In this section, we shall discuss only controlled clinical trials (Tables 3 and 4) and omit such evidence where it relates to the conventional use of chemically extracted or newly synthesized plant constituents, for example morphine for abdominal pain.
A systematic literature search was undertaken using Medline database 1966–2001 records published either in English or with English abstracts available. Search headings and key words used were combinations of: complementary medicine, gastroenterology, herbal therapy, constipation, peptic ulcer, irritable bowel syndrome, nausea, vomiting, inflammatory bowel disease, colitis, Crohn’s disease, liver disease, hepatitis, cirrhosis, colorectal cancer and gastric cancer. Uncontrolled trials and animal studies are excluded from this report.
Plant extracts are commonly used in the conventional symptomatic approach to management of constipation. Anthraquinones are known to have stimulant laxative properties and are present in senna and aloes (from the sap of aloe vera leaves). Dietary fibre produces a bulk-forming laxative effect, e.g. isphagula husk and plant polysaccharides can be used to increase stool water, e.g. psyllium.20, 21 Many sufferers of constipation self-medicate and a number of other herbal remedies have been shown to be effective in controlled trials (Table 3).
A combination of celandin, aloe vera and psyllium was evaluated in 35 adults with chronic constipation in a double-blind placebo-controlled trial. After 2 weeks, a significant improvement in bowel frequency, stool consistency and laxative dependency was seen in the active treatment group compared with basal symptoms, with no such improvement seen in the placebo group.22
A Thai medical plant, Cassia alata, was tested against mist alba in a placebo-controlled, multicentre trial. Eighty patients were randomized into three groups and each received a blinded single dose of treatment. More patients in the cassia alata and mist alba groups had passed stools after 24 h than in the placebo group.23
Lastly, the Ayurvedic herbal remedy, Miskakasneham, was found to be as well-tolerated, effective and safe as a conventional senna-based laxative, Sofsena, in a controlled trial for the treatment of opiate-induced constipation in palliative care.24
Plants are very often used for relief and prevention of constipation both in dietary manipulation (e.g. extra rhubarb or spinach) and in specific remedies; clinical trial data would seem to support millennia of popular experience.
Nausea and vomiting
Ginger has been used as a remedy for nausea for centuries. It has been formally evaluated for the prevention and treatment of post-operative nausea and vomiting in four trials (Table 3). The first trial compared ginger with metoclopramide or placebo as an antiemetic after major gynaecological surgery. Ginger was superior to placebo in preventing nausea and vomiting and reducing the need for extra antiemetic.25 In a similar design of trial, with the same three parallel groups, 120 patients were randomized to receive treatment before laparoscopic gynaecological surgery. The incidence of nausea and vomiting was higher in the placebo group than metoclopramide- or ginger-treated groups.26 In contrast, in a study of 108 patients randomly allocated to receive ginger or placebo prior to laparoscopic surgery, there was no significant difference in symptoms of nausea or vomiting for 3 h post-operatively.27 Most recently, a randomized controlled trial compared ginger alone, placebo, droperidol alone or droperidol plus ginger in 120 patients undergoing gynaecological laparoscopy. Again no significant difference in outcome was seen between any groups.28
There are two other controlled studies of ginger for nausea and vomiting. One is for the prevention of sea-sickness, in which 80 sea cadets received either ginger or placebo. The placebo group suffered significantly more symptoms of sea-sickness than the ginger-treated group.29 In a crossover study of 27 women with hyperemesis gravidarum, there was a significant symptomatic benefit of ginger treatment over placebo.30 A systematic review of clinical trials of ginger for nausea and vomiting concluded that insufficient data exist as yet to establish whether ginger is efficacious.31 Further formal studies of ginger for the relief of nausea in other settings, such as chemotherapy, are needed before conclusions can be drawn as to its universal effectiveness.
Irritable bowel syndrome
No conventional treatment is reliably effective in irritable bowel syndrome and it is unsurprising that up to 40% of patients with irritable bowel syndrome use alternative therapies.17, 18 Herbal remedies are among the most common used by patients for this condition.
In one of the few double-blind, randomized controlled trials of traditional Chinese medicine to be published in the English literature, 106 patients with irritable bowel syndrome were randomized to one of the three treatments: individualized Chinese herbal preparations (prescribed specifically for individual patients according to diagnostic processes used in traditional Chinese medicine); a standardized Chinese herbal formulation (developed for general irritable bowel syndrome symptoms but not individual patients); and placebo, for 16 weeks (Table 3).32 Bowel symptom scores were significantly improved in the active treatment groups compared with placebo. There was also a reduction in the degree of interference with life caused by irritable bowel syndrome symptoms. Individually tailored Chinese herbal remedies afforded no benefit over a standard herbal treatment at the end of the 16-week treatment period. However, at the end of a further 14 weeks of follow-up, the only group to show sustained improvement was that given individualized treatment.
In another double-blind randomized, placebo- controlled trial, a compound Ayurvedic preparation containing Aegle marmelos correa and Bacopa monniere was compared with standard therapy (clinidium bromide, chlordiazepoxide and isphagula) and placebo given for 6 weeks. Improvement occurred in 65% of the Ayurvedic treatment group, compared with 78% in the standard treatment group and 33% in the placebo group. Ayurvedic therapy was particularly effective for diarrhoea. At 6 months there was no difference in relapse rates in any group.33
Padma-179 is a Tibetan herbal medicine which was tested in a double-blind, placebo-controlled, randomized trial of 72 patients for the treatment of constipation-predominant irritable bowel syndrome. There was significant benefit over placebo for abdominal pain, stool frequency, distension and flatulence as well as general well-being.34
In addition to these trials, which indicate a response of irritable bowel syndrome symptoms to several different herbal remedies, there are a number of trials of fibre preparations, such as isphagula husk and psyllium and also of peppermint oil.35, 36 These will not be discussed here but do represent a crossing of the divide between alternative and conventional therapy in the management of irritable bowel syndrome.
Peptic ulcer and chronic gastritis
Liquorice has long been recognized as an ulcer-healing agent, and both carbenoxolone and deglycirrhizinized liquorice (Caved-S) were derived from this plant.37 Other herbal treatments investigated for efficacy in peptic ulcer disease are capsaicin/chilli, mastic and curcumin.
The pungent ingredient of chilli, capsaicin is thought to have effects on substance P release and has been tested for its efficacy in peptic ulcer patients. The incidence of peptic ulcer varies between different ethnic groups in Singapore according to the amount of chilli used in the diet. In a case–control study of 103 patients with peptic ulceration, and 87 controls, median amounts of dietary chilli were significantly higher in controls than patients, indicating a possible protective effect of chilli (P < 0.001).38 Capsaicin itself has been shown to protect gastric mucosa against injury caused by 600 mg of oral aspirin in healthy volunteers in a blinded crossover study using 20 g of chilli vs. water (P < 0.05), with gastroduodenal injury assessed by gastroscopy at 6 h.39
Another ingredient of curry, Curcuma domestica val, tested for its efficacy in dyspepsia in a placebo-controlled, double-blind, randomized trial of 116 patients, produced an 87% response after 3–6 months treatment, compared with 53% in the placebo group.40
Mastic, the resin from the trunk of the mastic or lentisc tree, was superior to placebo for ulcer healing in a randomized, double-blind, placebo-controlled trial of 38 patients with symptomatic duodenal ulcer.41
Wei yang an (WYA) is a Chinese herbal therapy used for peptic ulcer. Symptom scores, healing and relapse rates were examined in a controlled trial of WYA (135 patients) vs. cimetidine (104 patients) for peptic ulcer.42 Symptomatic improvement (90% for WYA, 88% for cimetidine) and healing (60% and 67%, respectively) were similar in both groups, but the relapse rate at 1 year was significantly lower (59%) after WYA treatment than after cimetidine (84%; P < 0.05).
Chinese journals also report many studies of herbal remedies for the treatment of chronic gastritis and intestinal metaplasia. Two controlled trials have demonstrated a significantly greater improvement in gastritis and intestinal metaplasia for MSJ-2D, a modified Sijunzi decoction (202 patients), and for piweiping capsule (143 patients), than occurred in placebo-treated subjects.43, 44
Given the morbidity caused by peptic ulcer disease and dyspepsia the world over, cheap and easily available treatments will always be in demand. The success of the spice ingredient, curcumin, has led to further investigation into its pharmacological effects (see later), but in developed countries herbal remedies are unlikely to compete effectively against H2-receptor blockers and, particularly, proton pump inhibitors.40
Inflammatory bowel disease
Much interest has been focused on the high prevalence of use of herbal medicines by patients with inflammatory bowel disease in published surveys, but very little controlled evidence exists for efficacy of any herbal remedy in inflammatory bowel disease.14–17, 19
Studies reported in Chinese literature refer to the treatment of ulcerative colitis with various herbal remedies, but often only abstracts are available in English. In a randomized controlled trial, 153 patients with ulcerative colitis received either Jian Pi Ling tablets and RSF-FS concoction enemas (group I), conventional treatment with oral 5-ASA and prednisolone enemas (group II), or oral placebo and RSF-FS enemas (group III).45 Remission rates in group I were reported to be significantly higher (53%) than in groups II (28%) or III (19%), but the very low success rate of conventional therapy (group II) makes this study hard to interpret.
A trial of the traditional Chinese remedy, Kui jie qing (KJQ) studied 95 patients with ulcerative colitis given KJQ enemas four times daily for 20 days.46 Eleven patients treated conventionally with sulfasalazine 1.5 g t.d.s., oral prednisolone 30 mg o.d., and prednisolone enemas 20 mg q.d.s. for 20 days were used as controls. Effective ‘cure’ was reported in 72% of KJQ-treated patients compared with only 9% of controls (P < 0.001). A further 23% of patients in the KJQ-treated group showed marked improvement compared with 53% in the controls, leading the authors to conclude a 95% effectiveness rate of KJQ, against 62% for conventional western treatment. In a similar trial, 118 patients with active ulcerative colitis were treated with Yukui tang (‘decoction for ulcer healing’) orally and herbal decoction enemas, plus oral prednisolone 15 mg o.d., mycifradin (an antibiotic) and vitamin B for 40 days.47 Eighty-six control patients received prednisolone, mycifradin and vitamin B only. The overall effectiveness rate was 84% for the herbal therapy group (33% ‘cured’, 51% improved) and 60% for controls (17% ‘cured’, 43% improved; P < 0.01). These last two studies suffer from a lack of randomization and blinding.
In India, the effect of the gum resin from Boswellia serrata in moderately active ulcerative colitis was compared to sulfasalazine: remission was achieved in 82% of the Boswellia group and 75% of those given conventional therapy (P=0.2).48
Although published data show limitations of trial design, some of these results, and the anti-inflammatory effects of a range of herbal therapies in vitro (see later), suggest a place for further formal studies of the efficacy of herbal therapy in both Crohn’s disease and ulcerative colitis.
The most researched herbal treatment for liver diseases is Silybum or milk thistle. Its active constituents are collectively known as silymarin. Silybum has been reported in a number of uncontrolled studies and case reports as effective in the treatment of acute hepatic failure due to Amonita phalloides mushroom poisoning. In 18 patients, severity of liver damage was reduced according to the time to administration of silybum.49 In a family of four with severe poisoning, the course of hepatic failure was improved by the addition of silybum to their therapy at day 3, when regular supportive treatment was failing.50 In a retrospective study of 41 patients treated for amonita mushroom poisoning, the group that received intravenous silymarin treatment appeared to have a favourable outcome with no deaths.51
Other work has demonstrated possible hepatoprotective effects for silymarin in alcoholic liver disease. In 106 patients randomized to treatment with silymarin or placebo, the treated group had a significant reduction in transaminases after 4 weeks, and improved liver histology (Table 4).52 However, in a double-blind, placebo-controlled trial of 116 patients with moderately severe alcoholic liver disease, no benefit of silymarin treatment on progression of liver disease was seen over placebo after 3 months (Table 4).53 This negative result is supported by a randomized, double-blind, placebo-controlled trial in 200 patients with alcoholic cirrhosis, in which silymarin had no effect on survival or course of liver disease (Table 4).54 In contrast, in 170 patients with all causes of cirrhosis randomized to silymarin treatment or placebo, the 4-year survival rate in the treatment group was 58% compared with 39% in the placebo group (Table 4).55 Although the results of these trials make it unlikely that silymarin will have a useful role in alcoholic liver disease, controlled trials of its efficacy may be worthwhile in other settings, including acute liver failure and chronic viral and auto-immune hepatitis.
A trial in acute viral hepatitis compared Kamalahar with placebo in 52 patients and again showed quicker and greater improvement in serum liver enzymes and bilirubin in the active treatment group.56
Trials of Chinese herbs in chronic liver disease include a placebo-controlled study of CH-100 in chronic hepatitis C, demonstrating a significant reduction in serum alanine transaminase over 6 months, but no clearance of the virus (Table 4).57 Sho-saiko-to (SST) is a commonly used mixture of seven Chinese herbs. Its efficacy in 222 patients with chronic active hepatitis was studied in a placebo-controlled trial which showed that transaminases decreased significantly more in the SST group.58 In another study in cirrhosis, a Sho-saiko-to remedy (TJ-9, a version of SST available commercially in Japan) was compared to conventional management for its effects on the incidence of hepatocellular carcinoma (HCC) in patients with cirrhosis of various causes. The two groups were matched for severity of liver disease, hepatitis B status, age and sex, and followed for 60 months. In a sub-group of patients who were negative for hepatitis B infection, there was a significantly lower incidence of hepatocellular carcinoma in the TJ-9 treated subjects (Table 4).59
Kuorinone is a matrine extracted from Sophora Flavescens ait. In a study of 94 patients with chronic hepatitis B, 45 patients received Kuorinone 400 mg intramuscularly daily for 3 months; 49 patients were given Interferon-alpha, 3 million units, subcutaneously daily for 1 month followed by alternate days for 2 months. After 3 months, viral clearance was achieved in 60% of the kuorinone-treated group and 61% of the interferon-treated group.60 This interesting result needs to be confirmed by larger, longer-term studies.
Stronger Neo-Minophagen C (SNMC) is a Japanese medicine containing glycyrrhizin, an aqueous extract of liquorice root. Its effects were reported in a retrospective study of 84 patients treated for chronic hepatitis C with SNMC for 2–16 years and 109 patients with similar disease treated with other herbal remedies for 1–16 years.61 The two groups were compared with respect to incidence of hepatocellular carcinoma. The cumulative incidence of hepatocellular carcinoma over 15 years was significantly lower (12%) in the SNMC group than the controls (25%).
While these studies indicate promise for some herbal preparations for the treatment of liver disease, this organ, as indicated below, is particularly prone to serious and sometimes fatal adverse effects in patients taking herbal therapies.