Comfrey Root – Symphyti radix (Symphytum officinale L.)
|Latin name of the genus:||Symphyti radix|
|Latin name of herbal substance:||Symphytum officinale l.|
|Botanical name of plant:||Herbalref.com|
|English common name of herbal substance:||Comfrey root|
Latin name of the genus: Symphyti radix
Botanical name of plant: Symphytum officinale L.
English common name of herbal substance: Comfrey Root
1.1. Description of the herbal substance(s), herbal preparation(s) or combinations thereof
Symphytum officinale L. (Boraginaceae) or common comfrey is a perennial native of Europe and Asia and has been naturalised throughout North America (Longe, 2005). It is very common in all of Europe, especially in damp soils (Bruneton, 1999). There are about 25 species of the genus, including further medicinal plants apart from common comfrey (e.g. S. asperum Lepechin, S. tuberosum L., and S. × uplandicum Nyman (syn. S. peregrinum, S. asperum × officinale, according to Tutin, 1992) (Longe, 2005; De Smet et al., 1992).
Comfrey grows well in rich, moist, low meadows, or along ponds and river banks, where it may reach a height of 1.2 m (usually
Both roots and leaves are reported to be used for medicinal purposes. Comfrey is occasionally used as an ingredient of soups and salads. It is listed by the Council of Europe as natural source of food flavouring (category N4). This category indicates that although comfrey is permitted for use as food flavouring, insufficient data are available to assess toxicity (Barnes et al., 2007). The herb has long been used as a cooked green vegetable in early spring, and the fresh, young leaves have been added to salads. The widespread suffering caused by the Irish potato famine of the 1840s motivated Henry Doubleday, an Englishman, to fund research into comfrey’s potential as a nutritional food crop. Farmers have valued comfrey as a nutritious fodder for cattle (Longe, 2005).
Carbohydrates: gum (arabinose, glucuronic acid, mannose, rhamnose, xylose); mucilage (glucose, fructose) (Barnes et al., 2007)
Triterpenes: sitosterol and stigmasterol (phytosterols), steroidal saponins, isobauerenol, triterpene saponins symphytoxide A, cauloside D, leontoside A, leontoside B, leontoside D (Barnes et al., 2007; Ahmad et al., 1993; Mohammad et al., 1995)
Other constituents: allantoin
Alkaloids: Comfrey roots contain
The pyrrolizidine content of Symphytum varies with plant part, season, natural biological variation, and species. Small young leaves early in the season possess higher total alkaloid content than older leaves, and the roots contain greater concentrations of total pyrrolizidine alkaloids than
Figure 1. General structures of pyrrolizidine alkaloids and chemical structures of pyrrolizidine alkaloids in Symphytum officinale (Barceloux, 2008).
Dried rhizome and roots of Symphytum officinale L. (Kern W 1976, British Herbal Pharmacopoeia 1974, 1983, 1996).
Liquid extract prepared by extraction with ethanol 65% (V/V) followed by partial evaporation and adjustment to a DER 2:1; liquid extract in an ointment base (100 g ointment contains 10 g extract), for cutaneous use.
•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.
1.2. Information about products on the market in the Member States
Regulatory status overview
Table 1: Overview of data obtained from marketed medicinal products EU
This overview is not exhaustive. It is provided for information only and reflects the situation at the time when it was established.
The WEU products authorised in many European countries (AT, DE, HU) are not taken into account for the purpose of making a monograph since the extract used for those products is produced using a production process including several intermediate steps to lower the content of pyrrolizidine alkaloids. Therefore the final composition of the product is not known. Furthermore this extract is produced from fresh comfrey root. For some of the other extracts the 30 years of use could not been proven and/or their exact description is not known. Therefore the extract taken into the monograph is: liquid extract prepared by exhaustive extraction with ethanol 65% (V/V) followed by partial evaporation of the extracting solvent and dilution with ethanol to gain an extract with a DER 2:1 (with respect to mass of the starting plant material) from dried comfrey root.
1.3. Search and assessment methodology
Databases assessed and other sources used:
Databases Science Direct, SciFinder, PubMed and Web of Science were searched using the terms [Symphytum], [comfrey] and [pyrrolizidine alkaloid]. Handbooks and textbooks on the topic were also used. A detailed literature search was made by 31 October 2012; data on cutaneous absorption of pyrrolozidin alkaloid were searched for up to 28 February 2015.
Inclusion and exclusion criteria for literature:
Data concerning Symphytum species other than Symphytum officinale L. were excluded.
2. Historical data on medicinal use
2.1. Information on period of medicinal use in the Community
Symphytum officinale L. root and other parts of the herb have been valued medicinally for more than 2,000 years. The specific name “officinale” designates its inclusion in early lists of official medicinal herbs. Comfrey has been prepared as a poultice or compress with healing properties for blunt injuries, fractures, swollen bruises, boils, carbuncles, varicose ulcers, and burns. Poultices were also applied to ease breast pain in breastfeeding women. Comfrey, taken internally as a tea or expressed juice, has been used to soothe ulcers, hernias, colitis, and to stop internal bleeding. As a gargle it has been used to treat mouth sores and bleeding gums. The herbal tea has also been used to treat nasal congestion and inflammation, diarrhoea, and to quiet coughing. The hot, pulped root, applied externally, was used to treat bronchitis, pleurisy, and to reduce pain and inflammation of sprains (Longe, 2005).
Comfrey use was first documented by the ancient Romans and Greeks. Around 200 AD, the Greek physician Dioscorides praised the therapeutic uses of comfrey in his book Materia Medico, and coined the genus name Symphytum from the Greek word symphuo, which means “to make to grow together.” During the Middle Ages, comfrey in the form of an external poultice became popular for healing broken bones. As the popularity of comfrey grew over the centuries so did its indications for use. Comfrey has been used to treat respiratory problems (bronchitis, catarrh, haemoptysis, pleurisy, whooping cough), gastrointestinal diseases (cholecystitis, colitis, dysentery, diarrhoea, ulcers, hematemesis), metrorrhagia, phlebitis, and tonsillitis. Comfrey has also been touted for its nutritional value; it has been considered a good source of protein and vitamin B12, which is unusual for a plant (Cupp, 2000).
Symphytum officinale has been known by many names, including boneset, knitbone, bruisewort, black wort, salsify, ass ear, wall wort, slippery root, gum plant, healing herb, consound, or knit back. The common name comfrey is from the Latin “confirmare” meaning to join together. The herb is named after its traditional folk use in compress and poultice preparations to speed the healing of fractures, broken bones, bruises, and burns (Longe, 2005).
Symphytum officinale has a long tradition and is still applied nowadays as an external treatment for inflammatory disorders of joints, wounds, gout, bone fractures, distortions, haematomas and thrombophlebitis. It is also applied as a decoction for oral and pharyngeal gargle. For internal application, comfrey is claimed to benefit gastritis and gastroduodenal ulcers, though its effects have never been demonstrated in controlled investigations. In addition, herbal practitioners recommend comfrey capsules for the treatment of rheumatoid arthritis, bronchitis, various allergies and for diarrhoea, regardless of the pathogenic cause (Stickel and Seitz, 2000).
In the UK, the Medicine Control Agency (now the Medicines and Healthcare products Regulatory Agency (MHRA)) recently included comfrey in a list of herbs under consideration for restriction to physician prescription only (Rode, 2002).
The use of comfrey root in Germany is limited to external products. The Commission E suggest the external use of comfrey root (crushed root, extracts, the pressed juice of the fresh plant for
According to the Commission E, the daily dose should not exceed more than 100 μg pyrrolizidine alkaloids with 1,2 unsaturated necine structure, including its
In France, the only indication that may be claimed for the comfrey root is as follows: as an adjunct in the emollient and
Outside Europe: the distribution of comfrey in Canada has been restricted; in the USA, the Food and Drug Administration has requested voluntary compliance for removal of products containing comfrey (Rode, 2002).
2.2. Information on traditional/current indications and specified substances/preparations
The preparation which has been on the market for more than 30 years is the following:
Liquid extract prepared by extraction with ethanol 65% (V/V) followed by partial evaporation and adjustment to a DER 2:1; liquid extract in an ointment base (100 g ointment contains 10 g extract)
Therapeutic indication: A traditional herbal remedy used for the symptomatic relief of bruises and sprains.
2.3. Specified strength/posology/route of administration/duration of use for relevant preparations and indications
Ointments or other preparations for external use are made up of
In the British Herbal Pharmacopoeia (1974 and 1983), fresh Symphytum root is indicated externally for the treatment of ulcers, wounds, fractures and hernia with the following posology (for this preparation, no data are available concerning the preparation of the extract):
•Ointment: Symphytum root
In the United Kingdom, a Symphytum product is on the market at least since 1968:
Liquid extract prepared by extraction with ethanol 65% (V/V) followed by partial evaporation and adjustment to a DER 2:1; liquid extract in an ointment base (100 g ointment contains 10 g extract) Posology: For external use only. Adults: Bathe the affected areas in warm water and apply the ointment morning and night. Not to be applied over breaks in the skin. Use no longer than ten days at a time.
Although internal use of comfrey was not advised, dosages for oral administration for traditional uses were recommended in older standard herbal reference texts. The recommended oral (unless otherwise stated) doses of The British Herbal Pharmacopoeia (1974 and 1983) for the treatment of gastric and duodenal ulcer, colitis and hematemesis were as follows:
•Root, liquid extract:
The HMPC “Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs)” (EMA/HMPC/572844/2009) considers the possible oral use for products containing less than 0.007 μg/kg/day. However, such products can not been found on the market with 30 years of safe documented medicinal use. Therefore the monograph does not contain any preparation for oral use.
3.1. Overview of available pharmacological data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
In a screening study evaluating 29 traditionally used European herbal drugs used for
In an experiment, the concentration of pyrrolizidine alkaloids in crude Symphytum officinale extract (no further information) was changed by a factor of about 0.1 using protonated cation exchangers. Using an in vivo model it could be shown that the reduction of pyrrolizidine alkaloids result in a small but measurable decrease in antiphlogistic efficacy. The model was based on measuring the decrease of redness and pain sensitivity of
It was also reported, that the
Rosmarinic acid isolated from Symphytym officinale possessed an inhibitory activity on the formation of malondialdehyde in human platelets by the TBA method. The IC50 for rosmarinic acid was 3.37 mM.
Structurally related minor constituents, chlorogenic acid and caffeic acid did not show significant activity in this model (Gracza et al., 1985).
Andres et al. (1989) evaluated the antiphlogistic efficacy of 10 ointments containing comfrey root extract (no further information) with an in vivo model. Circular erythema was generated using
Since there are no data on the human bioavailability of the compounds/extracts studied for anti- inflammatory activity in the presented articles, no conclusion can be drawn for the efficacy of cutaneously applied comfrey products.
Due to the absence of relevant data (concentration of the extracts/compounds, bioavailability data) the presented articles on the
Wound healing effect
The pharmacological mechanisms are thought to be based partly upon allantoin, which is responsible for the stimulation of connective tissue proliferation and regeneration (Stickel and Seitz, 2000).
In an animal experiment, the crude juice of the leaves of Symphytum officinale afforded the cicatrization process by increasing at first (at the 7th, 11th and 14th days) the number of fibroblasts and, in a later phase (after 14 days), the number of collagen fibers in experimental lesions produced in rats. The number of blood vessels was also increased at the 7th day of treatment. On the experimental oedema induced by carrageenin in rat’s paws, the crude extract at doses of 150 and 300 mg/kg per os showed no effect compared to 75 mg/kg phenylbutazone. Analgesic effect was seen with doses
300 mg/kg per os (Goldman et al., 1985). Since these results were obtained with comfrey leaf preparations, they are not relevant for root extracts.
In an in vitro study, it was found that the total aqueous extract obtained from Symphytum officinale roots precipitated human glycoproteins, agglutinated sheep red blood cells (SRBC) and stimulated lymphocyte adherence to nylon fibers. The extract precipitated human gammaglobulins. If the cells were pretreated with rabbit antibodies against SRBC, the extract agglutinated the cells. The adherence of mouse but not human lymphocytes to nylon fibers were stimulated by extract of Symphytum officinale. This process was neither stimulated nor inhibited by mannose (Man), galactose (Gal), glucose (Glc),
In an in vitro study, 70% ethanol extract of Symphytum officinale was concentrated by tangential flow ultrafiltration. In the extract some polyphenolic compounds were identified by HPLC: chlorogenic acid, cafeic acid, ferulic acid, coumaric acid, rutin, rosmaric acid, luteolin and quercetin. The cytostatic activity of the total plant extract was studied on HeLa cells culture. By comparison to the bystander value of 100%, it was noticed that in vitro treatment of HeLa neoplasic cells with the concentrated extracts determined a mitoinhibitory effect with statistical and cytostatical significant amplitude. These values were almost 57.6% for Symphytum officinale (Roman et al., 2008).
In anaesthetised rats the ethanol extract of Symphytum officinale root and the bidesmosidic triterpene glycoside symphytoxide A caused a fall in systolic as well as diastolic blood pressure in a dose-
dependent manner. The hypotensive responses of both crude extract and the pure compound were quite similar, very briefly returning to normal within 1 minute while no significant decrease was observed on heart rate (Ahmad et al., 1993).
No relevant pharmacodynamic interactions have been documented. According to Barnes et al. (2007), the potential for preparations of comfrey to interact with other medicines administered concurrently, particularly those with similar or opposing effects, should be considered.
However, regarding the toxicity of comfrey, a study involving rats showed that phenobarbital induces the metabolism of pyrrolizidine alkaloids to their lethal metabolites. In a study using perfused organs, it was shown that some of the pulmonary damage caused by monocrotaline, a pyrrolizidine alkaloid is mediated by hepatic biotransformation of the compound. This metabolism was inducible with phenobarbital (a
Based on the assessed preclinical data the clinical plausibility cannot be proven since it is not demonstrated that the preclinically active extracts/compounds are present at the site of action in sufficient concentration to exert their effect.
3.2. Overview of available pharmacokinetic data regarding the herbal substance(s), herbal preparation(s) and relevant constituents thereof
In ex vivo experiments, permeation of rosmarinic acid across excised rat skin was about 8 times higher from alcoholic solution than from water, indicating that ethanol may act as a sorption promoter. The flux from water or alcoholic solution was 4.4 or 10 µg/cm2/h, and the lag time (tlag) was 7.8 or 3.7 h, respectively. Upon topical administration of rosmarinic acid in form of a W/O (water in oil) ointment (25 mg/kg, 50 cm2), the absolute bioavailability was 60% (Ritschel et al., 1989).
For available pharmacokinetic data concerning pyrrolizidine alkaloids it is referred to the “Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs)” (EMA/HMPC/893108/2011).
Rats suckled by mothers fed lasiocarpine, a pyrrolizidine alkaloid found in comfrey, developed liver damage (Cupp, 2000). After oral administration of tritiated senecionine and seneciphylline to lactating rats, radioactivity was excreted into the milk with concentrations 50% less compared to the blood concentrations. After 6 h 83% of the radioactive necine bases remaining in the blood were not dialyzables, indicating a tight (possibly covalent) binding to macromolecules, such as albumin. Six hours after administration of the pyrrolizidine alkaloids the highest concentrations were detected in the liver and lungs of the rats (De Smet et al., 1992). A study performed with lactating mice, using the same pyrrolizidine alkaloids but
3.3. Overview of available toxicological data regarding the herbal substance(s)/herbal preparation(s) and constituents thereof
The therapeutic application of comfrey is overshadowed by the
The hepatotoxicity, carcinogenicity and mutagenicity of pyrrolizidine alkaloids are discussed in detail in the Public statement on pyrrolizidine alkaloids (HMPC, 2014).
In one study, the activity of various hepatic
Mei et al. (2006) identified
The methanol extract of Symphytum officinale roots was investigated by Behninger et al. (1989) for its
14 μg/ml the extract had no effect; in concentrations of 140 μg/ml and 1400 μg/ml sister chromatid exchanges (SCE) as well as chromosome aberrations occurred. Additionally, the influence of rat liver enzymes (S9) was tested. The
Furmanowa et al. (1983) investigated the mutagenic effect of 3 alkaloidal fractions of Symphytum officinale roots, aqueous extract of roots and the alkaloid lasiocarpine. Mitotic index and chromosomal aberrations were measured on the lateral roots of Vicia faba L. var. minor. Alkaloid fraction I had antimitotic and mutagenic effects, fraction II showed no such effects, fraction III had only antimitotic action. The alkaloid fraction I containing lasiocarpine had a stronger mutagenic effect than lasiocarpine alone (metaphases with chromosomal aberrations: 18.9% and
Acetone extract of common comfrey herb was evaluated for mutagenic activity with Ames test utilising tester strains TA98 and TA100 and in the presence and absence of induced liver miocrosomes. The extract produced toxic responses that were abolished in the presence of the microsomal bioactivation system
Chou and Fu (2006) determined that the metabolism of tumorigenic pyrrolizidine alkaloids (riddeliine, intermedine, symphytine, lycopsamine, senecionine, lasiocarpine, heliotrine, senkirkine, clivorine) resulted in the formation of a set of 6,
supplements for three consecutive days. The doses were
Comfrey root liquid extract (liquid extract from fresh Symphytum officinale root; extraction solvent: ethanol 60% (V/V), DER 1:2, pyrrolizidine alkaloid content <1 ppm) was investigated for its ability to induce gene mutations in the bacterial reverse mutation assay (Ames test) in Salmonella typhimurium strains TA 98, TA 100, TA 102, TA 1535 and TA 1537 with and without metabolic activation using the mammalian microsomal fraction S9 mix (liver microsomal fraction derived from male Wistar rats) and plated on selective medium according to the direct plate incorporation and the
Mei et al. (2005) evaluated the mutagenicity of comfrey in the liver cII gene of Big Blue rats. To determine an appropriate dose for treatment, a preliminary experiment was conducted by feeding diets containing 2, 4 and 8% comfrey. Based on a minimum effect on weight gain, lack of overt toxicity to the liver, and a maximum effect on mutagenicity, a diet containing 2% comfrey root was chosen for the mutagenesis experiment. Groups of six
All the carcinogenity studies on animals were carried out with the oral administration of the herbal substance or extract. For external use, no data are available.
by comfrey and riddelliine, there were a number of common genes and function processes that were related to carcinogenesis. There was a strong correlation between the two treatments for
In a study published in 1978 (Hirono et al., 1978a), seven groups of inbred strain ACI rats were fed dried comfrey leaves (Symphytum officinale) or dried comfrey roots (Symphytum officinale) over a 480 to 600 day period. Three groups of rats consisting of
Gomes et al. (2010) investigated the effects of chronic oral treatment of rats with 10% comfrey ethanolic extract in a ‘resistant hepatocyte model’ (RHM). In this model, it is possible to observe easily the phenomena related to the early phases of tumour development, since
1 mm, the percentage of oval cells and mitotic figures, as well as the number of Proliferating Cell Nuclear Antigen (PCNA) positive cells and acidophilic
Hirono et al. (1978b) concluded that the highest incidence of tumours might be attributed to the regimen of normal and 0.5% comfrey root diets alternately administered at
No studies are available for comfrey preparations.
A study with heliotrine injected at doses
Conflicting data are available regarding the toxicity of pyrrolizidine alkaloids on embryonic livers. On the one hand, foetal liver seems to be more resistant to toxic pyrrolizidine alkaloids than maternal ones; on the other hand, lasiocarpine given at doses of 35 mg/kg to pregnant rats on days 13 and 17 of pregnancy was harmful for the foetal livers without affecting the mother (De Smet et al., 1992).
3.4. Overall conclusions on
Data on pharmacokinetic and toxicity concerning the herbal substance or herbal preparations are incomplete. Symphyti radix contains pyrrolizidine alkaloids that (either in pure form or in an alkaloid rich comfrey extract) exhibited hepatotoxic, carcinogenic and mutagenic activities in preclinical studies, after oral administration. For assessment of these data it is referred to the “Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs)” (EMA/HMPC/893108/2011). Studies using different preparations of comfrey suggest that genotoxic/carcinogenic activities can also be found with comfrey preparations.
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
No relevant data available.
4.1.2. Overview of pharmacokinetic data regarding the herbal substance(s)/preparation(s) including data on relevant constituents
No relevant data are available. Concerning pyrrolizidine alkaloids it is referred to the “Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs)” (EMA/HMPC/893108/2011).
4.2. Clinical Efficacy
4.2.1. Dose response studies
According to the available literature, no
4.2.2. Clinical studies (case studies and clinical trials)
Four randomised, controlled studies and one
Koll et al. (2004) investigated the percutaneous efficacy of SCE in a
(55.9%) received verum and 63 received placebo (44.1%). The duration of treatment (6 cm strand of 2 g verum/placebo ointment) was 8 days.
According to the publication the following results were observed:
In the verum group, there was a significantly stronger (p<0.0001) alleviation of pain (tonometrically recorded pressure pain) during the course of the study compared to the placebo group.
The reduction of swelling
Predel et al. (2005) carried out a
According to the publication the following results were observed:
The 95% CI the area under curve (AUC) of the pain reaction to pressure (tonometer) on the injured area (Symphytum officinale extract minus diclofenac gel) was
Grube et al. (2007) investigated the effect of a daily application of 6 g SCE (3×2 g 6 cm long thread) over a 3 week period with patients suffering from osteoarthritis of the knee in a randomised, double- blind, bicenter,
According to the publication the following results were observed:
The pain at rest declined significantly in the verum group when compared to placebo (56.6% vs 12.2%, p<0.001). With regard to pain on movement, the verum group had undergone a reduction of pain on movement of 30.7 mm (53.5%) while the placebo group had only undergone a reduction of 5.6 mm (9.9%). In respect of the explorative secondary target values
that the comfrey root extract ointment is useful in the
The objective of the study carried out by Giannetti et al. (2010) was to show the superiority of SCE to placebo ointment in patients with acute upper or low back pain. The study was conducted as a double- blind,
According to the publication the following results were observed:
There was a significant treatment difference between comfrey extract and placebo regarding the primary variable. In the course of the trial the pain intensity on active standardised movement decreased on average (medians) about 95.2% in the verum group and 37.8% in the placebo group. The results of this clinical trial were
Koll and Klingenburg (2002) conducted a prospective open multicentre observational study involving 162 general practitioners to analyse the
According to the publication the following results were observed:
Pain at rest and movement, as well as tenderness have improved in the overall observation group by an average of
Table 2. Randomised, controlled clinical studies with a special Symphytum officinale preparation (SCE)
4.2.3. Clinical studies in special populations (e.g. elderly and children)
Staiger and Wegener (2008) carried out a multicentric, prospective
4.3. Overall conclusions on clinical pharmacology and efficacy
No relevant information is available with regard to the pharmacodynamic properties of common comfrey and no
No appropriate clinical studies have been carried out in special populations, e.g. elderly and children.
5. Clinical Safety/Pharmacovigilance
Common comfrey has been a traditional medicinal herb, which earlier was used both externally and internally. While comfrey is the most
In case of Symphytum officinale, there are no data on acute adverse events in case of the cutaneous therapeutic application of medicinal products. According to Barnes et al. (2007), percutaneous absorption of pyrrolizidine alkaloids present in comfrey is reported to be low, although application of comfrey preparations to the broken skin should be avoided.
For further information referring to pyrrolizidine alkaloids see (EMA/HMPC/893108/2011).
5.1. Overview of toxicological/safety data from clinical trials in humans
No data exist for preparations covered by the monograph.
From the clinical trials with the SCE basically good or excellent tolerability/local tolerance was reported with overall more than 500 patients (verum). It is important to emphasise that in cases of medicinal products for cutaneous use the vehicle of the preparation and the excipients in it might have great influence of the absorption of the active/toxic components. Therefore the data from the studies Koll et al. (2004), Predel et al. (2005), Grube et al. (2007), Staiger and Wegener (2008), Schmidtke- Schrezenmeier et al. (1992) and Koll and Klingenburg (2002) do not add relevant safety information for the preparation in the monograph.
5.2. Patient exposure
No data exist for the preparation covered by the monograph.
The four controlled clinical trials with SCE evaluated in the assessment report comprised altogether 647 patients (Knoll et al., 2004; Predel et al., 2005; Grube et al., 2007; Giannetti et al., 2010). In one multicentric, prospective
Products containing comfrey extracts are on the European market since at least 1968.
5.3. Adverse events and serious adverse events and deaths
Although there are human data on the central nervous system and pulmonary system affecting effects of certain pyrrolizidine
For the hepatotoxicity of pyrrolizidine alkaloids, see the “Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs)” (HMPC, 2014).
The daily consumption of comfrey
A 13 year old boy was admitted in July 1986 for investigation of hepatomegaly and ascites. Three years earlier Crohn’s disease had been diagnosed. He was treated with prednisolone and sulphasalazine with benefit. At his parents’ request these drugs were discontinued and he was treated with acupuncture and comfrey root, prescribed by a naturopath. Up to 1986 he had been regularly given a herbal tea containing comfrey leaf. The exact quantities of leaves given and frequency of administration are unknown. An exacerbation of his inflammatory bowel disease in 1984 required a further course of prednisolone. In June 1986 he presented with fatigue, diarrhoea, and weight loss and a few weeks later developed fever, abdominal pain, and swelling. He was taking prednisolone and sulphasalazine. On examination, he had ascites and tender hepatomegaly but no dehydration, jaundice, or heart failure and no stigmata of chronic liver disease. He had raised serum bilirubin
concentration and aspartate aminotransferase activity. Percutaneous liver biopsy showed the thrombotic variant of hepatic
For Symphyti radix, no data are available.
Concerning the carcinogenity of pyrrolizidine alkaloids, see the Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs) (HMPC, 2014).
5.4. Laboratory findings
In the clinical setting, hepatic function is commonly assessed by monitoring the serum concentrations of proteins of hepatic origin. For example, elevations in aspartate aminotransferase (AST) might reflect liver pathology,
5.5. Safety in special populations and situations
According to Barnes et al. (2007), in view of the toxicity associated with the alkaloid constituents, comfrey should not be taken during pregnancy or lactation. However, Commission E suggests that during pregnancy comfrey should be used only after consultation with a physician (Blumenthal et al., 1998).
Though no information is available concerning the application of comfrey on neonates, two neonatal deaths were reported in Canada after mothers used comfrey as a cream on the nipples; consequently it was banned in Canada (Schaefer et al., 2007).
No information is available on drug interactions, overdose, abuse and effects on ability to drive or operate machinery or impairment of mental ability.
5.6. Overall conclusions on clinical safety
Due to the List of herbs and herbal derivatives with serious risks dated 1992 prepared by Committee for Proprietary Medicinal Products and other measures made by national medicine authorities there is no product containing Symphyti radix for oral use as herbal medicine in Europe (CPMP, 1992).
Only some preparations for cutaneous use are available as well with limited content of unsaturated pyrrolizidine alkalkaloids (PA).
Based on “Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs)” prepared and issued by HMPC (EMA/HMPC/893108/2011) the following recommendations were taken into account for the purpose of the monograph on Symphyti radix:
Because of their known involvement in human poisoning and their putative carcinogenicity, exposure to toxic, unsaturated PAs should be kept as low as practically achievable.
In the evaluation of HMPs/THMPs containing toxic, unsaturated PAs Member States should take steps to ensure that the public are protected from exposure and the following thresholds should be applied.
Until now only rudimentary data concerning absorption of PAs through the skin exist. The study by Brauchli et al. (1982) suggests that at least in rats, the dermal absorption could be
It is to ensure that the amount of toxic, unsaturated PA within the daily dose is <0.35 μg for adults
Higher contents of toxic, unsaturated PA within the products would be possible if for the relevant product (means the relevant matrix, because absorption might be greatly influenced by the excipients, for instance essential oils as enhancers) low absorption rates (generated with modern analytical techniques; in animal species which are more comparable to human beings in relation to the skin or in vitro human skin preparations) can be shown, not exceeding the daily intake of 0.35 μg toxic, unsaturated PA for adults.
If children are included in the usage of certain products the daily amount of toxic, unsaturated PA has to be adjusted to the body weight of the age group: e.g. body weight of 20 kg would lead to an acceptable
Pregnant and breast feeding woman:
Sensitive groups such as pregnant and breast feeding woman are also covered by the limit calculated above. If these limits are complied with, the chapter 4.6 of the SmPC of the products concerned should be phrased according to the Guideline on risk assessment of medicinal products on human reproduction and lactation: from data to labelling (EMEA/CHMP/203927/2005) (CHMP 2008).
6. Overall conclusions
Based on the provided data on comfrey products by National Competent Authorities, the traditional medicinal cutaneous use of Symphytum officinale has been confirmed in the treatment of bruises and sprains throughout a period of at least 30 years, including at least 15 years within the EU.
Although the efficacy in bruises, sprains, osteoarthritis and back pain is clinically investigated for a specific product a
There are no rational objections (self medication character, plausibility and safety) to the traditional use of comfrey products with limited pyrrolizidine alkaloid content, and the data provided support the long standing use of Symphytum officinale preparations. However, even with products for cutaneous use, the main concern for the clinical safety of comfrey preparations is the content of pyrrolizidine alkaloids, the potential of absorption through intact skin and metabolic activation in the liver; all factors which influence the hepatotoxicity/carcinogenicity of these preparations. Information on the pyrrolizidine alkaloid content of the traditional preparations needs to be determined for individual products.
Based on the HMPC “Public statement on the use of herbal medicinal products containing toxic, unsaturated pyrrolizidine alkaloids (PAs)” (EMA/HMPC/572844/2009) the acceptable daily intake is maximum 0.007 μg/kg/day for cutaneous preparations.
Generally for adults the calculation is done with a body weight of 50 kg. Therefore the daily dosage would be: 0.007 μg/kg/day x 50 kg body weight = 0.35 μg/person/day for
The public statement does not exclude the use of the preparations with a lower limit on the PAs content (0.014 µg PA/day) in children and during pregnancy, however, taking into consideration the general rule that there are not adequate data on the use of the preparation mentioned in the monograph in these populations for more than 30 years, the use is not recommended.