Herbal medicines in functional dyspepsia—Untapped opportunities not without risks

Abstract Background Contemporary treatments for functional dyspepsia have limitations. Herbal medicine has been suggested as adjunctive treatment. With growing scientific recognition and public interests, an in‐depth review of this is timely. Aims/Purpose To evaluate the therapeutic potential and problems that may be associated with the adoption of herbal medicines in functional dyspepsia. Methods We reviewed the treatment landscape of functional dyspepsia and assessed the scientific community's interest in herbal medicine. Preclinical pharmacological and clinical trial data were reviewed for several herbal medicines available in the market. Challenges associated with adoption of herbal medicine in mainstream medicine were critically evaluated. Results We found that herbal medicines frequently comprise a combination of herbs with multiple reported pharmacological effects on gastrointestinal motility and secretory functions, as well as cytoprotective and psychotropic properties. We identified a number of commercially available herbal products that have undergone rigorous clinical trials, involving large numbers of well‐defined subjects, reporting both efficacy and safety for functional dyspepsia. Persisting concerns include lack of rigorous assessments for majority of products, toxicity, consistency of ingredients, dose standardizations, and quality control. We provide a quality framework for its evaluation. Conclusions We commend herbal medicine as a viable future option in managing functional dyspepsia. An attractive appeal of herbal medicine is the prospect to simultaneously target multiple pathophysiological mechanisms. Wider adoption and acceptance of herbal medicines in treatment algorithms of functional dyspepsia will require the application of the scientific rigor expected of chemical therapies, to all stages of their development and evaluation.


| TRE ATMENT L ANDSC APE IN FD
Therapeutic options for FD are currently limited and include prokinetics, antisecretory agents, eradication of Helicobacter pylori, and centrally acting neuromodulators. 1 With gains over placebo not exceeding 10-20%, the efficacy is limited (see Table 1). 1,2 Conventional chemically defined treatment approaches ideally target specific more or less well-characterized pathophysiologic disease mechanisms while many first-line treatments are recommended based upon specific symptom clusters (e.g., acid blockers in patients with epigastric pain syndrome (EPS) or prokinetic agents for the postprandial distress syndrome (PDS). 2 Possible explanations for the limited effects of available chemically defined therapies include the heterogeneity of putative pathophysiologies. 3 In addition, the links between disturbed functions and symptoms (e.g., gastric emptying and postprandial fullness) are weak, and consequentially, there is a lack of robust predictors of response. 1,4 Substantial numbers of patients also fulfill both EPS and PDS criteria by the Rome III criteria, rendering a subgroup-based initial therapy recommendation ineffective. 5 Thus, multiple pathophysiological disturbances may co-exist in patients who manifest with more than one symptom cluster. Early data suggest that the Rome IV criteria may produce a sharper discrimination among the different subgroups. 6,7 However, this has yet to be substantiated in clinic populations. 8 Furthermore, in the outpatient clinic there is substantial overlap of FD with other functional gastrointestinal disorders (FGID) syndrome. In a pan-Asian survey of primary and secondary care GI clinics, an estimated 83% of FD (by Rome III) had an overlapping condition. 9 This was reinforced by a study from Australia where in a tertiary center, the majority of FGID patients had overlapping FD and irritable bowel syndrome (IBS). 10 Importantly, FD patients who have overlapping symptoms are more difficult to treat; they report greater symptom severity, treatment dissatisfaction, more physician visits, specialist referrals, and surgery. [11][12][13][14][15]

| HERBAL MED I CINE A S A THER APEUTI C OP TI ON IN FG ID
The therapeutic potential of herbal medicine in general is gain- dose standardizations, and quality control. We provide a quality framework for its evaluation.

Conclusions:
We commend herbal medicine as a viable future option in managing functional dyspepsia. An attractive appeal of herbal medicine is the prospect to simultaneously target multiple pathophysiological mechanisms. Wider adoption and acceptance of herbal medicines in treatment algorithms of functional dyspepsia will require the application of the scientific rigor expected of chemical therapies, to all stages of their development and evaluation. In Italy, a study of GI outpatient clinics found that 36.7% of FGID patients had used herbal drugs, whereas only 8% had received antidepressants. 20 Furthermore, two-thirds would use a combination of treatment modalities. A study of patients with functional bowel disorders in the USA found a CAM usage of 35%. 21 Dissatisfaction with their physicians or with conventional medicines did not appear to be a factor driving use of CAM, while female gender, college education, and anxiety were positive predictors. However, a study from Australia found that seeking care from an alternative healthcare provider was not related to psychological morbidity. 22 While in the Western world the utilization is patchy, 23 in Asia, there is a long tradition of use and high acceptance, of herbal medicine. For example, Liu Jun Zi Tang (LJZT) (known in Japan as Rikkunshito), a traditional herbal medicine which has been used to treat dyspepsia, was described as early as the 16 th Century. 24 In Taiwan, Chinese herbal medicines (CHM) are covered under their national health insurance, with constipation and functional disorders of stomach two of the conditions receiving the highest prescription of CHM. 25,26 In a Taipei general hospital, of 50 patients attending a GI outpatient clinic, traditional herbal medicines had been used by one-third, with 85% using in combination with conventional Western medications. 27

| P OTENTIAL OF HERBAL MED I CINE S IN FD -PRECLINI C AL AND CLINIC AL S TUD IE S
A recent review proposed to position herbal medicines as adjunctive therapy that could be introduced at all levels (primary to tertiary) in the management algorithm of FD. 1  Among the herbal formulations studied for FD, we found specific systematic reviews for Rikkunshito and peppermint oilcaraway oil. For both compounds, the data were found to be inconclusive for efficacy due to the limited number of studies considered to be at low risk of bias. 24

| STW-5 (IBEROGAST ® )
The combination herbal formulation known as STW-5 (Iberogast ® , better known as chamomile flower, is reported to have antidepressive and anxiolytic effects. 23 In a preclinical study of 12 healthy subjects, STW-5 administered at 1.1 ml single dose daily was associated with increased proximal gastric volumes and antral motility but did not appear to affect pyloric or duodenal motility, gastric emptying of solids and liquids or intragastric distribution of test meals. 28 In clinical studies of FD patients, the dose used was much higher at 3 × 20 drops/day (Total 3 ml daily), similar to the recommended dose.
There are three published double-blind, placebo-controlled studies showing superiority of STW-5 in improving symptoms in FD.
In a relatively small study, 60 patients were treated for 4 weeks with STW-5 after a 6-day run-in without medication. Patients treated with STW-5 experienced a significantly better improvement of the symptoms score. 41 In a randomized crossover study, 120 FD  42 As all three studies had not pre-specified the FD subtype, and all had applied a composite GIS, it is not possible to ascertain whether there is any symptom-or subtype-specific response.

| Peppermint oil-caraway oil (POCO)
Peppermint oil is extracted from the leaves of Mentha piperita L., and the peppermint oil and caraway oil combination is available commercially as a proprietary formulation known as Menthacarin.
Peppermint oil has calcium antagonistic properties that could induce relaxation of smooth muscles 43 -promoting increased gastric accommodation and having antispasmodic action in the intestine.
Similarly, smooth muscle relaxant effect has also been reported for caraway oil, and its combination with peppermint oil (POCO) has reported effects on gastric and gallbladder emptying, and modulating visceral hypersensitivity. 32 effect. 28,51 Ghrelin is a peripheral hormone which is involved in appetite stimulation and modulation of several GI functions. 51,52 Hesperidin, a major active compound in RKT extracted from Citri unshiu pericarpium, exerts its effect on gastric emptying through suppression of serotonin receptors. 53 In a recent large systematic review and meta-analysis for upper gastrointestinal symptoms (24 studies with a combined total of 2175 participants), RKT significantly relieved upper GI symptoms on a 5-point scale but was insignificant when compared with other treatments. 33 Another meta-analysis focusing on FD showed that RKT compared with prokinetic drugs increased dyspeptic symptom improvement. 24 No adverse reaction for RKT was recorded in both stud-

| Artichoke leaf extract (ALE)
Artichoke (Cynara scolymus) leaf extract (ALE) has traditionally been used to treat FD symptoms. ALE has been reported to possess inhibitory activity to the contractile response elicited by acetylcholine in animal ileum. 28 The bitter compound, cynaropicrin, is believed to be responsible for the effects such as increase bile flow, leading to hepatoprotective, lipid-lowering, antioxidant, and antispasmodic actions. 28 In a large RCT with 244 FD patients, ALE demonstrated superior symptom alleviation (p < 0.001) and improved disease-specific quality of life (Nepean Dyspepsia Index) compared to placebo. Patients reported symptom improvement on ALE as early as the first week of therapy. 64

| Zhizhu Kuanzhong (ZZKZ)
Like propulsion rate compared to control treatment. 66,67 Zhi Shi is commonly used on its own as a TCM for FD treatment. 68 In in vitro experiments, Zhi Shi exhibited inhibitory action on the spontaneous contraction of pyloric circular smooth muscle strip. 68 Chai Hu has been proven to enhance gastric fluid emptying and small intestinal transit speed, with an antianxiety and antidepressant effect. 65 As a proprietary formula, ZZKZ demonstrated increased gastric emptying and intestinal propulsion and mobility in rats. 35  addition to their effects in the stomach. STW-5 has reported antispasmodic effects on intestinal smooth muscles, abrogation of enteric afferent nerve sensitivity, and prosecretory effects, all of which could be useful in treating the IBS. [69][70][71][72] There is one double-blind placebo-controlled trial in IBS, reporting superiority for STW-5. 73 A recent re-evaluation of data from three early clinical studies with Menthacarin found that some of the FD subjects in these trials had overlapping IBS symptoms of diarrhea and flatulence, which had also improved during treatment with Menthacarin. 74 In addition, peppermint oil by itself has reported efficacy in IBS. 75,76

| PROB LEMS AND CHALLENG E S WITH HERBAL MEDICINE
The following are specific issues pertaining to the adoption of herbal medicine that we have identified: lack of rigorous assessments, toxicity and safety concerns, drug formats, consistency of ingredients, and dosage standardization and quality control, and translation from traditional to contemporary health systems.

| Lack of rigorous assessments
The lack of rigorous assessments and clear evidence for TCM have been some of the reasons cited by critics against its inclusion into ICD-11. 77 The European Academies Science Advisory Council (EASAC) and Federation of European Academies of Medicine (FEAM) have stated categorically that TCM-originated compounds and other CAM should be reviewed critically before use, and should be subjected to the same rigorous assessment, that is, high-quality RCTs. 78 An evaluation of the available clinical trials of herbal medicines in FGID found significant risk of bias; out of fifty trials reviewed, only nine had low risk of bias. Four trials had high risk, and thirty-six trials had unclear risks due to poor design.
The authors concluded that the high risk of bias from the trials could be due to limitations in RCT design such as paucity of detailed methodology, non-standardized evaluation of efficacy, and the suboptimal quality of the study design. The most frequent methodological deficiencies identified in these trials were in the methods of allocation concealment, the blinding of outcome assessment, and incomplete outcome data of AEs. 34

| Toxicity and safety concerns of herbal medicine
Probably the strongest reservation that health authorities and mainstream Western medicine-trained physicians have with regard to herbal medicines is the risk of toxicity. A classic example is digitalis, derived from foxglove plants to produce digoxin for treatment of heart failure and arrhythmia.
In a study from Taiwan involving a million patients, it was found that 14% had received conventional drugs and CHM on the same day; 94% of these patients had received their prescriptions from different locations, with a high likelihood that prescribers were unaware of this co-prescription, thus increasing the risk of drug interactions. 79 Worryingly, in another study from Taiwan, two-thirds had not informed their doctors of this dual practice. 27 In general herbal medicines are one of the commonest treatment class implicated in liver failure. 80,81 Greater celandine, found in the herbal combination STW-5, has been reported to be linked with acute liver injury in a published case report from Europe, suggesting the potential hepatotoxicity of Greater Celandine. 82  In a recent study of causes of acute-on-chronic liver failure (ACLF) in Asia, drugs were implicated as a cause in 10.5%, but within this cate-  Table 3) While reported numbers appear low, we express reservations in view of the reports on contribution of herbal medicine to SAEs like liver failure. The commonest side effects of herbal medicine were GI related such as abdominal pain, diarrhea, and nausea, not unlike the side effects of some contemporary FD medications such as domperidone.

| Formats and consistency of ingredients
Herbal medicines may be presented in formats (e.g., powders, granules, raw herbs) that are less frequently employed in contemporary

| Dosage standardization and quality control
For clinical trials, it is essential to achieve consistency of ingredients and composition as these are key items for comparability between studies. Precise quantification of each and every ingredient is also essential not only to ensure a minimum effective dose, but also to avoid toxicity from overdosing. In order to ensure that  Table 4 Furthermore, the traditional herbalist employs a more personalized approach whereby the proportion of individual herbs within a compound herbal decoction may be varied according to the individual patient's constitution.
One suggestion that we have is the use of N-of-1 trial as a means to marry the robustness of contemporary clinical trial methodology with the personalized medicine approach of traditional herbal medicine. N-of-1 trial is a subgroup of the RCT methodology, with a single patient being exposed to double-blinded, randomized crossover conditions. 97 The University of Oxford Centre for Evidence-Based Medicine (CEBM) recently graded N-of-1 trials as Level 1 evidence, in the same category as systematic reviews of randomized trials. 98 promising results for the treatment of FD are reviewed in more detail. In the background, we also see a growing interest among the general public in using herbal medicines. However, toxicity, efficacy, and standardization of herbal products remain concerns. Therefore, the same scientific rigor that is applied to chemical defined therapies should be applied to the evaluation of herbal therapies at all stages of the development process. We commend herbal medicines as a potential option for the treatment of FD.

ACK N OWLED G M ENT
We would like to thank Ting Chen for providing translations between Chinese and English texts.

D I SCLOS U R E
Kok-Ann Gwee has given scientific advice to Adare and Biocodex, and has been on the speaker bureau of Biocodex, Eisai, and Takeda.

Safety
• Appropriate toxicologic assessment of the plant extracts is done; doses tested should provide an enough safety margin (e.g., doses >100-fold higher compared to clinically used doses). • Quality assurance of raw materials: (a) Concentrations of active ingredients and/or lead substances are monitored in raw materials to enable adjustments of production process to ensure consistent product qualities and concentration of active ingredients in the marked product (b) Monitoring of potential contaminations (e.g., heavy metals, mold) • Appropriate pharmacovigilance of products used in the routine clinical setting consistent with the procedures in place for chemically defined treatment Efficacy • In vivo and in vitro studies to explore mechanisms of action of the plant extracts in isolation and in combination • State-of-the-art clinical trials to proof efficacy regarding relevant outcome parameters (symptom reduction, improvement of QoL) paired with studies on mechanisms Registration, market access • Formal registration that mirrors chemically defined products for the respective jurisdictions TA B L E 4 Proposed quality framework for herbal medicines in FGID (adapted from Holtmann et al 83 )