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Treatments Used in Complementary and Alternative Medicine
C H A P T E R
46 Treatments Used in Complementary and Alternative Medicine H.W. Zhang*, Z.X. Lin*, K. Chan†,1 *School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, PR China † The National Institute of Complementary Medicine, University of Western Sydney, Penrith, NSW, Australia 1 Corresponding author: [email protected]
INTRODUCTION With an increasing use of complementary and alternative medicine by the general public worldwide, the safety issues of possible interactions between complementary and alternative medicine (CAM) and other medicines have attracted much more attention in recent years, especially in high-risk populations like cancer and preoperative patients. For example, a questionnaire survey of 100 consecutive gynecological outpatients in a cancer center in Germany reported that 64% of patients used CAM and 48% used at least one substance-based CAM. A third of all patients were in danger of interactions of CAM with cancer therapy, and more than half of all CAM users and three quarters of users of substancebased CAM are at risk of interactions [1c]. An analysis on the prescription data from 4975 patients in U.S. has found that 40% of 302 cancer patients and 43% of 908 non-cancer respondents had at least one potential drug interaction, and 12% were at risk for fatal or permanently debilitating effects [2C]. A survey conducted in Italy on 478 preoperative patients has found that 49.8% of these patients used at least one herbal remedy. Among them, 23.1% were actually exposed to at least one potential interaction [3C]. The general lack of compositional and toxicological information of a particular herbal product presents a challenge for clinical safety. A survey on 200 patients in a Hungarian hospital reported that of the 85.5% of patients who took supplementary products in the previous 2 weeks, 45.2% of them were detected with potentially severe drug–supplement interactions [4c].
Side Effects of Drugs Annual, Volume 37 ISSN: 0378-6080 http://dx.doi.org/10.1016/bs.seda.2015.08.010
An overview of 26 systematic reviews reported that many herbal medicinal products were adulterated or contaminated with dust, pollen, insects, rodent debris, parasites, microbes, fungi, mold, toxins, pesticides, toxic heavy metals and/or prescription drugs. The most severe adverse effects were agranulocytosis, meningitis, multi-organ failure, perinatal stroke, arsenic, lead or mercury poisoning, malignancies or carcinomas, hepatic encephalopathy, hepatorenal syndrome, nephrotoxicity, rhabdomyolysis, metabolic acidosis, renal or liver failure, cerebral edema, coma, intracerebral hemorrhage, and death. Adulteration and contamination were most commonly noted for traditional Indian and Chinese remedies, respectively [5M]. The needs for natural health product regulations, guidance on safety and toxicity testing of herbal medicinal products, and more stringent quality control measures have been proposed [6H].
TRADITIONAL CHINESE HERBAL MEDICINE PREPARATIONS Traditional Chinese medicine (TCM) has a wellestablished theoretical system to understand, analyze, and use herbal medicines for the treatment of various diseases. Adverse effects associated with Chinese herbal medicines are greater if they are used under the guidance of modern medicine principles rather than TCM. Xiaochaihu Decoction is a popular traditional herbal formula which contains Bupleuri radix (Chaihu). “Xiaochaihu Decoction event (XCHDE)” occurred in late 1980s
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in Japan, which involved some related adverse drug reaction (ADR), including interstitial pneumonitis, drug induced liver injury (DILI) and even death. A retrospective analysis on XCHD-related ADRs reported in China and Japan reported that XCHDE in Japan probably resulted from multiple factors, including combinatory use with interferon, application under the guidance of modern medicine theory and based on disease diagnosis instead of TCM syndrome differentiation. Few ADE cases, mostly manifesting with hypersensitivity responses of skin and perfuse perspiration, were reported for XCHD in China when compared to that in Japan [7H]. According to TCM theory, a herbal formula composed of a mixture of different herbal ingredients is designed to work synergistically to reduce possible toxicity of the product; however, clinical safety issues should not be overlooked. An observational study conducted in Taiwan found an association between the consumption of Chinese formulae composed of aristolochic acidcontaining herbs such as Mutong (Aristolochia manshuriensis Caulis) and an increased risk of chronic kidney disease and urinary tract cancer. Dizziness, headache, stomachache, and diarrhea were believed to be probably related to a traditional formula named Suan Zao Ren Tang (Ziziphi Spinosae Semen Decoction) [8C]. A literature review of papers published since 2011 on TCM products and hepatotoxicity has identified some TCM herbal mixtures and individual herbs with potential health hazards. The herbal mixture products include Ban Tu Wan (Pill for Treating Alopecia), Jia Wei Xia Yao San (Augmented Rambling Powder), Kamishoyosan (a traditional Japanese herbal drug similar to Jia Wei Xia Yao San), Long Dan Xie Gan Tang (Decoction of Gentian to Purge the Liver), ‘White flood’ (a nutritional supplement) and Xiao Chai Hu Decoction (XCHD). The single herbs include Chinese green tea (Camellia sinensis, or Lucha in Chinese), Polygoni Multiflori Radix (Heshouwu), Hovenia dulcis (Jiguja), Notoginseng Radix Et Rhizoma (Sanqi), Angelicae Pubescentis Radix (Duhuo), Scutellariae Radix (Huangqin) [9R]. Among 1100 Hong Kong Chinese adults interviewed via telephone, 789 (71.7%) respondents reported the use of over-the-counter TCM products, and 25 (2.3%) of them reported at least one related adverse event (AE) in the past year. The most common AEs were allergic reactions, dizziness, and gastro-intestinal problems [10C]. The result of a survey conducted in Europe and China suggested the use of Chinese materia medica (CMM) appeared to be largely safe in both areas, except potential AEs with Pinelliae Rhizoma (Banxia), Persicae Semen (Taoren), Tripterygium Wilfordii Herba (Leigongteng), and Aconiti Radix (Chuanwu). In China, only a few toxic CMMs are commonly used, and some of them are used mainly for serious disorders and only be prescribed after proper preparation [11C].
Chushizhiyang Paste Chushizhiyang paste (or Expel dampness to stop itching paste in English) is a topical Chinese herbal paste for the treatment of eczema, which is largely due to invasion of damp pathogen according to the TCM theory. Chushizhiyang paste is composed of Cnidii Fructus (Shechuangzi), Coptidis Rhizoma (huanglian), Phellodendri Chinensis Cortex (huangbo), Dictamni Cortex (Baixianpi), Sophorae Flavescentis Radix (Kushen), Polygoni Cuspidati Rhizoma (Huzhang), Violae Herba (Zihuadiding), Kochiae Fructus (Difuzi), Polygoni Avicularis Herba (Bianxu), Artemisiae Scopariae Herba (Yinchen), Atractylodis Rhizoma (Cangzhu), Zanthoxyli Pericarpium (Huajiao) and Borneolum Syntheticum (Bingpian). A case of contact dermatitis caused by this topical product has been reported [12A]. An 18-year-old man with chronic scrotum eczema developed strong itchiness and sting locally 1 hour after topical application of chushizhiyang paste. He subsequently developed swollen scrotum which extended to the right groin with increasing pain and itchiness after the second topical application. The paste was removed immediately, and the symptoms gradually subsided 24 hours after receiving injection of chlorphenamine maleate, dexamethasone sodium phosphate, and vitamin D2 with calcium colloid.
Qizhengxiaotong Paste Qizhengxiaotong paste (or Qizheng pain relieving paste), commonly used to relieve various musculoskeletal pain, is consisted of several traditional Tibetan medicines, including Lamiophlomis Herba (Duyiwei), Bubali Cornu (Shuiniujiao), Curcumae Longae Rhizoma (Jianghuang), Oxytropis Falcata (Jidou), and Myricaria bracteata (shuibaizhi). It was reported to cause skin allergic reactions, including acute or tardive rashes, 5–24 hours after topical application [13A,14A]. It has also been reported to cause nausea and vomiting [14A]. A 48-year-old man developed flushed face, staggering, and nausea and vomiting about 30 minutes after applying qizhengxiaotong paste to treat his frozen shoulder. The paste was removed immediately, and the symptoms gradually resolved after resting for 1 hour.
Shenqifuzheng Injection Shenqifuzheng injection (or Codonopsis and Astragalus Injection of Restoring Energy) is made from Codonopsis Radix (Dangshen) and Astragali Radix (Huangqi), and has the function of strengthening the immune system and nourishing vitality. A post-marketing safety monitoring study reported that the incidence of an ADR was 1.85% among 20 100 cases, with 27 slight and 10 moderate
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cases, while no severe case was found. The adverse reaction symptoms included thrombocytopenia, rash, chills, palpitation, dyspnea, edema of a lower extremities, palpebral edema, and superficial vein inflammation [15C].
HERBAL MEDICINE An overview of 50 systematic reviews on the adverse effects of herbal medicines (HMs) has found serious adverse effects from a number of herbs or herb parts from the following plants: Pulvis standardisatus, Larrea tridentate, Piper methysticum and Cassia senna. The most severe adverse effects were liver or kidney damage, colon perforation, carcinoma, coma and death [16M]. The safety of topical preparations containing botanical extracts needs more attention. A recent survey conducted in Italy reported that of the 1274 users of natural topical products, 139 (11%) reported cutaneous adverse reactions after botanical product application. The reactions were a worsening of the previous dermatitis or the development of new, different cutaneous symptoms and/or signs such as itching, burning, erythema, swelling, and vesiculation. The commonest botanically derived allergens were propolis, Compositae extracts, and Melaleuca alternifolia (tea tree) oil [17C].
GREEN TEA NUTRITIONAL SUPPLEMENTS Green Tea Extract Green tea, made from steaming of the leaves of tea plant Camellia sinensis, is a popular beverage consumed worldwide and generally considered safe. However, there has been increasing concern regarding the potential hepatotoxicity following the consumption of green tea extract [18M,19R]. A case of acute liver failure has been reported to be associated with green tea extract [20A]. A 16-year-old Hispanic boy presented with newly onset jaundice after taking several dietary supplements for weight loss which included Applied Nutrition® Green Tea Fat Burner for 60 days. His peak international normalised ratio (INR) and conjugated bilirubin (CB) increased dramatically. He gradually recovered 2 months after medical treatment. As several possible causes were ruled out, and his liver histology was found to be consistent with previous cases of hepatotoxicity associated with green tea extract, it was believed that his liver injury could most likely be attributed to the weight loss supplement containing green tea extract.
SPECIFIC PLANTS Astragali Radix (Huangqi) The root of Astragalus membranaceus is one of the most often used qi tonifying herbs in TCM to treat various diseases. Adverse effects associated with the use of Astragalus Radix have been reported [21A]. A 70-year-old man developed dizziness, limb numbness, red face, chest tightness and scattered blisters and subsequent desquamation on both hands and feet after orally taking one decoction of a TCM formula named Huangqiguizhiwuwu tang (Decoction Made of Five Herbs Including Astragalus and Cinnamon Twigs) on the first treatment. The symptoms gradually subsided without any medical treatment. The similar symptoms reappeared after taking Huangqi with Xiangshaliujunzi tang (Six Gentlemen Decoction with Aucklandia and Amomum) on the second occasion. He was then diagnosed as exfoliative keratolysis, and recovered after topical application of fluocinonide and tretinoin ointment. Similar symptoms reoccurred twice subsequently after taking TCM formulae containing huangqi.
Luffa echinata (Bristly luffa) Bristly luffa, a member of the Cucurbitaceae family, is found in East Asia and some parts of Africa. Its dried fruit is used in Ayurvedic medicine for various illnesses such as chronic bronchitis, dropsy, nephritis, intestinal and biliary colic, fever and jaundice. A case report indicates that excessive consumption of the fruit may be toxic to human [22A]. A 50-year-old man presented with acute onset of abdominal pain, vomiting, and bleeding per rectum 20 hours after consumption of 100–150 g of dried fruits of Bristly luffa soaked in water. He was found to have antral gastritis and duodenal erosions through upper gastrointestinal endoscopy examination and deranged liver function. He gradually recovered over a period of 7–10 days after receiving intravenous fluids, one unit of whole blood infusion and administrations of fresh frozen plasma, vitamin K, vasopressors and proton pump inhibitors.
Cade Oil Cade oil is a kind of dark, faintly aromatic oil which is distilled from the branches and wood of Juniperus oxycedrus. It is used in some cosmetics preparations and incense. It is also used in Moroccan folk medicine for the treatment of bronchitis, abdominal pain and diarrhea, psychiatric disorders, cancer, fever, cephalgia, angina, weight loss, common cold, and hypotonia. The oil contains phenols, which are believed to be the most toxic
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components. An analysis of a Moroccan pharmacovigilance of herbal products database from January 1, 2004 to December 31, 2012 found that 30 (2.4%) of 1251 reported adverse events associated with herbal products were related to cade oil. Reported cases were mainly due to topical application (60%), oral ingestion (36.7%) or nasal application (3.3%). The reported adverse effects involved many organs but renal disorders were the most common. After hospitalization and with supportive and symptomatic treatment, 23 (76.7%) patients recovered and were discharged. However, three deaths (10%) were reported in relation to the use of cade oil. The results of WHO-UMC causality assessment demonstrated the adverse effects were rated as “probable” in 4 cases, “possible” in 24 cases, “unlikely” in 1 case and “unassessable” in 1 case [23R].
(Loranthaceae). It is the most frequently used complementary medicine in the treatment of cancer patients in German-speaking countries [28M]. A multi-center, observational study has found that of 1923 cancer patients treated with subcutaneous injection of mistletoe extracts, 162 (8.4%) patients reported a total of 264 ADRs, with mild in 50.8%, moderate in 45.1%, and severe in 4.2% of the patients. The adverse reactions appeared to be dose-related and could be explained by the immunestimulating, pharmacological activity of mistletoe [29C]. Intravenous mistletoe therapy seems to be safer than subcutaneous application. An observational study on 475 cancer patients who received intravenous infusions of Helixor, Abnoba viscum, or Iscador mistletoe preparations, 22 patients (4.6%) reported 32 ADRs of mild (59.4%) or moderate severity (40.6%) [30C].
Cannabis sativa (Marijuana)
Polygoni Multiflori Radix (Chinese Fleeceflower Root, Heshouwu)
A survey of 313 patients with inflammatory bowel disease reported that 17.6% of respondents use Cannabis to relieve symptoms, with the majority by inhalational route (96.4%). Although Cannabis could subjectively improve pain and diarrheal symptoms, it was associated with higher risk of surgical treatment in patients with Crohn's disease. It was suspected that Cannabis use may mask the clinical symptoms related to the ongoing inflammation [24C].
Tribulus terrestris (Bulgarian tribulus) Tribulus terrestris is an herb belonging to the Zygophyllaceae family which is indigenous to the Southern Europe, Southern Asia, Australia, and Africa. It is often used in the treatment of infertility, low sex drive, and erectile dysfunction. It is also used by athletes to increase muscle strength and improve performance in sports [25M,26C]. Bulgarian tribulus has been reported to increase transaminases via rhabdomyolysis [27A]. A 44-year-old man, with a history of Hodgkin's lymphoma, was referred to a gastroenterology/hepatology department for elevated transaminases. He was asymptomatic but admitted consuming alcohol every 2 weeks. Laboratory tests showed elevated liver function indexes that are higher than normal. He had recently taken Bulgarian tribulus for 2 weeks [route, dosage, indication and time to reaction onset not stated]. The herb was stopped, and transaminase measurement and creatine kinase were normalized within 10 days.
A warning has been issued by China Food and Drug Administration for the potential risk of liver damage caused by raw and processed Polygoni Multiflori Radix. Generally, the cases of liver damage were mild or moderate, and mostly reversible. The main manifestations of the DILI associated with Heshouwu were weakness, poor digestion and anorexia, and jaundice. The risk of DILI may be increased by the following situations: (1) large dosage and long-term administration, (2) patients with history of liver damage caused by Polygoni Multiflori Radix, and (3) combined use with other medicines of potential liver toxicity. Raw Polygoni Multiflori Radix is more likely to cause liver damage than the processed plant [31S].
Smilacis Glabrae Rhizoma (Tufuling) Smilacis Glabrae Rhizome, a traditional Chinese herb, is commonly used to expel dampness in the treatment of eczema, rheumatoid arthritis, urinary tract infection and other diseases. It has been reported to cause one case of allergic shock [32A]. A 45-year-old man with eczema suddenly developed nausea, palpitation, purple mouth and lip, respiratory distress, profuse sweating, and cold extremities when he manually smashed Smilacis Glabrae Rhizome for his prescribed topical paste. He gradually recovered 30 minutes after receiving inhalation of salbutamol and muscular injection of dexamethasone and adrenaline.
ACUPUNCTURE Mistletoe Extracts (Viscum album L.) The commercially available mistletoe extracts are prepared from the semi-parasitic plant Viscum album
Acupuncture seems generally safe to pregnant women. A systematic review has identified a total of 429 (incidence rate 1.9%) AEs in the 27 reports involving
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approximately 22 283 sessions of acupuncture in 2460 pregnant women. Among these AEs, 291 of them (incidence rate 1.3%) were evaluated as causally (certain, probably or possibly) related to acupuncture, and were rated as mild to moderate in severity, with needling pain being the most frequent. Severe AEs or deaths were few and all considered unlikely to have been caused by acupuncture [33M]. Acupuncture was reported to induce transient paralysis in one patient with history of idiopathic complex partial seizures (CPS) [34A]. A 38-year-old man had a history of CPS which was regarded as being well controlled by lamotrigine 150 mg and sodium valproate 2000 mg daily. Four hours after receiving the first session of mild acupuncture treatment for a painful musculoskeletal condition, he reported to have one of his vague staring episodes. During the second acupuncture treatment 3 weeks later, he developed heaviness, a tingling ice-cold sensation, loss of muscle power, and became unable to move his eyes and speak. He subsequently fell asleep for a few seconds, and gradually came around to normal after 50 minutes. He later experienced an increased frequency of CPS. Follow-up analysis suggested that the patient probably had comorbidities in the form of rapid eye movement sleep behaviour disorder and dysfunctional somatosensory/ vestibular processing. Acupuncture may have triggered the adverse event via shared neurosubstrates. Skin pigmentation changes have been reported to be associated with silver needle implantation, electroacupuncture and repeated strong manual stimulation of the needles [35A,36A]. A case of skin pigmentation and textural changes following repeated needling of Yintang (EX-HN3) has been reported [37A]. A 43-year-old Caucasian woman received intermittent acupuncture treatment on a weekly or biweekly basis over 6 years for heavy menstrual bleeding and clots. Yintang was used 95 times out of 98 treatments and GV20 (Baihui) in all the treatments along with other acupoints such as SP6 (Sanyinjiao), ST36 (Zusanli), LV3 (Taichong) and LI4 (Hegu). She reported a dark, beige, dry, scaly spot at the point of Yintang. The discoloration remained unresolved 10 months after cessation of all treatment.
CUPPING A case report of cupping treatment administered on a patient undergoing concomitant therapy with bevacizumab, an angiogenesis inhibitor, suggested further research is needed on the safety issue of cupping during anticancer therapy, and raised awareness of the need to improve communication between CAM practitioners and oncologists when it comes to the care of patients with cancer [38A].
A 62-year-old Taiwanese man with advanced nonsmall-cell lung cancer (NSCLC) received four cycles of carboplatin AUC 6, paclitaxel 200 mg/m2, and bevacizumab 15 mg/kg, and the maintenance dose of bevacizumab 15 mg/kg was continued once every 3 weeks. The patient underwent 3 sessions of glass dry cupping lasting 15 minutes on an every-other-day schedule for 18 days after receiving maintenance bevacizumab. He developed usual characteristic rounded skin ecchymoses at sites of cupping, which completely resolved 24 days after initial cupping. No overt cutaneous adverse events or bleeding was found.
MOXIBUSTION The smoke of burned moxa during moxibustion treatment may cause adverse reaction. A case of allergic reaction has been reported to be associated with moxibustion treatment [39A]. A 50-year-old woman developed red and swollen eyes with tears, runny nose, sneezing, and flushed face with itching 3 days after receiving tui na and moxibustion treatment for recurrent low back pain. The moxibustion was stopped immediately, and her symptoms gradually resolved 3 days after topical application of cold pad and oral administration of cetirizine and prednisone.
OSTEOPATHY Osteopathic treatment seems to be associated with vascular and neurological complications. The most frequent complication is stroke, spinal disc herniation with spinal cord compression, radiculopathy and cauda equina syndrome [40M]. A case of cervical disc herniation was reported to be associated with spinal manipulative therapy [41A]. A 33-year-old woman reported numbness and tingling feeling in her right posterior arm, together with marked weakness of the right upper extremity the following day after receiving an osteopathic treatment including cervical spine manipulation. The MRI revealed an interruption of the subarachnoid spaces (due to a right posterolateral disc herniation pushing back the spinal cord) in the spine at the C6–C7 location and a protrusion of the C4–C5 and C5–C6 discs. The condition was alleviated by surgical operation and subsequent physiotherapy.
TAI CHI A systematic review on the safety of tai chi identified 153 eligible randomised controlled trials, of which only 50 trials (33%) included reported AEs. Reported
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AEs were typically minor musculoskeletal aches and pains, and no intervention-related serious AEs were found [42M].
TUI NA Tui na, also called Chinese medical massage, is a traditional hands-on manipulation treatment method guided by TCM theory. Through manual manipulations, tui na is used widely to treat various diseases, including not only musculoskeletal disorders, but also diseases of internal organs. Like acupuncture that may cause faint, tui na has been also reported to induce faint. Proper stimulation strength (non-excessive) of manipulation was suggested to avoid such events [43A]. A 38-year-old woman with neck pain developed minor faint after receiving the first tui na treatment intended to treat common cold. The symptom was relieved after 5-minute rest. Two weeks later, she suddenly developed dizziness, palpitation, nausea, pale face and lips, cold limbs with sweating after receiving another session of tui na treatment. She gradually recovered after drinking warm honey water and resting for about 30 minutes.
YOGA Yoga, rooted in Indian philosophy, has become a worldwide popular way to promote physical and mental well-being through controlling the body and mind. A systematic review on 35 case reports and 2 case series of 76 subjects reported 27 AEs (35.5%) affecting the musculoskeletal system, 14 (18.4%) the nervous system, and 9 (11.8%) the eyes. Of these cases, 15 subjects (19.7%) fully recovered, 9 (11.3%) partially recovered, 1 (1.3%) did not recover, and 1 subject (1.3%) died. It is advisable for Yoga beginners to avoid extreme movements/stretching and be instructed by qualified instructors [44M].
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46 Treatments Used in Complementary and Alternative Medicine H.W. Zhang*, Z.X. Lin*, K. Chan†,1 *School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, PR China † The National Institute of Complementary Medicine, University of Western Sydney, Penrith, NSW, Australia 1 Corresponding author: [email protected]
INTRODUCTION With an increasing use of complementary and alternative medicine by the general public worldwide, the safety issues of possible interactions between complementary and alternative medicine (CAM) and other medicines have attracted much more attention in recent years, especially in high-risk populations like cancer and preoperative patients. For example, a questionnaire survey of 100 consecutive gynecological outpatients in a cancer center in Germany reported that 64% of patients used CAM and 48% used at least one substance-based CAM. A third of all patients were in danger of interactions of CAM with cancer therapy, and more than half of all CAM users and three quarters of users of substancebased CAM are at risk of interactions [1c]. An analysis on the prescription data from 4975 patients in U.S. has found that 40% of 302 cancer patients and 43% of 908 non-cancer respondents had at least one potential drug interaction, and 12% were at risk for fatal or permanently debilitating effects [2C]. A survey conducted in Italy on 478 preoperative patients has found that 49.8% of these patients used at least one herbal remedy. Among them, 23.1% were actually exposed to at least one potential interaction [3C]. The general lack of compositional and toxicological information of a particular herbal product presents a challenge for clinical safety. A survey on 200 patients in a Hungarian hospital reported that of the 85.5% of patients who took supplementary products in the previous 2 weeks, 45.2% of them were detected with potentially severe drug–supplement interactions [4c].
Side Effects of Drugs Annual, Volume 37 ISSN: 0378-6080 http://dx.doi.org/10.1016/bs.seda.2015.08.010
An overview of 26 systematic reviews reported that many herbal medicinal products were adulterated or contaminated with dust, pollen, insects, rodent debris, parasites, microbes, fungi, mold, toxins, pesticides, toxic heavy metals and/or prescription drugs. The most severe adverse effects were agranulocytosis, meningitis, multi-organ failure, perinatal stroke, arsenic, lead or mercury poisoning, malignancies or carcinomas, hepatic encephalopathy, hepatorenal syndrome, nephrotoxicity, rhabdomyolysis, metabolic acidosis, renal or liver failure, cerebral edema, coma, intracerebral hemorrhage, and death. Adulteration and contamination were most commonly noted for traditional Indian and Chinese remedies, respectively [5M]. The needs for natural health product regulations, guidance on safety and toxicity testing of herbal medicinal products, and more stringent quality control measures have been proposed [6H].
TRADITIONAL CHINESE HERBAL MEDICINE PREPARATIONS Traditional Chinese medicine (TCM) has a wellestablished theoretical system to understand, analyze, and use herbal medicines for the treatment of various diseases. Adverse effects associated with Chinese herbal medicines are greater if they are used under the guidance of modern medicine principles rather than TCM. Xiaochaihu Decoction is a popular traditional herbal formula which contains Bupleuri radix (Chaihu). “Xiaochaihu Decoction event (XCHDE)” occurred in late 1980s
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in Japan, which involved some related adverse drug reaction (ADR), including interstitial pneumonitis, drug induced liver injury (DILI) and even death. A retrospective analysis on XCHD-related ADRs reported in China and Japan reported that XCHDE in Japan probably resulted from multiple factors, including combinatory use with interferon, application under the guidance of modern medicine theory and based on disease diagnosis instead of TCM syndrome differentiation. Few ADE cases, mostly manifesting with hypersensitivity responses of skin and perfuse perspiration, were reported for XCHD in China when compared to that in Japan [7H]. According to TCM theory, a herbal formula composed of a mixture of different herbal ingredients is designed to work synergistically to reduce possible toxicity of the product; however, clinical safety issues should not be overlooked. An observational study conducted in Taiwan found an association between the consumption of Chinese formulae composed of aristolochic acidcontaining herbs such as Mutong (Aristolochia manshuriensis Caulis) and an increased risk of chronic kidney disease and urinary tract cancer. Dizziness, headache, stomachache, and diarrhea were believed to be probably related to a traditional formula named Suan Zao Ren Tang (Ziziphi Spinosae Semen Decoction) [8C]. A literature review of papers published since 2011 on TCM products and hepatotoxicity has identified some TCM herbal mixtures and individual herbs with potential health hazards. The herbal mixture products include Ban Tu Wan (Pill for Treating Alopecia), Jia Wei Xia Yao San (Augmented Rambling Powder), Kamishoyosan (a traditional Japanese herbal drug similar to Jia Wei Xia Yao San), Long Dan Xie Gan Tang (Decoction of Gentian to Purge the Liver), ‘White flood’ (a nutritional supplement) and Xiao Chai Hu Decoction (XCHD). The single herbs include Chinese green tea (Camellia sinensis, or Lucha in Chinese), Polygoni Multiflori Radix (Heshouwu), Hovenia dulcis (Jiguja), Notoginseng Radix Et Rhizoma (Sanqi), Angelicae Pubescentis Radix (Duhuo), Scutellariae Radix (Huangqin) [9R]. Among 1100 Hong Kong Chinese adults interviewed via telephone, 789 (71.7%) respondents reported the use of over-the-counter TCM products, and 25 (2.3%) of them reported at least one related adverse event (AE) in the past year. The most common AEs were allergic reactions, dizziness, and gastro-intestinal problems [10C]. The result of a survey conducted in Europe and China suggested the use of Chinese materia medica (CMM) appeared to be largely safe in both areas, except potential AEs with Pinelliae Rhizoma (Banxia), Persicae Semen (Taoren), Tripterygium Wilfordii Herba (Leigongteng), and Aconiti Radix (Chuanwu). In China, only a few toxic CMMs are commonly used, and some of them are used mainly for serious disorders and only be prescribed after proper preparation [11C].
Chushizhiyang Paste Chushizhiyang paste (or Expel dampness to stop itching paste in English) is a topical Chinese herbal paste for the treatment of eczema, which is largely due to invasion of damp pathogen according to the TCM theory. Chushizhiyang paste is composed of Cnidii Fructus (Shechuangzi), Coptidis Rhizoma (huanglian), Phellodendri Chinensis Cortex (huangbo), Dictamni Cortex (Baixianpi), Sophorae Flavescentis Radix (Kushen), Polygoni Cuspidati Rhizoma (Huzhang), Violae Herba (Zihuadiding), Kochiae Fructus (Difuzi), Polygoni Avicularis Herba (Bianxu), Artemisiae Scopariae Herba (Yinchen), Atractylodis Rhizoma (Cangzhu), Zanthoxyli Pericarpium (Huajiao) and Borneolum Syntheticum (Bingpian). A case of contact dermatitis caused by this topical product has been reported [12A]. An 18-year-old man with chronic scrotum eczema developed strong itchiness and sting locally 1 hour after topical application of chushizhiyang paste. He subsequently developed swollen scrotum which extended to the right groin with increasing pain and itchiness after the second topical application. The paste was removed immediately, and the symptoms gradually subsided 24 hours after receiving injection of chlorphenamine maleate, dexamethasone sodium phosphate, and vitamin D2 with calcium colloid.
Qizhengxiaotong Paste Qizhengxiaotong paste (or Qizheng pain relieving paste), commonly used to relieve various musculoskeletal pain, is consisted of several traditional Tibetan medicines, including Lamiophlomis Herba (Duyiwei), Bubali Cornu (Shuiniujiao), Curcumae Longae Rhizoma (Jianghuang), Oxytropis Falcata (Jidou), and Myricaria bracteata (shuibaizhi). It was reported to cause skin allergic reactions, including acute or tardive rashes, 5–24 hours after topical application [13A,14A]. It has also been reported to cause nausea and vomiting [14A]. A 48-year-old man developed flushed face, staggering, and nausea and vomiting about 30 minutes after applying qizhengxiaotong paste to treat his frozen shoulder. The paste was removed immediately, and the symptoms gradually resolved after resting for 1 hour.
Shenqifuzheng Injection Shenqifuzheng injection (or Codonopsis and Astragalus Injection of Restoring Energy) is made from Codonopsis Radix (Dangshen) and Astragali Radix (Huangqi), and has the function of strengthening the immune system and nourishing vitality. A post-marketing safety monitoring study reported that the incidence of an ADR was 1.85% among 20 100 cases, with 27 slight and 10 moderate
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cases, while no severe case was found. The adverse reaction symptoms included thrombocytopenia, rash, chills, palpitation, dyspnea, edema of a lower extremities, palpebral edema, and superficial vein inflammation [15C].
HERBAL MEDICINE An overview of 50 systematic reviews on the adverse effects of herbal medicines (HMs) has found serious adverse effects from a number of herbs or herb parts from the following plants: Pulvis standardisatus, Larrea tridentate, Piper methysticum and Cassia senna. The most severe adverse effects were liver or kidney damage, colon perforation, carcinoma, coma and death [16M]. The safety of topical preparations containing botanical extracts needs more attention. A recent survey conducted in Italy reported that of the 1274 users of natural topical products, 139 (11%) reported cutaneous adverse reactions after botanical product application. The reactions were a worsening of the previous dermatitis or the development of new, different cutaneous symptoms and/or signs such as itching, burning, erythema, swelling, and vesiculation. The commonest botanically derived allergens were propolis, Compositae extracts, and Melaleuca alternifolia (tea tree) oil [17C].
GREEN TEA NUTRITIONAL SUPPLEMENTS Green Tea Extract Green tea, made from steaming of the leaves of tea plant Camellia sinensis, is a popular beverage consumed worldwide and generally considered safe. However, there has been increasing concern regarding the potential hepatotoxicity following the consumption of green tea extract [18M,19R]. A case of acute liver failure has been reported to be associated with green tea extract [20A]. A 16-year-old Hispanic boy presented with newly onset jaundice after taking several dietary supplements for weight loss which included Applied Nutrition® Green Tea Fat Burner for 60 days. His peak international normalised ratio (INR) and conjugated bilirubin (CB) increased dramatically. He gradually recovered 2 months after medical treatment. As several possible causes were ruled out, and his liver histology was found to be consistent with previous cases of hepatotoxicity associated with green tea extract, it was believed that his liver injury could most likely be attributed to the weight loss supplement containing green tea extract.
SPECIFIC PLANTS Astragali Radix (Huangqi) The root of Astragalus membranaceus is one of the most often used qi tonifying herbs in TCM to treat various diseases. Adverse effects associated with the use of Astragalus Radix have been reported [21A]. A 70-year-old man developed dizziness, limb numbness, red face, chest tightness and scattered blisters and subsequent desquamation on both hands and feet after orally taking one decoction of a TCM formula named Huangqiguizhiwuwu tang (Decoction Made of Five Herbs Including Astragalus and Cinnamon Twigs) on the first treatment. The symptoms gradually subsided without any medical treatment. The similar symptoms reappeared after taking Huangqi with Xiangshaliujunzi tang (Six Gentlemen Decoction with Aucklandia and Amomum) on the second occasion. He was then diagnosed as exfoliative keratolysis, and recovered after topical application of fluocinonide and tretinoin ointment. Similar symptoms reoccurred twice subsequently after taking TCM formulae containing huangqi.
Luffa echinata (Bristly luffa) Bristly luffa, a member of the Cucurbitaceae family, is found in East Asia and some parts of Africa. Its dried fruit is used in Ayurvedic medicine for various illnesses such as chronic bronchitis, dropsy, nephritis, intestinal and biliary colic, fever and jaundice. A case report indicates that excessive consumption of the fruit may be toxic to human [22A]. A 50-year-old man presented with acute onset of abdominal pain, vomiting, and bleeding per rectum 20 hours after consumption of 100–150 g of dried fruits of Bristly luffa soaked in water. He was found to have antral gastritis and duodenal erosions through upper gastrointestinal endoscopy examination and deranged liver function. He gradually recovered over a period of 7–10 days after receiving intravenous fluids, one unit of whole blood infusion and administrations of fresh frozen plasma, vitamin K, vasopressors and proton pump inhibitors.
Cade Oil Cade oil is a kind of dark, faintly aromatic oil which is distilled from the branches and wood of Juniperus oxycedrus. It is used in some cosmetics preparations and incense. It is also used in Moroccan folk medicine for the treatment of bronchitis, abdominal pain and diarrhea, psychiatric disorders, cancer, fever, cephalgia, angina, weight loss, common cold, and hypotonia. The oil contains phenols, which are believed to be the most toxic
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components. An analysis of a Moroccan pharmacovigilance of herbal products database from January 1, 2004 to December 31, 2012 found that 30 (2.4%) of 1251 reported adverse events associated with herbal products were related to cade oil. Reported cases were mainly due to topical application (60%), oral ingestion (36.7%) or nasal application (3.3%). The reported adverse effects involved many organs but renal disorders were the most common. After hospitalization and with supportive and symptomatic treatment, 23 (76.7%) patients recovered and were discharged. However, three deaths (10%) were reported in relation to the use of cade oil. The results of WHO-UMC causality assessment demonstrated the adverse effects were rated as “probable” in 4 cases, “possible” in 24 cases, “unlikely” in 1 case and “unassessable” in 1 case [23R].
(Loranthaceae). It is the most frequently used complementary medicine in the treatment of cancer patients in German-speaking countries [28M]. A multi-center, observational study has found that of 1923 cancer patients treated with subcutaneous injection of mistletoe extracts, 162 (8.4%) patients reported a total of 264 ADRs, with mild in 50.8%, moderate in 45.1%, and severe in 4.2% of the patients. The adverse reactions appeared to be dose-related and could be explained by the immunestimulating, pharmacological activity of mistletoe [29C]. Intravenous mistletoe therapy seems to be safer than subcutaneous application. An observational study on 475 cancer patients who received intravenous infusions of Helixor, Abnoba viscum, or Iscador mistletoe preparations, 22 patients (4.6%) reported 32 ADRs of mild (59.4%) or moderate severity (40.6%) [30C].
Cannabis sativa (Marijuana)
Polygoni Multiflori Radix (Chinese Fleeceflower Root, Heshouwu)
A survey of 313 patients with inflammatory bowel disease reported that 17.6% of respondents use Cannabis to relieve symptoms, with the majority by inhalational route (96.4%). Although Cannabis could subjectively improve pain and diarrheal symptoms, it was associated with higher risk of surgical treatment in patients with Crohn's disease. It was suspected that Cannabis use may mask the clinical symptoms related to the ongoing inflammation [24C].
Tribulus terrestris (Bulgarian tribulus) Tribulus terrestris is an herb belonging to the Zygophyllaceae family which is indigenous to the Southern Europe, Southern Asia, Australia, and Africa. It is often used in the treatment of infertility, low sex drive, and erectile dysfunction. It is also used by athletes to increase muscle strength and improve performance in sports [25M,26C]. Bulgarian tribulus has been reported to increase transaminases via rhabdomyolysis [27A]. A 44-year-old man, with a history of Hodgkin's lymphoma, was referred to a gastroenterology/hepatology department for elevated transaminases. He was asymptomatic but admitted consuming alcohol every 2 weeks. Laboratory tests showed elevated liver function indexes that are higher than normal. He had recently taken Bulgarian tribulus for 2 weeks [route, dosage, indication and time to reaction onset not stated]. The herb was stopped, and transaminase measurement and creatine kinase were normalized within 10 days.
A warning has been issued by China Food and Drug Administration for the potential risk of liver damage caused by raw and processed Polygoni Multiflori Radix. Generally, the cases of liver damage were mild or moderate, and mostly reversible. The main manifestations of the DILI associated with Heshouwu were weakness, poor digestion and anorexia, and jaundice. The risk of DILI may be increased by the following situations: (1) large dosage and long-term administration, (2) patients with history of liver damage caused by Polygoni Multiflori Radix, and (3) combined use with other medicines of potential liver toxicity. Raw Polygoni Multiflori Radix is more likely to cause liver damage than the processed plant [31S].
Smilacis Glabrae Rhizoma (Tufuling) Smilacis Glabrae Rhizome, a traditional Chinese herb, is commonly used to expel dampness in the treatment of eczema, rheumatoid arthritis, urinary tract infection and other diseases. It has been reported to cause one case of allergic shock [32A]. A 45-year-old man with eczema suddenly developed nausea, palpitation, purple mouth and lip, respiratory distress, profuse sweating, and cold extremities when he manually smashed Smilacis Glabrae Rhizome for his prescribed topical paste. He gradually recovered 30 minutes after receiving inhalation of salbutamol and muscular injection of dexamethasone and adrenaline.
ACUPUNCTURE Mistletoe Extracts (Viscum album L.) The commercially available mistletoe extracts are prepared from the semi-parasitic plant Viscum album
Acupuncture seems generally safe to pregnant women. A systematic review has identified a total of 429 (incidence rate 1.9%) AEs in the 27 reports involving
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approximately 22 283 sessions of acupuncture in 2460 pregnant women. Among these AEs, 291 of them (incidence rate 1.3%) were evaluated as causally (certain, probably or possibly) related to acupuncture, and were rated as mild to moderate in severity, with needling pain being the most frequent. Severe AEs or deaths were few and all considered unlikely to have been caused by acupuncture [33M]. Acupuncture was reported to induce transient paralysis in one patient with history of idiopathic complex partial seizures (CPS) [34A]. A 38-year-old man had a history of CPS which was regarded as being well controlled by lamotrigine 150 mg and sodium valproate 2000 mg daily. Four hours after receiving the first session of mild acupuncture treatment for a painful musculoskeletal condition, he reported to have one of his vague staring episodes. During the second acupuncture treatment 3 weeks later, he developed heaviness, a tingling ice-cold sensation, loss of muscle power, and became unable to move his eyes and speak. He subsequently fell asleep for a few seconds, and gradually came around to normal after 50 minutes. He later experienced an increased frequency of CPS. Follow-up analysis suggested that the patient probably had comorbidities in the form of rapid eye movement sleep behaviour disorder and dysfunctional somatosensory/ vestibular processing. Acupuncture may have triggered the adverse event via shared neurosubstrates. Skin pigmentation changes have been reported to be associated with silver needle implantation, electroacupuncture and repeated strong manual stimulation of the needles [35A,36A]. A case of skin pigmentation and textural changes following repeated needling of Yintang (EX-HN3) has been reported [37A]. A 43-year-old Caucasian woman received intermittent acupuncture treatment on a weekly or biweekly basis over 6 years for heavy menstrual bleeding and clots. Yintang was used 95 times out of 98 treatments and GV20 (Baihui) in all the treatments along with other acupoints such as SP6 (Sanyinjiao), ST36 (Zusanli), LV3 (Taichong) and LI4 (Hegu). She reported a dark, beige, dry, scaly spot at the point of Yintang. The discoloration remained unresolved 10 months after cessation of all treatment.
CUPPING A case report of cupping treatment administered on a patient undergoing concomitant therapy with bevacizumab, an angiogenesis inhibitor, suggested further research is needed on the safety issue of cupping during anticancer therapy, and raised awareness of the need to improve communication between CAM practitioners and oncologists when it comes to the care of patients with cancer [38A].
A 62-year-old Taiwanese man with advanced nonsmall-cell lung cancer (NSCLC) received four cycles of carboplatin AUC 6, paclitaxel 200 mg/m2, and bevacizumab 15 mg/kg, and the maintenance dose of bevacizumab 15 mg/kg was continued once every 3 weeks. The patient underwent 3 sessions of glass dry cupping lasting 15 minutes on an every-other-day schedule for 18 days after receiving maintenance bevacizumab. He developed usual characteristic rounded skin ecchymoses at sites of cupping, which completely resolved 24 days after initial cupping. No overt cutaneous adverse events or bleeding was found.
MOXIBUSTION The smoke of burned moxa during moxibustion treatment may cause adverse reaction. A case of allergic reaction has been reported to be associated with moxibustion treatment [39A]. A 50-year-old woman developed red and swollen eyes with tears, runny nose, sneezing, and flushed face with itching 3 days after receiving tui na and moxibustion treatment for recurrent low back pain. The moxibustion was stopped immediately, and her symptoms gradually resolved 3 days after topical application of cold pad and oral administration of cetirizine and prednisone.
OSTEOPATHY Osteopathic treatment seems to be associated with vascular and neurological complications. The most frequent complication is stroke, spinal disc herniation with spinal cord compression, radiculopathy and cauda equina syndrome [40M]. A case of cervical disc herniation was reported to be associated with spinal manipulative therapy [41A]. A 33-year-old woman reported numbness and tingling feeling in her right posterior arm, together with marked weakness of the right upper extremity the following day after receiving an osteopathic treatment including cervical spine manipulation. The MRI revealed an interruption of the subarachnoid spaces (due to a right posterolateral disc herniation pushing back the spinal cord) in the spine at the C6–C7 location and a protrusion of the C4–C5 and C5–C6 discs. The condition was alleviated by surgical operation and subsequent physiotherapy.
TAI CHI A systematic review on the safety of tai chi identified 153 eligible randomised controlled trials, of which only 50 trials (33%) included reported AEs. Reported
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AEs were typically minor musculoskeletal aches and pains, and no intervention-related serious AEs were found [42M].
TUI NA Tui na, also called Chinese medical massage, is a traditional hands-on manipulation treatment method guided by TCM theory. Through manual manipulations, tui na is used widely to treat various diseases, including not only musculoskeletal disorders, but also diseases of internal organs. Like acupuncture that may cause faint, tui na has been also reported to induce faint. Proper stimulation strength (non-excessive) of manipulation was suggested to avoid such events [43A]. A 38-year-old woman with neck pain developed minor faint after receiving the first tui na treatment intended to treat common cold. The symptom was relieved after 5-minute rest. Two weeks later, she suddenly developed dizziness, palpitation, nausea, pale face and lips, cold limbs with sweating after receiving another session of tui na treatment. She gradually recovered after drinking warm honey water and resting for about 30 minutes.
YOGA Yoga, rooted in Indian philosophy, has become a worldwide popular way to promote physical and mental well-being through controlling the body and mind. A systematic review on 35 case reports and 2 case series of 76 subjects reported 27 AEs (35.5%) affecting the musculoskeletal system, 14 (18.4%) the nervous system, and 9 (11.8%) the eyes. Of these cases, 15 subjects (19.7%) fully recovered, 9 (11.3%) partially recovered, 1 (1.3%) did not recover, and 1 subject (1.3%) died. It is advisable for Yoga beginners to avoid extreme movements/stretching and be instructed by qualified instructors [44M].
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