Comfrey

Scientific Name(s): Symphytum officinale L., S. asperum Lepechin, S. tuberosum L., Symphytum x uplandicum Nyman. Family: Boraginaceae (Borage)

Common Name(s): Comfrey , bruisewort , blackwort , knitbone , radix consolidate , Russian comfrey , slippery root

Uses

Therapeutic use of comfrey is limited because of its toxicity. A limited number of clinical trials show short-term efficacy of topically applied, alkaloid-free comfrey preparations in skin abrasions and inflammatory conditions. Although not examined in clinical trials, comfrey may possess antifungal and anticancer activity.

Dosing

Oral use of comfrey is not supported because of potential hepatotoxicity. Additionally, because externally applied alkaloids are well absorbed and detected in the urine, topical use of comfrey should not exceed an alkaloid exposure of 100 mcg/day. Limited trials have evaluated the efficacy of alkaloid-free preparations for topical use; however, these studies do not report on hepatic laboratory indices of study participants.

Contraindications

Comfrey is not recommended for internal use because of the hepatotoxic pyrrolizidine alkaloid content. Patients with hypersensitivity or allergic reactions to the plant should avoid external use. Use is contraindicated during pregnancy and lactation, in infants, and in patients with liver or kidney disease.

Pregnancy/Lactation

Contraindicated because of documented adverse effects. Pyrrolizidine alkaloids have abortifacient effects and increase the risk of fatal hepatic veno-occlusive disease. Animal experiments have detected alkaloids in breast milk.

Interactions

None well documented.

Adverse Reactions

Neither internal nor extensive topical use of comfrey is recommended because of numerous reports of liver toxicity (see Toxicology). Case reports show hepatic veno-occlusive disease and pulmonary hypertension related to comfrey use. Infants are more susceptible to pyrrolizidine-related, veno-occlusive disease; therefore, the use of comfrey in this population is contraindicated.

Toxicology

The Food and Drug Administration (FDA) released an advisory in July 2001 recommending that comfrey products be removed from the market because of cases of hepatic veno-occlusive disease. Comfrey is generally considered unsafe, with numerous toxicological effects in animals and humans.

Botany

Comfrey is a perennial plant found in moist grasslands in western Asia, as well as in North America. It grows to heights of 50 to 150 cm and has long, hairy lanceolate leaves and bell-shaped, red-violet or yellowish flowers. S. x uplandicum Nyman is a hybrid of S. officinale and S. asperum , and has been cultivated to contain insignificant amounts of alkaloids in the aerial parts of the plant. 1 , 2 , 3

History

Comfrey has been cultivated in Japan as a green vegetable and has been used as an herbal medicine for more than 2,000 years. Comfrey's original name, knitbone, derives from the external use of poultices of its leaves and roots to heal burns, sprains, swelling, and bruises. In Western Europe, comfrey has been used topically for treating inflammatory disorders such as arthritis, gout, and thrombophlebitis, and internally for treating diarrhea. Comfrey has been claimed to heal gastric ulcers and hemorrhoids, and to suppress bronchial congestion and inflammation. Comfrey distribution is restricted in Germany and Canada because of its substantial toxicity. 2 , 4

Chemistry

Numerous hepatotoxic pyrrolizidine alkaloids with differing toxicities have been identified in the plant, including symphytine, echimidine, intermedine, symviridine, and lasiocarpine (retronecine mono- and diester alkaloids). Roots contain a 100-fold higher alkaloid content than the aerial portions. 2 , 5 , 6

The healing action of poultices of comfrey roots and leaves may be related to the presence of allantoin. The underground roots contain allantoin 0.6% to 0.7% and tannin 4% to 6.5%; the leaves contain a higher proportion of tannin relative to allantoin. The roots also contain rosmarinic and lithspermic acid. 7 , 8 , 9 , 10

Large amounts of mucilage, fructanes, and starch are found in the leaves and roots, 11 , 12 while a pentacyclic triterpene glycoside of oleanolic acid was identified in the root. 9 , 10

Uses and Pharmacology

The therapeutic use of comfrey is due in part to allantoin and rosmarinic acid content, but it is limited by the toxicity of pyrrolizidine alkaloids. 4 Controlled cultivation of S. x uplandicum is said to produce a plant devoid of the toxic alkaloids in the aerial plats, enabling the production of relatively nontoxic comfrey preparations. 3 Pyrrolizidine alkaloid-free preparations of comfrey have been used in clinical studies in Germany.

Inflammation

A limited number of clinical trials have been conducted to assess the efficacy of topically applied, alkaloid-free comfrey preparations in ankle sprains, osteoarthritic knee conditions, and back pain/myalgia. 13 , 14 Outcome measures include patient assessment of pain and mobility, as well as measures of ankle swelling and clinician evaluations. Most studies show a statistically significant advantage of active preparation over placebo in the short term; however, because many of these trials have been conducted by product manufacturers, the possibility of publishing bias exists. 3 , 11 , 12 , 14 , 15 , 16 Other open-label or single-blind trials with topical comfrey preparations have been conducted; however study design limits the validity of the results. 17 , 18 , 19 Preparations generally contained a 35% liquid root extract from which toxic alkaloids were removed and standardized to allantoin 0.2% to 0.5%, 11 , 12 , 15 , 19 or to a preparation with 10% extract of S. x uplandicum aerial parts. 3 , 16 Duration of use ranged from 5 days to 3 weeks in these studies. The studies report no adverse effects, although liver function test results were not reported.

Mechanisms of action include effects on platelet activating factor, as well as on the synthesis of the enzymes catalase and superoxide dimutase. 20 , 21

Wound healing

The use of a dermal preparation of comfrey derived from alkaloid-free cultivars of S. x uplandicum has been studied in limited clinical trials. Applied to fresh abrasions, a 10% preparation showed faster decreases in wound size and shorter times to healing, with no cutaneous reactions to the preparation reported. 3 , 22 The preparations were applied to the skin over short time periods (days) only. Efficacy in wound healing may be related to the presence of allantoin, rosmarinic acid, or another hydrocolloid polysaccharide. 23 , 24

Other effects
Antifungal activity

Aqueous extracts from comfrey leaves strongly inhibited plant pathogenic fungi, most likely because of the plant's phenolic compounds. 25

Cancer

Various extracts and fractions of S. officinale have inhibited tumor cell proliferation and exerted antimitotic effects in animal and in vitro experiments. 26 , 27 , 28 , 29

Hormonal

Lithospermic acid isolated from the root appears to have antigonadotropic activity. 9

Dosage

The oral use of comfrey cannot be supported because of potential hepatotoxicity. Because externally applied alkaloids are well absorbed (detected in the urine), topical use of comfrey should not exceed an alkaloid exposure of 100 mcg/day. 2

Limited trials have evaluated the efficacy of alkaloid-free preparations for topical use; however, these studies do not report on hepatic laboratory indices of the participants.

Pregnancy/Lactation

Avoid use because of documented adverse effects. Pyrrolizidine alkaloids have abortifacient effects and increase the risk of fatal hepatic veno-occlusive disease. 30 , 31 , 32 An extract of S. officinale has been reported to enhance uterine tone. 33 Animal experiments have detected comfrey alkaloids in breast milk. 34 , 35

Interactions

Case reports are lacking. Experimental evidence exists of the potentiation of toxicity of comfrey's alkaloids by phenobarbital via the cytochrome P450 pathway. 2

Adverse Reactions

Neither internal nor extensive topical use of comfrey can be recommended because of numerous reports of liver toxicity (see Toxicology). Case reports show hepatic veno-occlusive disease and pulmonary hypertension related to comfrey use. 2 , 36 Infants are more susceptible to pyrrolizidine-related, veno-occlusive disease; therefore, the use of comfrey in this population is contraindicated. 2

Toxicology

Hepatotoxic effects

The FDA released an advisory in July 2001 recommending that comfrey products be removed from the market following several cases of hepatic veno-occlusive disease in which the destruction or obliteration of small hepatic veins led to cirrhosis and, eventually, liver failure. Also in 2001, the Federal Trade Commission brought enforcement action against a company marketing comfrey-containing products. The parties agreed to a preliminary injunction that prohibited the company from marketing any comfrey-containing products intended for internal use or use on open wounds, as well as requiring a warning on comfrey products intended for external use. 37 , 38 , 39 , 40 , 41 , 42 , 43

Human poisonings with pyrrolizidine alkaloids are usually accidental and may be caused by ingestion of contaminated flour, milk, certain goat products that are resistant to the alkaloids, honey produced by bees fed on pyrrolizidine-containing weeds, and consumption of certain herbal or bush teas. It also may be caused by comfrey used in salads. 4 , 5 , 34 , 35

Carcinogenicity

S. officinale extract and components lasiocarpine and symphytine are carcinogenic in rats, possibly via genotoxic mechanisms 44 , 45 , 46 , 47 ; however, an association of comfrey consumption with cancer in humans is lacking. 2

A pyrrolizidine alkaloid-free liquid extract of comfrey root was not mutagenic when tested by the bacterial reverse mutation assay. 48

Bibliography

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