everywhere on the body. Mostly it begins in childhood. Frequently, it is related to other atopic diseases such as asthma. Both genetic and
Anstey et al. (1990) performed a randomised,
Very low quality of evidence.
Gehring et al. (1999) conducted a
Low quality of evidence.
Lovell et al. carried out a randomised,
Patients or their relatives and a doctor were asked to score the severity of the eczema on a continuous 10 cm linear scale, at the beginning and the end of the treatment periods. The authors concluded that the patients receiving Efamol® showed a modest but significant improvement on both the doctor’s (P < 0.01) and their own assessment (P < 0.05).
Low quality of evidence.
Wright & Burton (1982: cited by
12 weeks in a blocked randomisation with approximately equal numbers.
Efamol® containing 500 mg evening primrose oil (= 360 mg LA, 45 mg GLA) was administered in different doses. Adult patients received 3 different doses: 2 capsules 2 times daily, 4 capsules 2 times daily and 6 capsules 2 times daily. Children received 2 different doses: 1 capsule 2 times daily and 2 capsules 2 times daily. The placebo was 500 mg liquid paraffin. The use of mild topical steroids, emollients, oral antihistamines was allowed. Sixteen adults and 3 children dropped out early.
In the lowest dose groups for children and adults, itch was the only symptom which improved more with Oenothera as compared to placebo (P < 0.05). In the higher dose groups, a significant clinical improvement was found on a 10 cm linear scale. The patient assessment is significantly superior to the placebo in itch, scaling and general impression of severity (P < 0.01 to 0.002). There was also a beneficial effect shown in the doctor’s assessments (P < 0.002). There was a mean improvement of about 30% of the overall severity of the eczema.
Moderate quality of evidence.
Bamford et al. (1985) conducted a
Side effects were minor and temporary. The complaints were equal in both groups: nausea and bloating (5 subjects using Oenothera versus 1 subject using placebo), hyperactivity (3 children placebo versus 1 Oenothera).
Eighty patients achieved a compliance of 50%, 56 patients achieved 75%. Both patients (or parents of child patients) and physicians had a similar rating of the average appearance of lesions. The patients had 3 evaluation visits, namely before the trial, and 3 and 6 months after the beginning of the study. No changes in weight, triceps,
Moderate quality of evidence.
All the clinical parameters (overall severity and grade of inflammation, dryness and itch, reduction surface area) significantly improved in patients treated with Oenothera. These patients used less topical steroids than the placebo groups. The latter had a significant reduction in inflammation. Patients treated with Oenothera had a more significant reduction in inflammation than the placebo group.
The DGLA concentration increased significantly after 6 weeks of treatment with Oenothera. However, PGE1, a metabolite of DGLA, did not rise. The ratio of PGE1 to PGE2 was unaltered. A clinical improvement in the patients suggested that the increased DGLA level may play a role in the effects of Oenothera. The use of topical steroid during Efamol® treatment could be reduced to about 30% (Morse & Clough 2006).
Moderate quality of evidence.
Morse et al. (1989) reported on a
In the parallel trials, patient’s and doctor’s score had a highly significant improvement of the symptoms like inflammation grade, dryness, scaliness, itching and overall skin involvement. Furthermore, the authors noticed a
Moderate quality of evidence.
antihistamines could continue their treatment. The study demonstrated no improvement in the active treatment and no effect of EFA supplementation in atopic dermatitis patients.
Moderate quality of evidence.
Humphreys et al. (1994) carried out a
Results of the study demonstrated that there was no conclusive evidence for the two female groups regarding the different reactions in the different stages of the menstrual cycle. A highly significant difference is marked in erythema and surface damage between Oenothera and placebo after 4 months and post treatment. There was no significant effect in lichenification. A more sustained fall of serum soluble
Low quality of evidence.
Senapati et al. (2008) performed a randomised
Table 2: The amount of capsules given twice a day dependent on the age.
Low quality of evidence.
Table 3: Oenothera biennis oil: oral intake in adults for the indication ‘atopic dermatitis’
Other dermatological studies
Chalmers & Shuster (1983) first performed an uncontrolled pilot study. Six children with atopic dermatitis participated in the trial and there was a benefit response seen in 2 patients with ichthyosis vulgaris, but not with atopic eczema. The researchers expanded this study to a randomised, double- blind trial with 30 patients with ichthyosis vulgaris. Twenty patients (3 to 35 years) were atopic: 11 had active eczema, 6 had a history of atopic eczema and 3 had rhinitis or asthma. Ten other patients (6 to 69 years) were not atopic. The trial took 9 weeks. The placebo was liquid paraffin. The adults were administered 3 g daily, while the children received only 2 g a day. There were no patients with severe eczema. Patients topically treated could continue their therapy.
A slight improvement in the mean scores of ichthyosis vulgaris was seen in all groups. No progress was seen in the eczema patients, both Oenothera (6 subjects) and placebo (5 subjects) treated. In both atopic and non atopic patients, there was no improvement in ichthyosis vulgaris noted. In atopic eczema treated with Oenothera, no benefit was remarked.
Very low quality of evidence.
Whitaker et al. (1996) studied 39 patients with stable chronic hand dermatitis during 24 weeks. The patients were between 19 and 75 years. During 16 weeks, 20 of them took 12 capsules of 500 mg Oenothera, which is equal to 50 mg GLA. The other 19 subjects received capsules of 500 mg sunflower. After the treatment, the study was continued by a wash out period of 8 weeks. The patients could take unlimited amounts of standard emollients and limited amounts of a semi potent group III topical steroid cream. Five patients dropped out, of which 1 from the Oenothera group and 4 from the placebo group.
After 16 weeks, no statistically significant difference was noted in both groups. At the end of week 24, the Oenothera group gave statistically significant clinical improvement in all parameters, while the placebo group did not. The study demonstrated an improvement of clinical parameters in Oenothera and placebo, but no significant difference between the two groups. During the treatments, there was no change in lipid composition of plasma RBC or the epidermis. This
Very low quality of evidence.
Muggli (2005) studied the biophysical skin parameters in 22 healthy volunteers.
There was no significant difference between baseline and 4 weeks in both groups. After 12 weeks, skin moisture, transepidermal water loss, firmless, elasticity, fatigue resistance and roughness improved in the Oenothera group compared to the placebo group. There was no significant improvement for redness.
Moderate quality of evidence. This study is not a clinical trial for medicinal use, as there was no real therapeutic indication.
PMS is a condition characterised by a number of physical and mental symptoms during the luteal phase of the menstrual cycle; this is between 7 and 14 days before the onset of the menstrual period. A lot of symptoms are attributed to PMS, the most common are headache, backache, swollen abdomen, breast discomfort (including mastalgia), irritability, depression, anxiety, changes in sexual drive and lack of energy (Larsson et al. 1989, Wang et al. 2008).
Puolakka et al. (1985) carried out a placebo controlled, randomised
Casper (1987) studied 66 patients with PMS in a
Larsson et al. (1989) studied the effects of Oenothera fatty oil in a pilot study with 19 women between 25 and 48 years old. Two women left the study. The subjects received 4 capsules of Oenothera in the morning and 4 in the evening during the last 2 weeks before menstruation in 5 consecutive cycles. There were 8 premenstrual symptoms listed and scored every day: irritability, swollen abdomen, breast discomfort, depression, anxiety, swollen fingers or ankles, tiredness and headache. The symptom scores were significantly lower for 6 symptoms during the treatment cycles 1 and 2 compared to control. The scores were lower for 7 symptoms during the 5th cycle. Also the total PMS score was significantly lower in the 5th cycle compared to the
Khoo et al. (1990) studied the therapeutic effectiveness of Oenothera fatty oil (Efamol®). Thirty- eight women, age
Collins et al. (1993) carried out a randomised,
A lot of women suffer from cyclical premenstrual breast pain, which resolves with menstruation. It is physiological, hormonally driven and normal.
Pashby et al. (1979: cited by Anonymous 1981) investigated the effect of Oenothera fatty oil in mastalgia in 73 patients in a randomised
Blommers et al. (2002) carried out a randomised,
about the changes in their breast complaints at the time of randomisation and after 3 and 6 months. There was a significant decrease of percentage of days with pain found for the total study population. The severity of pain was not significantly decreased. Oenothera showed less decrease in the percentage of pain days than the control oils. However, none of these results were significant.
Srivastava et al. (2007) conducted a
Chenoy et al. (1994) evaluated the efficacy of oral GLA provided by Oenothera fatty oil on menopausal flushing in a
Rheumatoid arthritis (RA) is a chronic inflammatory disease of the synovium. This causes pain, stiffness, swelling, deformity and eventually loss of function in the joints (Soeken et al. 2003).
Jäntti et al. (1989) studied the effect of 10 ml of Oenothera fatty oil and olive oil in 18 patients with RA. Twenty patients were randomly assigned to two groups of 10 patients, each group with 9 women and 1 man. One group (mean age of 50 years) received Oenothera containing 9% of
Brzeski et al. (1991) carried out a
group, 3 subjects reduced their NSAID dose with one tablet. In the Oenothera treated patients the morning stiffness was significantly reduced at 6 months, in the placebo treated patients the AI was significantly reduced at 6 months. The trial found that only 23% of the subjects receiving Oenothera treatment could reduce their NSAID dose and none could stop, which was the same for the placebo group.
Belch et al. (1988) treated patients (age between 28 and 74) with 12 capsules Oenothera or Oenothera/fish oil daily for 12 months to determine whether Oenothera or Oenothera/fish oil could replace NSAID treatment in RA. Liquid paraffin was used as placebo (18 patients). Sixteen and 15 patients received 540 mg GLA or 240 mg EPA, respectively, plus 450 mg GLA a day. There was a wash out phase from 12 to 15 months. All patients received placebo capsules without vitamin E to assess whether any improvement was due to the antioxidant and radical scavenging effect of the vitamin E. From three months the patients were instructed to decrease or stop their NSAID and from 12 to 15 months they were told to maintain the dose, if possible.
One patient in the Oenothera group and two in the Oenothera/fish oil group were withdrawn. Assessment of morning stiffness, grip strength and the Ritchie articular index was performed at 0, 3, 6, 12, and 15 months, also blood samples were taken at these times, ESR, CRP, Hb and rheumatoid factor estimation were measured.
Eleven Oenothera treated patients and 12 Oenothera/fish oil treated patients reduced or stopped their NSAIDs by 12 months compared to 5 out of 15 patients from the placebo group. No significant changes were noted in the laboratory and clinical measurements. After the 3 months placebo phase, almost all patients from the Oenothera and Oenothera/fish oil groups returned to baseline or became worse compared to 14% of the placebo group.
The results showed that it is possible to reduce or stop the NSAID medication in some RA patients by using Oenothera or Oenothera/fish oil treatment. The improvement, however, is purely subjective as there are no measurements found to support it. Therefore, the authors claim that it is unlikely that
Sjögren syndrome (SS) is a common systemic autoimmune disease. It occurs most in menopausal women, frequent symptoms are fatigue, oral and ocular dryness. The secondary Sjögren syndrome is often associated with RA. In these patients, the GLA concentrations are reduced (Belch & Hill 2000, Theander et al. 2002).
Manthorpe et al. (1984) evaluated 36 patients in a randomised,
Oxholm et al. (1986) carried out a randomised,
The patients’ ocular and oral status, fatty acid levels in plasma and erythrocytes were evaluated after 0, 4, 8, 12 and 16 weeks. The values after 8 weeks of Efamol® treatment were compared with scores
after placebo treatment and the values after 8 weeks of Efamol® treatment were compared with Efamol® start values.
Significant improvements were found in the ocular status when start values were compared with values after Efamol treatment. Results of the fatty acid analyses showed a pronounced increase of DGLA values after Oenothera treatment, although compared to the placebo treatment it is thought not to be significant. No significant difference was observed between DGLA erythrocyte values at the end of placebo and Efamol® treatments. The authors concluded that, in the absence of further data, this treatment cannot be recommended to patients with Sjögren syndrome (Belch & Hill 2000).
Raynaud’s phenomenon is characterised by local vasospasm, cyanosis and rubor. It is evoked by cold or emotions and bloodflow, mainly in the limbs, slows down due to vasospasms, most often followed by hyperemia. Enhanced platelet aggregation, decreased RBC deformability, increased leukocyte aggregation and release are also associated with Raynaud’s phenomenon (Belch & Hill 2000).
Belch et al. (1986) assessed the effect of Oenothera on the manifestations of Raynaud’s phenomenon (RP) in 21 patients in a
The Oenothera group experienced less and shorter vasospastic attacks then the control group when the weather became colder. There was no significant improvement in hand temperature and cold challenge, both measured to indicate the blood flow. The drug appears to be able to stimulate production of PGE2 and decrease production of TxB2, possibly leading to some antiplatelet effect. The trial demonstrated that some patients with RP experience benefit from Oenothera treatment, but larger controlled studies are needed.
Peripheral neuropathy is a complication of both insulin dependent (type 1) and
Jamal & Carmichael (1990: cited by Halat & Dennehy 2003) included 22 diabetic patients with also a mild distal diabetic neuropathy for a mean of 3 years. Twelve subjects received 360 mg Oenothera fatty oil daily, 10 subjects got a placebo during a period of 6 months. The Oenothera treated patients had statistical significant improvements in nerve function measurements, wrist and ankle heat threshold values and overall symptoms scores. Glycohemoglobin (HbA1C) was not significantly different between the 2 groups and indicated that GLA had no effect on glucose control.
NOTE: In view of the fact that one of the investigators in this study was found guilty of research fraud in the clinical trials on Evening Primrose oil for diabetic neuropathy. The HMPC considers that no further use should be made of this publication and it is included here solely for completeness. BMJ 2003;326:730.2 http://www.bmj.com/content/326/7392/730.2
Keen et al. (1993: cited by Halat & Dennehy 2003) included 111 diabetic patients with a mild or moderate neuropathy. They received 480 mg Oenothera a day or a placebo (liquid paraffin) during 12 months.
Purewal et al. (1997: cited by Halat & Dennehy 2003) studied 51 diabetic patients with autonomic peripheral neuropathy for 12 months. They administered a dose of 480 mg daily of Oenothera or placebo. No improvements were shown in the vibratory perception threshold compared to placebo.
4.2.3 Clinical studies in special populations (e.g. elderly and children)
Ferreira et al. (1998: cited by Hoare et al. 2000) examined 23 patients, aged 3 to 15 years, for 4 months in a randomised controlled trial with a parallel design. The patients had an atopic dermatitis which was in remission. Two patients were withdrawn from the study. The emollients contain 10% GLA versus borage oil (24% GLA) versus rose hip oil
Clinical assessment of xerosis and pruritis revealed improvement in all 4 groups, slightly more pronounced in the 3 GLA groups. The changes were not statistically significant.
Also see 4.2.2 for studies on children Anstey et al. (1990).
Bordoni et al. (1987) studied 24 children with atopic dermatitis, of which 14 boys and 10 girls aged 2 to 4 years. The children were divided in 2 equal groups. One group received 6 capsules of Efamol® a day. The other group swallowed the same amount capsules which contained 0.5 g of olive oil. An Oenothera capsule consisted of 0.5 g Oenothera fatty oil, of which 74.7% LA; 8.9% GLA; 6.8% palmitic acid and 1.9% stearic acid. During the parallel,
Only in the Oenothera treated children, there was an increase of DGLA and AA and a decrease of 18:2/20:4 ratio measured.
After 4 weeks, the trial showed an improvement of 2/3 of clinical symptoms in
Low quality of evidence.
Biagi et al. (1988) studied 12 children, 8 boys and 4 girls, with atopic dermatitis between 2 and 4 year during 20 weeks in a
Low quality of evidence.
Hederos & Berg (1996) studied children, between 1 and 16 years, with atopic dermatitis, who met the criteria of Hanifin and Rajka and who needed the regular treatment with topical skin corticosteroids. Sixty children started the study and were divided in 2 equal groups. Two subjects group dropped out of the study.
Low quality of evidence.
Yoon et al. (2002) studied 14 children with atopic eczema, which had an itchy dry scale skin. The persons, who had an apparent erythema or oozing were excluded. Five boys and 9 girls, with an average age of 5.5 years, participated in the trial. Seven of them had a mild atopic dermatitis; the other 7 had a severe atopic dermatitis. They received 2 capsules twice a day. Each capsule contained 40 mg GLA. The control group consisted of 4 boys and 2 girls, with an average age of 7.2 years. Before the start of the study the serum interferon γ was lower and the serum IgE concentration was higher than these of the normal group. After 2 weeks treatment with Oenothera, there was a significant raise of serum interferon and decrease of serum IgE found. The study marked a reduced level of skin lesions and pruritus. No serious side effects were noticed. This study demonstrated that both supplementation of GLA and modulation of immunological abnormalities improved atopic dermatitis.
Grading: 2 (Observational study with pilot character)
Very low quality of evidence.
Also see 4.2.2 for studies on children: Lovell et al. (1981), Wright & Burton (1982), Bamford et al. (1985),
Table 4: Oenothera biennis oil: Oral intake in children for the indication ‘atopic dermatitis’
Other skin studies
See 4.2.2 for studies on children Chalmers & Shuster (1983)
Attention deficit hyperactivity disorder
ADHD is a development and behaviour disorder. The three principal symptoms are hyperactivity, concentration problems and impulsiveness. To date, the mechanism is unprecedented.
Aman et al. (1987) conducted a study with 31 hyperactive children (4 girls and 27 boys; age not specified) in Australia.
Blood samples were taken and analysed. The results showed a significant decrease of palmitoleic acid and a 14% increase of DGLA during Oenothera treatment. Other EFA did not change, but there was a
4.3. Overall conclusions on clinical pharmacology and efficacy
A difference must be made between the pathological conditions for which Oenothera oil has been used. Most of the studies concern with patients suffering from moderate or severe atopic dermatitis. Personal characteristics of these patients were representative for a usual population. The age varied from 8 months to 66 years. A total of 740 patients were included in 9 studies. The number of patients per study varied from 12 to 200. In most cases, a
The patients received an equivalent to 360 mg LA and 45 mg GLA, mostly as soft capsules containing 500 ml of Oenothera (Efamol®). Treatment periods were up to 6 months.
In 7 out of 9 trials, a positive clinical outcome was seen. When measured, plasma levels of DGLA, GLA and AA were increased. There seemed to be a relation between the increase in these plasma levels and the clinical outcome. The level of evidence is LOW to MODERATE.
Four small scale studies were done with children between 1 and 16 years old (n=88), suffering from atopic dermatitis or eczema. Two of these studies – of which one with an open design – resulted in a positive outcome. However, the number of subjects in these studies is lower, compared to studies with adults. It should be noted that children were also included in the other clinical trials mentioned before. The level of evidence is LOW to VERY LOW.
Other indications were non specified dermatitis, PMS, mastalgia, menopausal complaints, RA, SS, Raynaud’s phenomenon and diabetic neuropathy. It is notable that the results in the case of PMS (the most common indication for Oenothera) failed to show efficacy. In 3
There were no serious adverse events reported during the clinical trials taken into consideration.
Outcomes described in patients with Raynaud’s phenomenon may point to possible antiaggregating effects on blood platelets.
Overall conclusions on clinical efficacy of the oil of Oenothera biennis:
–Positive outcomes were only seen for eczema/atopic dermatitis. The evidence generated by the studies is graded very low to moderate even by using a less conservative approach with respect to some of the parameters applied. One study with moderate evidence had a negative outcome.
–Negative results were reported for studies on other therapeutic uses including non specified dermatitis, PMS, mastalgia, menopausal complaints, RA, SS, Raynaud’s phenomenon and diabetic neuropathy.
–Although several hundreds of patients participated in the clinical studies, the number is low in the individual studies. Furthermore, in most cases children and adults are included in the same study which makes the study population diverse and the drawing of conclusions difficult.
–Most studies have involved preparations of 500 mg oil of Oenothera biennis which facilitates comparison between studies.
–The instruments used for therapeutic evaluation are diverse and subjective.
In conclusion, the evidence for a
With regard to the use of cutaneous preparations, the studies fail to support a
5. Clinical Safety/Pharmacovigilance
5.1. Overview of toxicological/safety data from clinical trials in humans
See sections below.
5.2. Patient exposure
More than 800 patients (of whom more than 100 children) were exposed in clinical studies dealing with atopic dermatitis. For other conditions (e.g. PMS, menopausal complaints, SS, Raynaud, diabetes, inflammatory conditions) another 600 patients were involved.
5.3. Adverse events
The World Health Organization’s Uppsala Monitoring Centre
5.4. Serious adverse events and deaths
No serious adverse events were reported in the
The most serious side effects reported in the
5.5. Laboratory findings
5.6. Safety in special populations and situations
Intrinsic (including elderly and children)/extrinsic factors
Puri (2007) criticises the fact that 2 trials concluded that Oenothera leads to a higher risk of epileptic seizures in schizophrenic patients.
The first trial, which was performed by Vaddadi (1981: cited by Puri 2007), was an open study. Three
The second trial was carried out by Holman & Bell (1983: cited by Puri 2007). It was a double- blind
In rats, researchers demonstrated that a
There may be an increased risk of seizure in schizophrenic patients, temporal lobe epileptic patients and others who take epileptogenic drugs such as phenothiazines. Patients with a history of these illnesses should use Oenothera products with caution (Barnes et al. 2007).
Also see paragraph above Puri (2007) for studies on phenothiazines.
Assessor’s comment: There is no consensus whether a
Patients taking antiplatelet or anticoagulant medications should use Oenothera with caution or should not use it at all. Oenothera consumption decreases thromboxane formation and increases PGE1 formation, which leads to an inhibition of the platelet aggregation with increased risk of bleeding (Halat & Dennehy 2003).
Assessor’s comment: Use of Oenothera oil concomitantly with antiplatelet drugs could enhance the effect of the latter. This combination should be discouraged.
Theoretically, there is a risk of interaction with
Morse & Clough (2006) made a
Use in pregnancy and lactation
Oral treatment given to atopic pregnant and nursing mothers and Oenothera given to newborns with an increased risk of atopic eczema may prevent atopic dermatitis. During the growth of the thymus, it can compensate the D6D deficit and the lack of lymphocytic PGE receptors (Kerscher & Korting 1992). However, not enough data are available on the safety of Oenothera during pregnancy and therefore it is not recommended to use Oenothera products during pregnancy. Oenothera treatment is, however, possible during pregnancy when the potential benefits outweigh the potential harms, but attention should be paid to high doses, above 4 g daily (Barnes et al. 2007; Bédard 2003).
Dove & Johnsons (1999) studied the effect of oral Oenothera fatty oil on the length of pregnancy and selected intrapartum outcomes in
Symptoms of overdosage are loose stool and abdominal pain, treatment is not necessary (Barnes et al. 2007).
Withdrawal and rebound
Effects on ability to drive or operate machinery or impairment of mental ability
5.7. Overall conclusions on clinical safety
There are no major concerns related to serious adverse reactions. Possible implication of Oenothera fatty oil (Oenothera) lowering the convulsive threshold is debated. The HMPC did not consider that the data justify including in the monograph a statement on drug interactions during the use of Oenothera in patients taking anticonvulsive drugs or antipsychotics. Oenothera has been used during pregnancy without major problems. Use during in the perinatal period is not recommended, due to interference with delivering. The HMPC concluded that safety during pregnancy and lactation has not been established; in the absence of sufficient data, the use during pregnancy and lactation is not recommended.
6. Overall conclusions
The herbal preparation is a fatty oil, described in the European Pharmacopoeia. It contains unsaturated fatty acids. Besides oxidation after exposure to air and light, the oil is sensitive to heat and humidity. Consequently, the storage conditions (cool dark place) are important. There are no cases of contamination or adulteration mentioned in literature, but the quality parameters/specifications for Oenothera oil are referred to in the European Pharmacopoeia, especially as far as the percentage non oxidized linoleic acid is concerned.
The use of Oenothera oil can be considered as well known, as its use has been reported in the 17th century in Europe, coming from North America (Indians). In the Vigisearch database of the World Health Organization’s Uppsala Monitoring Centre reported side effects are listed. As most serious side effects, convulsions, hepatitis, bronchospasms and interference with platelet function were related to the use Oenothera oil. A variety of minor side effects was also collected in the database. The type of preparation and the dose are not always specified. Ingestion of overdoses can lead to fatty diarrhoea. This effect may be considered as
There is no consensus whether a
Use of Oenothera oil concomitantly with antiplatelet drugs could enhance the effect of the latter. This combination should be considered carefully. The HMPC decided that the data do not justify including a statement in the monograph.
There is limited information from clinical observations in pregnant women. Oenothera oil did not cause any harm, but more systematically gathered reports are needed, also in case of
As Ames testing has not been performed on the oil, no list entry can be granted.
Conclusion: taking into consideration available information on side effects and
Oenothera oil has been studied for atopic dermatitis in more than 400 adults and more than 100 children (from 8 months of age). The quality of evidence varied from very low to moderate. The outcome was not consistent but was mainly negative for other indications such as premenstrual syndrom, rheumatoid arthritis, mastalgia, menopausal symptoms, Sjögren syndrome, Raynaud’s phenomenon, ADHD and diabetic neuropathy. Concerns have been raised about the quality of the evidence to support the therapeutic claims for Oenothera oil. In 2002, the UK Medicines Agency withdrew all marketing authorisations for oral evening primrose oil capsules. This followed a review by the UK Medicines Agency of all the relevant information, including new studies and statistical analyses. The UK Medicines Agency concluded that the data did not support the current standards of efficacy required for authorisation of these products as medicines for the treatment of eczema and mastalgia (Anonymous 2002).
Studies on the use of Oenothera oil for diabetic neuropathy have been marred by the fact that one of the investigators in the studies was found guilty of research fraud in the clinical trials.
In view of the uncertainties concerning the available bibliographic data together with the poor quality of the evidence of efficacy in the published studies, the HMPC considers that there is insufficient evidence on which to base a
In the absence of adequate genotoxicity testing, no Community list entry can be established.
List of references
Table 5: Summary of spontaneous reports (n=187) of suspected adverse drug reactions associated with
aSpecific reactions described where n=3 or more.
bCaveat statement. These data were obtained from the Vigisearch database held by the WHO Collaborating Centre for International Drug Monitoring, Uppsala, Sweden. The information is not homogeneous at least with respect to origin or likelihood that the pharmaceutical product caused the adverse reaction. Any information included in this report does not represent the opinion of the World Health Organization.
* RES – Reticuloendothelial system