sign in sign up
<<
Home , Aesculin, Barbiturate, Buprenorphine, Chamomile, Ginkgolide, Shogaol

Journal of Clinical Pharmacy and Therapeutics (2002) 27, 391–401

REVIEW ARTICLE : potential for adverse interactions with

W. Abebe PhD Department of Oral Biology and Maxillofacial Pathology, School of Dentistry, Medical College of Georgia, Augusta, GA, USA

of the potential adverse interactions between SUMMARY herbal supplements and analgesic drugs, and take The use of herbal supplements in the US has appropriate precautionary measures to avoid their increased dramatically in recent years. These possible occurrences. However, as most of the products are not regulated by the Food and interaction information available is based on Administration (FDA) with the same scrutiny as individual case reports, animal studies and in vitro conventional drugs. Patients who use herbal data, further research is needed to confirm and supplements often do so in conjunction with assess the clinical significance of these potential conventional drugs. This article is a review of interactions. potential adverse interactions between some of the commonly used herbal supplements and Keywords: acetaminophen, adverse drug inter- analgesic drugs. Non-steroidal anti-inflammatory actions, analgesic drugs, herbal supplements, drugs (NSAIDs), particularly , have the NSAIDs, potential to interact with herbal supplements that are known to possess antiplatelet activity (, , , bilberry, dong quai, INTRODUCTION feverfew, , , meadowsweet and willow), with those containing (cham- The use of herbal supplements in the US has omile, motherworth, horse chestnut, become increasingly popular in recent years. In a and red clover) and with tamarind, enhancing the survey conducted in 1999, about 49% of adult risk of bleeding. Acetaminophen may also inter- Americans were estimated to have used herbal act with ginkgo and possibly with at least some of products during the previous year (1). Of these, the above to increase the risk of bleeding. about 24% had used these products on a regular Further, the incidences of hepatotoxicity and basis. These fall into the category of nephrotoxicity may be augmented by acetamino- alternative ⁄ complementary medicines and, as such, phen when concomitantly used with the poten- are not regulated by the Food and Drug Admin- tially hepatotoxic herbs Echinacea and , istration (FDA) with the same scrutiny as conven- and with herbs containing salicylate (willow, tional drugs. Their regulation by the FDA is meadowsweet), respectively. The concomitant use restricted as a result of the Dietary Supplement of with the herbal Health and Education Act (DSHEA) passed by supplements, , kava and , may US Congress in 1994. These products are avail- lead to increased central nervous system (CNS) able to consumers as over-the-counter (OTC) depression. The analgesic effect of opioids may items in various forms of preparations or dos- also be inhibited by ginseng. It is suggested that ages. Several factors are believed to contribute to health-care professionals should be more aware the increasing trend of herbal supplement util- ization in this country: ease of accessibility, the Received 1 August 2001, Accepted 14 October 2002 desire for self-medication, and the perceptions Correspondence: Worku Abebe PhD, Department of Oral Bio- logy and Maxillofacial Pathology, School of Dentistry, CB 3710, that herbs are safer, gentler and less costlier Medical College of Georgia, Augusta, GA 30912–1128, USA. Tel.: than conventional drugs, among others. These 706 721 3181; fax: 706 721 6252; e-mail: [email protected] and related aspects of utilization of herbal

2002 Blackwell Science Ltd 391 392 W. Abebe supplements have been reviewed in some details , , meclofenamide and etdolac; recently (2–4). (ii) acetaminophen and (iii) the opioids, , As the use of herbal supplements in the US , , , hydro- continues to grow under the prevailing scenario, morphone, , , , some concerns have become apparent regarding suphentanyl, , , meperidine, the safety of these products. Of particular safety , , , butor- concern is potential interactions of these products phanol, , dihydrocodeine and pro- with conventional drugs. It has been documented poxyphene (6–8). The widespread use of analgesics, that as many as 31% of the patients who use herbal both as OTC and prescription items, demands that supplements do so in conjunction with prescribed health-care professionals should be aware of their drugs and about 70% of these patients do not possible interactions with herbal supplements. regularly report the use of these products to their Such information has not yet been compiled health care providers (1). Another study also systematically and this brief review is the first demonstrated that about 26% of presurgical pa- attempt towards that goal. For the purpose of this tients who utilize herbal supplements take OTC review, the analgesics are classified as described drugs concurrently (5). In view of the ongoing above and their possible interactions with herbal trend, it is likely that health-care professionals will supplements are examined according to this encounter more often than before patients who use classification. herbal supplements and who may seek their help concerning –drug interactions. In order to POTENTIAL INTERACTIONS OF ASPIRIN appropriately tackle this problem and provide a AND NON-SALICYLATE NSAIDS WITH more adequate health-care service to such patients, HERBAL SUPPLEMENTS practitioners should be knowledgeable of at least the commonly occurring or anticipated interactions Aspirin and non-salicylate NSAIDs are commonly between herbal supplements and conventional used for the management of mild-to-moderate drugs. These interactions may be additive or sy- . These drugs reduce the synthesis of prosta- nergistic, whereby the herbal product increases or glandins and thromboxanes by inhibiting ⁄ inacti- potentiates the action of the drug. By contrast, the vating the cyclooxygenase (6, 7). While the herb may also be antagonistic to the action of the inhibitory effect of aspirin on cyclooxigenase is drug. While herb–drug interactions may involve irreversible, that of the non-salicylate NSAIDs is pharmacodynamic and pharmacokinetic mecha- reversible. Therefore, compared with the non- nisms, they may result in either beneficial or salicylate NSAIDs, aspirin has a greater potential adverse effects. for causing effects resulting from inhibition of In this paper, possible adverse interactions that cyclooxygenase. However, for both groups of may occur between some of the popular herbal drugs, interactions may occur with herbal supple- supplements in the US market and analgesic drugs ments whose actions involve the production of are reviewed briefly based on the available litera- prostaglandins and ⁄ or thromboxanes. In addition, ture information. Some of the information provi- both aspirin and the non-salicylate NSAIDs are ded is supported with documented data, whereas highly plasma protein-bound and this may further others have their basis on theoretical grounds. predispose them to possible interactions with herbs Along with this information, a brief description of that share this property, although such interactions the major therapeutic applications of each herb is have not yet been documented in the literature. provided. Aspirin, at relatively high doses (e.g., >3 g ⁄ day), Analgesics are one of the most frequently used also causes a reduction in prothrombin, a plasma drugs for medical as well as dental purposes in the factor involved in blood clotting (8). US. These drugs are available as OTC and ⁄ or pre- A survey of the literature indicates that a num- scription items. The commonly used analgesic ber of herbal supplements have antiplatelet and drugs include (i) aspirin and the non-salicylate (i.e., those containing coumarin de- non-steroidal anti-inflammatory drugs (NSAIDs), rivatives) properties, and tamarind can interact , flurbiprofen, diflunisal, , with aspirin and some of the other NSAIDs (9–16).

2002 Blackwell Science Ltd, Journal of Clinical Pharmacy and Therapeutics, 27, 391–401 Herb–analgesic interactions 393

spontaneous bleeding in the eyes of a 70-year-old Interactions with antiplatelet herbs man who was given aspirin while taking ginkgo One of the consequences of thromboxane synthesis extracts (21, 22). Therefore, the concurrent admin- inhibition by aspirin and the non-salicylate istration of aspirin or other NSAIDs with ginkgo NSAIDs is a reduction in platelet aggregation. This may present an additional risk of bleeding. process interferes with clotting mechanisms, pro- Appropriate precautions are recommended for longing bleeding time. High doses of aspirin by avoiding such herb–drug interactions. reducing prothrombin production can also con- tribute to bleeding problems, as noted above. Garlic (Allium sativum). Garlic is one of the largest Moreover, NSAIDs, particularly aspirin, by inhib- selling and most extensively researched herbs. It is iting prostaglandin generation in the gastric popularly believed to provide several cardiovas- mucosa, eliminate cytoprotection with possible cular benefits including the lowering of blood damaging effects on the mucosa, leading to gastric pressure, prevention of age-related changes in the bleeding, specially in the elderly (17). Therefore, vasculature and a reduction of serum lipids (9, 11, when NSAIDs are used by patients taking herbal 13–15, 18, 19). Garlic is available as , minced supplements with antiplatelet activity, there clearly bulb, oil-filled capsules and tablets. Among other is an increased risk of bleeding in the stomach and ingredients, it contains alliin ⁄ and its degra- elsewhere in the body. In fact, some antiplatelet dation products, and sulphur-containing essential herbs have been reported to cause bleeding on their oils. Dosage forms are standardized for alliin con- own (i.e., in the absence of NSAIDs or any other tent as well as garlic oil. These constituents of drugs), strengthening this contention. The follow- garlic, particularly alliin ⁄ allicin, have been dem- ing are herbal supplements that have been docu- onstrated to possess antioxidant properties, and to mented or suspected to possess antiplatelet inhibit the production and ⁄ or release of mediators activity, thus having the potential to cause in- such as PAF, , prostaglandins and creased risk of bleeding with NSAIDs, particularly thromboxanes (9, 13, 19). The inhibitory effect of aspirin. garlic on the production and ⁄ or release of one or more of these mediators decreases platelet func- Ginkgo ( L.). Ginkgo is one of the tion. In support of this, there is a report indicating most popular herbal products available in the US. that platelet aggregation could be reduced by garlic An extract of ginkgo leaves is commonly used for oil in blood samples from healthy adults (23). In conditions associated with cerebral and peripheral addition, in an elderly man, the development of a ischaemia (e.g. dementia, impotency, claudication) spontaneous epidural haematoma was observed in various dosage forms including capsules, tablets after ingestion of garlic (24). Also, in a male patient and tinctures. Among several other effects, ginkgo who underwent transurethral resection of the is reputed to have vasorelaxant, anti-oxidant and prostate, haemorrhage occurred for a period of 4 h anti-inflammatory properties. Ginkgo extract is after surgery as a result of prior ingestion of garlic composed of several compounds including the tablets (25). However, there have been no reports flavone , kaempferole and , that directly relate the occurrence of adverse in- diterpenes ( A, B, C and M) and ses- teractions between NSAIDs and garlic in humans. quiterpenes (9, 11, 13–15, 18, 19). Of these, gin- It is, nevertheless, prudent that patients should be kgolides (particularly B) have also been appropriately instructed or closely observed if shown to inhibit the binding of platelet activating garlic consumption occurs concomitantly with the factor (PAF) to its receptors on platelet membranes, use of these analgesics. resulting in reduced platelet aggregation. In this regard, a study in human volunteers found marked Ginger (Gingiber officinale). Ginger has been used inhibition of platelet aggregation after single doses primarily as a prophylaxis in nausea and vomiting. of mixed ginkgolides (9, 18, 20, 21). Consistent It is also promoted for use in anorexia, certain with this, bleeding has been reported in patients cardiovascular problems, bronchitis and arthritis taking ginkgo with and without concomitant (9, 15, 18, 21). The herb is available as fresh or dried administration of NSAIDs. A case report suggested root, powder, liquid extract, tablets, capsules, or

2002 Blackwell Science Ltd, Journal of Clinical Pharmacy and Therapeutics, 27, 391–401 394 W. Abebe . The volatile oil of ginger is composed of zin- direct inhibition of giberene, bisabolene, shogaol and (9, 15, (27–30). Therefore, although not reported in the 21). Ginger has also been reported to reduce literature, these data suggest that dong quai may platelet aggregation through inhibition of throm- potentiate the risk of bleeding if combined with boxane synthase (26). It is therefore suspected that NSAIDs. the use of aspirin or other NSAIDs may enhance bleeding tendency when simultaneously taken Feverfew (). Common use of with ginger supplements, particularly in amounts feverfew is for prophylaxis and treatment of of ginger greater than regularly found in food headaches. Other uses include the treat- products. ment of arthritis, gastrointestinal disorders and fever (9, 15, 18). The herb is available as dry bulk, Bilberry (Vaccinium myrtillus). This herb has been pills, capsules and tinctures. It is believed that the variously used for the treatment of diarrhoea, above effects of the herb are produced primarily circulatory diseases, eye conditions, inflammation because of its constituent parthenolide, which blocks and diabetes (9, 15, 18, 21). It is supplied as tinc- the synthesis and ⁄ or release of various inflamma- tures, fluid extracts, dried leaves and berries. tory mediators (e.g. prostaglandins, thromboxanes, Bilberry contains anthocyanins and flavonoid gly- leuekotriens, histamine, serotonin) from platelets cosides. It is believed that bilberry’s medicinal and polymorphonuclear leucocytes (31, 32). As a properties stem primarily from the anthocyanins, result, feverfew has a significant inhibitory effect on which also exert antagonism of platelet aggregation platelet aggregation (9, 15, 18). Although there are no (9, 15, 21). Although no drug–herb interactions documented reports of feverfew interacting with have been documented to date, it would be pru- NSAIDs, the pharmacological data suggest at least dent to avoid concomitant use of aspirin and other the potential for additive antiplatelet effect in the NSAIDs with bilberry, which may elicit additive or presence of these analgesics. synergistic antiplatelet effect and possibly hae- morrhage (9, 15, 21). There is also the possibility Ginseng. At least three varieties of ginseng are that other berries (e.g. blackberry, blueberry, can- available on the American market: American gin- berry, red raspberry, grape, wild cherry) may have seng (Panax quinquefolius), Asian ginseng (Panax similar adverse interactions with these analgesics. ginseng) and Siberian ginseng ⁄ eleuthero (Eleuthero- coccus senticosus). Asian ginseng is considered to be Dong quai (Angelica sinensis). Dong quai is a Chi- the most potent (33). All three varieties are used for nese medicine promoted in the US for the treat- the purposes of boosting the immune system, and ment of several gynaecological complaints. It is enhancing stamina and physical capacity. Such also claimed to have mild sedative, analgesic, ‘adaptogenic’ properties of ginseng are believed to antispasmodic, anti-inflammatory and antiplatelet be more useful for the elderly and those recovering properties (9, 15, 27). Preparations used include from illness (9, 15, 18, 33). Ginseng roots are tablets, and extracts. available as fresh or dried root, powder, capsules, analysis found that don quai consists of ferulic tablets, tea and candy. American ginseng has been acid, and several natural coumarin derivatives shown to contain panaxosides and Siberian gin- such as oxypeucedan, osthole, , seng, eleutherosides (9, 15, 33). Although the and furocoumarin derivatives (9, 15, 21, 27). In vivo mechanisms remain unclear, these ingredients and in vitro studies have shown that ferulic acid produce effects on the central nervous system and osthole have antithrombotic activity (27–30). (CNS), cardiovascular system, neuro-endocrine These chemicals exert this effect by interfering with function, carbohydrate metabolism and lipid two pathways responsible for platelet activation. metabolism, and immune function (9, 15, 33). Ferulic acid interrupts platelet aggregation by Regarding effects on platelets, in vitro studies have inhibiting the release of serotonin and adenosine shown that several components of P. ginseng inhibit diphosphate from platelets and by reducing the thromboxane A2 formation and thus platelet production of thromboxane A2. Osthole interferes aggregation (9, 15, 33). In rats fed P. ginseng for with platelet activation and aggregation through 3 weeks, platelet aggregation was found to be

2002 Blackwell Science Ltd, Journal of Clinical Pharmacy and Therapeutics, 27, 391–401 Herb–analgesic interactions 395 impaired, as measured by thrombin time and components of willow are salicylates, which are activated partial thromboplastin time (34). More- similar to aspirin (11, 12, 15, 18, 21). As with over, in a 72-year-old woman, vaginal bleeding meadowsweet, there are no documented reports on was observed to occur after ingestion of a tablet the interactions between salicylates of willow and containing ginseng (35). Uterine bleeding was NSAIDs. Therefore, concerns about concurrently also reported in a 44-year-old woman after apply- using willow and NSAIDs remain theoretical. ing a ginseng-containing cream to her face (36). Although there are no supporting clinical data of Interactions with coumarin-containing interactions, as a result of the antiplatelet effects, (anticoagulant) herbs ginseng is expected to interact with NSAIDs and increase the risk of bleeding. Hence, concomitant There are also herbal supplements that contain use of NSAIDs with ginseng is ill-advised or coumarin derivatives possessing anticoagulant ac- should be closely monitored. tivity (9, 11–15, 18, 19). These herbs provide ad- ditive blood thinning effects to the antiplatelet or Turmeric (Curcuma longa). Turmeric has been hypoprothrombinaemic actions of aspirin and ⁄ or used medicinally for various conditions including other NSAIDs when used concomitantly. They act indigestion, pain, arthritis and infections (exter- as K antagonists by interfering with the nally). Preparations available are powdered root, coagulation processes (38). Consequently, these capsules and liquid extracts. Turmeric contains anticoagulant herbal supplements increase clotting the volatile oils zingiberen and turmerone that time. The following is a list of such herbs. have antispasmodic and antibiotic activities, and with anti-inflammatory and antiplatelet Motherworth (Leonurus cardiaca). Motherworth is properties (9, 15, 18). Most of these effects of commonly used for treatment of menstrual disor- turmeric ⁄ curcumin (including antiplatelet) have ders, menopause, and heart diseases (9, 11, 15, 18). been reported to be due to inhibition of synthesis of It has also been reported to produce anticoagulant, prostaglandins and thromboxanes, and stimulation anti-inflammatory, antispasmodic, anti- and of hydrocortisone release (9, 15, 18). It is thus anticancer effects. Among several other chemicals, possible that NSAIDs additively interact with tur- motherworth contains alkaloids, leonurine, diter- meric in certain aspects of their pharmacology, and penes, prehispanolone, flavonoids and cafeic acid, concomitant therapy with these substances may and the herb is available as tincture, extract and in lead to clotting disorders and enhanced risk of bulk (11, 15, 39). The anticoagulant effect of moth- bleeding. erworth was confirmed in a study of 105 partici- pants who demonstrated a decrease in fibrinogen Meadowsweet (Filipendula ulmaria). Meadowsweet and blood viscosity (39). Prehispanolone is one of is commonly used for muscle aches, headaches, the chemical components reported to be respon- colds and flu, digestive upsets, menstrual cramps, sible for this effect of the herb. It is therefore arthritis and congestive heart failure (9, 12, 15, 18). possible that the administration of NSAIDs while It is available as tincture and dried bulk. The herb taking motherworth may increase the risk of contains salicylates and phenolic glycosides, which bleeding. Appropriate precautionary measures are thought to contribute to its medicinal properties need to be provided in order to avoid the possi- (9, 15, 18, 37). Because of the presence of salicylates, bility of such herb–drug interactions. meadowsweet demonstrates antiplatelet activity. However, no interaction has been reported Chamomile (Matricaria recutita, Chamaemelum between meadowsweet and NSAIDs, and concerns mobile). Chamomile is popularly used for its sed- about prescribing NSAIDs to patients taking this ative and antispasmodic effects (9, 15, 18). It has herb remain theoretical. also antiseptic and anti-inflammatory activity, for which it is applied as a vulnerary agent. The sup- Willow (Salix spp.). Willow has been used for fever, plement is available as capsules, fluid extracts and flu, inflammation, pain and rheumatism. It comes as in the form of topical preparations. Chamomile dried bark, capsules and liquid extracts. The active consists of several ingredients including coumarin,

2002 Blackwell Science Ltd, Journal of Clinical Pharmacy and Therapeutics, 27, 391–401 396 W. Abebe , heniarin, flavonoid, farnesol, nerolidol loids, amino acids and coumarin, among other and germacranolide (9, 15, 18, 40). Despite the ingredients (9, 15, 18). Due to coumarin, the presence of coumarin, as chamomile’s effect on the possibility of enhanced tendency of bleeding exists coagulation system has not yet been studied, it is when fenugreek is used in combination with anti- unknown if a clinically significant drug–herb inter- platelets/anticoagulant drugs including NSAIDs. action exists with antiplatelet ⁄ anticoagulant drugs, such as aspirin or non-salicylate NSAIDs. However, Interactions with tamarind (Tamarindus indica) until more information is available, it is not recommended to use these substances concurrently. Tamarind is commonly used as a laxative. It is also indicated for stomachaches, and and gall- Horse chestnut (Aesculus hipposcastanum). Horse bladder ailments (15). Tamarind is also an ingre- chestnut has been traditionally consumed to treat dient in steak sauces. The fruit of the herb is varicose veins and haemorrhoids (9, 15, 18). The available as extracts, syrup, or molded into cakes or herb is available as standardized extracts of the balls for oral consumption. Tamarind is composed leaves, bark and ⁄ or seeds for , of tartaric acid, sugar, pectin, pyrazines and thia- and as tea and poultice for external use. As a zols. The organic acids and pectin are believed to principal active ingredient, horse chestnut contains contribute at least to its laxative effect. With the anti-inflammatory compound aescin, which regardstoherb–druginteractions,tamarindhasbeen helps to strengthen blood vessel walls and reduce reported to increase the of aspirin, fluid leakage (9, 15, 18). In addition, horse chestnut leading to gastrointestinal bleeding (16). Whether contains the coumarin, aesculin, which can addi- or not tamarind interacts with other NSAIDs in a tively interact with blood thinners such as NSAIDs, similar manner has not yet been documented. potentially leading to increased bleeding tendency (9, 15, 18). Patients taking horse chestnut supple- POTENTIAL INTERACTIONS ment and NSAIDs simultaneously should therefore OF ACETAMINOPHEN WITH HERBAL be advised to watch for symptoms of bleeding. SUPPLEMENTS Red clover (Trifolium pratense). This herb has been Like the NSAIDs, acetaminophen is also indicated promoted for the treatment of skin conditions, for mild-to-moderate levels of pain. Although its menopause, cough and other respiratory problems mechanism of action is poorly understood, it is (9, 15, 18). Some of these effects could be due to the believed to involve inhibition of prostaglandin and antispasmodic and expectorant properties of its thromboxane synthesis (7). However, acetamino- ingredients. Red clover is available as tablets, cap- phen may exert a varying degree of inhibition of sules, tea, liquid preparations and raw spouts. The mediator synthesis at different sites, contributing to supplement contains several volatile oils such as its unique pharmacological properties. Acetamino- benzyl alcohol, and methyl phen has the advantage of providing analgesia anthranilate; isoflavonods; cyanogenic glycosides and without most of the side-effects associated with (9, 15, 18). Because of the presence of cou- aspirin, other NSAIDs or opioids (see below). It is marins, red clover is suspected to have anticoagulant generally considered to be safe when taken in activity and thus may interact with such blood thin- recommended doses for a short duration. How- ners as NSAIDs to augment the risk of bleeding. ever, with prolonged or habitual usage, more seri- ous adverse reactions such as nephropathy may Fenugreek (Trigonella foenum-graecum). Fenu- occur (38). Further, the ingestion of high doses of greek is commonly indicated for diabetes mellitus, acetaminophen (>10 mg) may result in severe gout, inflammation, gastrointestinal problems, hepatic necrosis because of formation of a highly muscle pain and tuberculosis (9, 15, 18). It is sup- reactive metabolite which depletes (38). plied as unprocessed seeds, extracts, capsules and Although herb–acetaminophen interactions are not poultice. Some of these actions are associated with common, the possibility for such interactions have its anti-inflammatory and anti-oxidant properties. been mentioned under certain conditions. Below The herb is composed of various , alka- are listed potential herb–acetaminophen adverse

2002 Blackwell Science Ltd, Journal of Clinical Pharmacy and Therapeutics, 27, 391–401 Herb–analgesic interactions 397 interactions that need to be noted by patients and vance is available, it is reasonable to assume that health-care professionals. the combined use of acetaminophen and herbs containing salicylate can also result in nephrotox- icity, particularly over long-term and at high doses. Interactions with ginkgo (Ginkgo biloba L.) Appropriate precautions need to be taken by and possibly with other antiplatlet herbs patients and health practitioners in order to avoid The medicinal properties of gingko and its possible or minimize such possible interactions. Salicylate- interactions with NSAIDs are discussed above. containing herbs with the potential for causing Although acetaminophen has relatively less drug interactions with acetaminophen include meadow- interactions in the usually recommended doses, a sweet and willow (12, 18, 21). It should also be recent report demonstrates that ginkgo can also noted that the concomitant use of acetaminophen interact with this analgesic. This effect is believed and salicylates can induce additive inhibitory effect to be linked to the inhibitory effect of acetamino- on platelet function as stated earlier. phen on thromboxane synthesis (and hence platelet aggregation). In a 33-year-old woman taking Interactions with echinacea (various species, ginkgo, the administration of acetaminophen was including Echinacea angustifolia, Echinacea found to induce spontaneous bilateral subdural pallida, ) haematomas (41). This condition is attributed to the presence of ginkgolide B in ginkgo, which leads to Echinacea is promoted for treating abscesses, the inhibition platelet aggregation. However, it is burns, colon cancer, eczema, liver cancer, upper not known whether similar interactions with acet- respiratory tract infection, urinary tract infection, aminophen occur with the other antiplatelet herbs skin wounds and varicose leg ulcers (9, 15, 18, 40). listed above. Until further information is available, The herb has been found to possess antiviral, health-care professionals should be cautious of antibacterial, antifungal and anti-inflammatory potential interactions of these herbs not only with activities and to stimulate the immune system. NSAIDs but also with acetaminophen. Echinacea is available as tablets, capsules, lozenges, liquid extracts and tinctures. Among other natural ingredients, it contains several essential oils, phe- Interactions with coumarin-containing nylpropenoids, alkaloids, flavonoids and alkyl- (anticoagulant) herbs (9, 18, 21, 40). An important concern about Coumarin-containing anticoagulant herbal supple- echinacea is that certain species of the herb contain ments possibly interacting with NSAIDs are noted pyrrolizidine alkaloids, which can cause liver tox- above. In view of the recently reported increased icity by depleting glutathione (14, 18, 40). Although anticoagulation by acetaminophen in patients it has not yet been shown experimentally ⁄ clinic- taking (42), it is suspected that the anal- ally, this effect of the supplement has the potential gesic can also interact with supplements containing to enhance the chance of hepatotoxicity when coumarin derivatives to elicit augmented bleeding. acetaminophen is co-administered. Health-care As pointed out earlier, the inhibitory effect of providers as well as patients should therefore be acetaminophen on thromboxane production may cautious when acetaminophen is administered contribute to this adverse reaction. Therefore, pre- together with echinacea. cautions are in order in taking acetaminophen with such herbs as chamomile, horse chestnut, mother- Interactions with kava (Piper methysticum) worth, red clover and fenugreek. Kava is popularly used for anxiety, asthma, de- pression, , muscle spasms, pain, psycho- Other possible interactions sis, rheumatism, and wounds (9, 11, 18). with salicylate-containing herbs Products of kava are available as tablets, capsules, It has been reported that acetaminophen is associ- beverages, extracts and tinctures. The herb consists ated with nephrotoxicity, when used in combination of a number of ingredients including kava lactones, with aspirin (38). Although no data of direct rele- which are also known as kava pyrones. Recently,

2002 Blackwell Science Ltd, Journal of Clinical Pharmacy and Therapeutics, 27, 391–401 398 W. Abebe the FDA has issued a warning concerning liver gamma-amino butyric acid (GABA) neurotrans- toxicity of kava. About 25 reports of serious liver mission and function (9–11, 18). In experi- toxicity in and Switzerland, including mental animals, valerian has been shown to cases of cirrhosis, hepatitis and liver failure have cause increased -induced sleeping time been reported (43). There is also documentation of (10, 12). Further, in a human patient, valerian a case in the US of a previously healthy young withdrawal appeared to mimic the withdrawal women who required a liver transplant after using syndrome of after the patient a kava-containing supplement. The mechanism(s) presented with delirium and cardiac complications for the hepatotoxic effect of kava has not yet been following surgery (9, 12, 14, 18). The patient’s delineated. As a precautionary step, it is advisable symptoms were attenuated by not to use acetaminophen in conjunction with kava, administration. Based on these findings, valerian particularly in high doses for prolonged periods, as would be expected to potentiate the sedative effects this combination may have the potential to enhance of opioids, and thus caution is advised if these are the risk of hepatotoxicity. used in combination.

POTENTIAL INTERACTIONS OF OPIOIDS Interactions with kava (Piper methysticum) WITH HERBAL SUPPLEMENTS Kava is briefly discussed above in connection to its Opioid analgesics are used primarily for the man- possible hepatotoxic effect. Kava is used at least agement of moderate-to-severe pain, either alone partly because of its CNS action. Among or in combination with NSAIDs or acetaminophen. other ingredients, the herb is composed of kava The use of these analgesics is associated with a lactones which are believed to provide at least its number of side-effects, including sedation and , analgesic and effects, respiratory depression (7). These effects become by potentiating GABA neurotransmission (9, 18). more severe in the elderly, pregnant women, Accordingly, the kava lactones have been observed young children and the foetus. While there are a to increase barbiturate-induced sleeping time in few documented herb–opioid interactions, most of laboratory animals and effects in the interactions are theoretical. These interactions humans (44). Kava has also been shown in mice to may occur at the CNS level with herbal supple- have antinociceptive effects that are not antagonized ments having sedative properties (i.e., valerian, by the (45). It is therefore kava, chamomile) and with ginseng eliciting in- likely that the administration of opioid analgesics hibitory effect on opioid-induced analgesia. As in patients taking kava may cause increased CNS described below, the sedative herbs are expected to depression ⁄ sedation, and vice versa. Caution is thus enhance the CNS depression ⁄ sedation caused by needed if these substances are used together. opioids, and vice versa. Interactions with chamomile (Matricaria recutita, Interactions with valerian (Valeriana officinalis) Chamaemelum mobile) Valerian is a widely recognized herbal sedative Chamomile is discussed above in relation to its used primarily for disorders and restlessness. anticoagulant property. The herb also has a sedative It is also promoted for nervous excitability, hys- effect (9–11, 18) believed to be due to the presence of terical states, cramps, rheumatic and dys- the flavonoid, (40). Therefore, chamomile menorrhoeal (9, 15, 18, 40). The action of the herb is has the potential to increase the CNS depressant related to a group of compounds that include the effects of drugs such as opioid analgesics. (e.g. valepotrites, valeric acids). Commercially available preparations are stan- Interactions with ginseng (Panax ginseng, Panax dardized to and are formulated as quinquefolius) infusions, solid extracts, tinctures and fluid extracts. Valerian has been demonstrated to induce In animal studies, ginseng has also been shown to sedation and hypnosis through modulation of cause a reduction in the analgesic effect of opioids

2002 Blackwell Science Ltd, Journal of Clinical Pharmacy and Therapeutics, 27, 391–401 Herb–analgesic interactions 399

(46). The mechanism(s) for this interaction between potential herb and drug interactions more relevant. ginseng and opioids is unknown, although it has This is particularly important for drugs that are been hypothesized to involve a non-opioid phe- frequently prescribed or used by patients, such as nomenon in the CNS. Therefore, it is worth noting analgesics. There is documented and theoretical that the possibility of reduced opioid-induced evidence in the biomedical literature for herbal analgesia exists in patients taking ginseng con- product–drug interactions. Health professionals comitantly. should question all patients about the use of herbs and report documented or suspected interactions to appropriate agencies such as the FDA under its LIMITATIONS OF THE REVIEW MedWatch Programme (800-FDA-1088). Consistent It is clear that most of the reported data on the reporting should improve knowledge and aware- potential interactions between herbal supplements ness of potential interactions and improve the and analgesic drugs are based on in vitro experi- quality of patient care. ments, animal studies, or individual clinical case reports. Clinical case reports may be confounded REFERENCES by patient-specific variables, such as age, sex, dis- ease, genetic and lifestyle factors and data from 1. Johnston BA. (2000) Prevention Magazine assesses animal and in vitro studies may not always predict use of dietary supplements. Herbalgram, 48, 65–72. responses in humans. A number of the herb–drug 2. Abebe W. (2003) An overview of herbal supplement utilization with particular emphasis on possible interactions suggested are on the basis of theoret- interactions with dental drugs, and oral manifesta- ical knowledge. These uncertainties make difficult tions. Journal of Dental Hygiene, in press:. informed decision-making by health-care profes- 3. Bauer BA. (2000) Herbal therapy: what a clinician sionals. needs to know to counsel patients effectively. Mayo A complicating factor is the lack of appropriate Clinic Proceedings, 75, 835–841. regulations governing the purity and potency of 4. Miller LG, Hume A, Harris M et al. (2000) White herbal products during manufacture and the lack paper on herbal products. Pharmacotherapy, 20, 877– of sufficient information about safety and thera- 889. peutic efficacy of most of the products. Unlike 5. Tsen LC, Segal S, Pothier M, Bader AM. (2000) conventional drugs, there is no premarketing use in presurgical patients. review and post-marketing surveillance require- Anesthesiology, 93, 148–151. ments for herbal supplements in the US. In addi- 6. Uionne RA, Gordo SM. (1994) Nonsteriodal ant-in- flammatory drugs for acute pain control. Dental tion, as the pharmacodynamic and pharmaco- Clinician of North America, 38, 645–664. kinetic properties of most herbal supplements are 7. Welch SP, Martin BR. (1997) Opiod and nonopioid poorly understood, potential interactions with analgesics. In: Graig CR, Stitzel RE, eds. Modern analgesics and other drugs cannot be predicted Pharmacology with Clinical Applications, 5th edn. with any certainty. Therefore, the information Boston: Little, Brown and Company, pp. 323. presented in this review cannot be claimed to be 8. Brouwers JR, DeSmet PA. (1994) Pharmacokinetic– definitive. There is an obvious need for further pharmacodynamic drug interactions with nonsteroi- research and documentation in this area. However, dal antinflammatory drugs. Clinical , until definitive interaction information becomes 27, 462–485. available, it is prudent for health practitioners as 9. Skidmore-Rose L. (2001) Mosby’s handbook of herbs well as patients to take account of the available to and natural supplements. St Louis, MO: Mosby Inc. avoid possible adverse interactions particularly by 10. Harkness R, Bratman S. (2000) Drug-Herb–Vitamin Interactions Bible. Rockline, CA: Prima Publishing. patients who are more vulnerable to such effects 11. Heck AM, DeWitt BA, Lukes AL. (2000) Potential (e.g. geriatric patients, infants, pregnant women). interactions between alternative therapies and war- farin. American Journal of Health System Pharmacy, 57, CONCLUDING REMARKS 221–227. 12. Lininger SW, Gaby AR, Batz F, Yarnell E, Brown DJ, The increased use of herbal supplements in the US Constantine G. (1999) A-Z Guide to Drug-Herb–Vita- in recent years has made information about min Interactions. Rockline, CA: Prima Publishing.

2002 Blackwell Science Ltd, Journal of Clinical Pharmacy and Therapeutics, 27, 391–401 400 W. Abebe

13. Vaes LPJ, Chyka RA. (2000) Interactions of warfarin 29. Yin ZZ. (1980) The effect of dong quai (Angelica with garlic, ginger, ginkgo or ginseng: nature of the sinsis) and its ingredient ferulic acid on rat platelet evidence. Annals of Pharmacotherapy, 34, 478–482. aggregation and release of 5-HT. Acta Pharmaceutica 14. Miller LG. (1998) Herbal medicinals: selected clinical Sinica, 15, 321–330. considerations focusing on potential herb–drug in- 30. Ko FN, Wu TS, Liou MJ, Huang TF, Teng CM. (1989) teractions. Archives of Internal Medicine, 158, 2200– Inhibition of platelet thromboxane formation and 2211. phosphoinositides breakdown by osthole from An- 15. Gruenwald J, Brendler T, Jaenicke C. (1998) The gelica pubescens. Thrombosis and Haemostasis, 62, 996– PDR for Herbal Medicines. Montvale, NJ: Medical 999. Economics Co. 31. Groenewegen WA, Heptinstall SA. (1990) A com- 16. Mustapha A, Yakasai IA, Aguye IA. (1996) Effect of parison of the effects of an extract of feverfew and Tamarinus indica L. on the bioavailability of aspirin in parthenolide, a component of feverfew on human healthy human volunteers. European platelet activity in vitro. Journal of Pharmacy and and Pharmacokinetics, 21, 223–226. Pharmacololy, 42, 553–557. 17. Shorr RI, Ray WA, Daughtery JR, Griffen MR. (1993) 32. Knight DW. (1995) Feverfew: chemistry and biolo- Concurrent use of nonsteriodal antinflammatory gical activity. Natural Products Report, 12, 271–276. drugs and oral places elderly persons 33. Kuo SC, Teng CM, Lee JG, Ko FN, Chen SC, Wu TS. at high risk for hemorrhagic peptic ulcer disease. (1990) Anti-platelet components in planax ginseng. Archives of Internal Medicine, 153, 1665–1670. Planta Medica, 56, 164–167. 18. Duke JA. (2000) The Green Pharmacy Herbal Handbook. 34. Park HJ, Lee JH, Song YB, Park KH. (1996) Effects of Emmaus, PA: Rodale Press. ditary supplementation of lipophilic fraction from 19. Gillis CN. (1998) rediscovered. Panax giseng on cGMP and cAMP in rat platelets Seminar in , Preoperative Medicine and Pain, and on blood coagulation. Biology and Pharmacy 17, 319–330. Bulletin, 19, 1434–1439. 20. Chung KF, Dent G, McCuster M, Guinot P, Page 35. Greenspan EM. (1983) Ginseng and vaginal bleed- CP, Barnes PJ. (1987) Effect of a ginkgolide mixture ing. JAMA, 249, 2018–2022. (BN 52063) in antagonising skin and platelet 36. Hopkins MP, Androff L, Benninghoff AS. (1988) responses to platelet activating factor in man. Lan- Ginseng face cream and unexplained vaginal bleed- cet, 1, 248–251. ing. American Jornal of Obstetrics and Gynecology, 159, 21. Tyler VE. (1996) The Honest Herbal: A Sensible Guide to 1121–1122. the Use of Herb and Related Remedies, 3rd edn. New 37. Liapina LA. (1993) A comparative study of the action York, NY: Pharmaceutical products press. of the hemostatic system of extracts from the flowers 22. Rosenblatt M, Mindel J. (1997) Spontaneous hyperema and seeds of the meadowaweet (Filipendula ulmaria associated with ingestion of Ginkgo biloba extract. L maxim). Izv Akad Nauk Series Biol, 4, 625–628. New England Journal of Medicine, 336, 1108–1115. 38. Desjardins PJ, Cooper SA. (1998) Perpherally acting 23. Bordia A. (1978) Effect of garlic on human platelet analgesics and antipyretics. In: Yagiela JA, Neidle aggregation in vitro. Atherosclerosis, 30, 355–360. EA, Dowd FJ, eds. Pharmacology and Therapeutics for 24. Rose KD, Croissant PD, Parliament CF, Levin MP. Dentistry, 4th edn. St Louis, MO: Mosby-Year Book, (1990) Spontaneous spinal epidural hemaroma with 281. associated platelet dysfunction from excessive garlic 39. Zou QZ. (1989) Effect of motherwort on blood ingestion: a case report. Neurosurgery, 26, 880–882. hyperviscosity. American Journal of Clinical Medicine, 25. Burnham BE. (1995) Garlic as a possible risk for 17, 65–70. postoperative bleeding. Plastic and Reconstruction 40. O’Hara MA, Kiefer D, Farrell K, Kemper K. (1997) A Surgery, 95, 213–219. review of 12 commonly used medicinal herbs. 26. Srivastava KC. (1984) Aqueous extract of , Archives of Family Medicine, 7, 532–536. garlic and ginger inhibit platelet aggregation and 41. Rowin J, Lewis SL. (1997) Spontaneous bilateral alter arachidonic acid metablosm. Biomedical Bio- subdural hematomas associated with chronic Ginkgo chimcal Acta, 43, 335–346. biloba ingestion. Neurology, 48, 1775–1776. 27. Page RL, Lawrence JD. (1999) Potentiation of war- 42. Hylck EM, Heiman H, Skates SJ, Sheehan MA, farin by dong quai. Pharmacotherapy, 19, 870–876. Singer DE. (1998) Acetaminophen and other risk 28. Qi-bing M, Jing-yi T, BoC. (1991) Advances in the factors for excessive warfarin anticoagulation. pharmacological studies of Radix Angelica sincensis JAMA, 279, 657–662. (OLIV) Diels (Chinese danggui). Chinese Medical 43. Lewis T. (2001) Dear health professional colleague – Journal of, 104, 776–781. letter. Rockville, MD: US food and Drug

2002 Blackwell Science Ltd, Journal of Clinical Pharmacy and Therapeutics, 27, 391–401 Herb–analgesic interactions 401

Administration. Available from: www.fda.gov/ Clinical and Experimental Pharmacology and Physiology, medwatch/safety/2001/kava.htm. 17, 495–507. 44. Brinker FJ. (1998) Herb Contraindications and Drug 46. Takahashi M, Tokuyama S. (1998) Pharmacological Interactions, 2nd edn. Sandy, OR: Eclectic Medical and physiological effects of ginseng on actions Publications. induced by opioids and psychostimulants. Methods 45. Jamieson DD, Duffield PH. (1990) The anti- and Findings in Experimental Clinical Pharmacology, 20, nociceptive actions of kava components in mice. 77–84.

2002 Blackwell Science Ltd, Journal of Clinical Pharmacy and Therapeutics, 27, 391–401