Herbal Medicines for Gastrointestinal Dennis Anheyer, MA, BSc,a​ Jane Frawley, PhD,​b Anna Katharina Koch, MSc,a,​ ​c Romy Lauche, PhD,a,​ b​ DisordersJost Langhorst, MD,a,​ ​c Gustav Dobos, in MD, Childrena​ Holger Cramer, PhDa,b​ and Adolescents: A Systematic Review CONTEXT: abstract

Gastrointestinal disorders are common childhood complaints. Particular types of complementary and alternative medicine, such as herbal medicine, are commonly used OBJECTIVES: among children. Research information on efficacy, safety, or dosage forms is still lacking. To systematically summarize effectiveness and safety of different herbal DATA SOURCES: treatment options for gastrointestinal disorders in children. Medline/PubMed, Scopus, and the Cochrane Library were searched through July STUDY SELECTION: 15, 2016. – Randomized controlled trials comparing herbal therapy with no treatment, placebo, or any pharmaceutical medication in children and adolescents (aged 0 18 years) DATA EXTRACTION: with gastrointestinal disorders were eligible. Two authors extracted data on study design, patients, interventions, control RESULTS: interventions, results, adverse events, and risk of bias.

FourteenPotentilla trials with erecta 1927 participants suffering from different acute and functional gastrointestinalMatricaria disorders chamomilla were included in this review. Promising evidence for effectiveness was found for , carob bean juice, and an herbal compound preparation including in treating diarrhea. Moreover, evidence was found for peppermint oil in decreasing duration, frequency, and severity of pain in children suffering from undifferentiated functional abdominal pain. Furthermore, evidence for effectiveness was found for different fennel preparations (eg, oil, tea, herbal compound) in treating LIMITATIONS: children with infantile colic. No serious adverse events were reported. Few studies on specific indications, single herbs, or herbal preparations could be CONCLUSIONS: identified. Because of the limited number of studies, results have to be interpreted carefully. To underpin evidence outlined in this review, more rigorous clinical trials are needed.

aDepartment of Internal and Integrative Medicine, Kliniken Essen-Mitte, and cDepartment of Integrative Gastroenterology, University of Duisburg-Essen, Essen, Germany; and bAustralian Research Centre in Complementary and Integrative Medicine (ARCCIM), University of Technology Sydney, Sydney, Australia

Mr Anheyer conceptualized and designed the study, conducted the literature review, collected the data, created the tables and figures, and drafted the initial manuscript; Drs Cramer and Lauche participated in conceptualizing and designing the review, participated in collecting the data, and reviewed and revised the manuscript; Dr Frawley and Ms Koch participated in drafting the initial manuscript, and reviewed and revised the manuscript; Drs Dobos and Langhorst critically reviewed the manuscript; and all authors approved the final manuscript as submitted.

To cite: Anheyer D, Frawley J, Koch AK, et al. Herbal Medicines for Gastrointestinal Disorders in Children and Adolescents: A Systematic Review. Pediatrics. 2017;139(6):e20170062

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Functional gastrointestinal disorders Whereas 52% of all children in ingredients of animal or mineral like irritable bowel syndrome Europe are using some kind of origin), the study was not included (IBS), functional abdominal pain, CAM, the use of particular types in this review. No other dosage constipation, and infantile colic of CAM, such –as herbal medicine, Srestrictionsearch Methods were made. as well as acute gastrointestinal is increasingly20,24​ 27 common among disorders like gastroenteritis are children. ‍ ‍ Although herbal common childhood– complaints that medicines are commonly used, Medline/PubMed, Scopus, and research detailing information on affect a large proportion1 4 of children the Cochrane Central Register of and adolescents. ‍‍ Beside the painful efficacy, safety, dosage forms, and Controlled Trials (Central) were impacts for the child, gastrointestinal dose quantities is still lacking. In searched from their inception dates disorders can lead to lower quality of response, the scope of this review to July 15, 2016. Embase was not is to systematically summarize the life, school absenteeism, and a 5,higher6​ searched separately because it is risk of depression and anxiety. ‍ effectiveness and safety of different included in Scopus. Because this Parents are also affected not only herbal treatment options for article is part of a major project to because they commiserate with their gastrointestinal disorders in children identify evidence for herbal therapy offspring but also because of the and adolescents. in children, the literature search was “ ” time needed to care for their child. Methods widely constructed around basic “ ” Therefore, gastrointestinal disorders search terms for children and in children and adolescents may lead search terms for herbal therapy. to both major reductions in quality This review was conducted in The complete search strategy of life for the child and parents– and accordance with the Preferred for PubMed/Medline is shown in Reporting Items for Systematic major socioeconomic impacts5 7 for the Supplemental Information. For each family and wider society. ‍‍ Reviews and Meta-Analyses database, the search strategy was guidelines and recommendations28,29​ of adapted as necessary. Abstracts The management of gastrointestinal Etheligibility Cochrane Criteria Collaboration. ‍ identified during the literature search disorders in children and Types of Studies were screened, and potentially adolescents, especially functional eligible articles were read in full independently by 3 review authors gastrointestinal8,9​ disorders, can be (DA, HC, and RL) to determine if challenging. ‍ Parents often visit Randomized controlled trials (RCTs), they met eligibility criteria. After different practitioners in search randomized cross-over trials, and identifying the literature in the field of a reliable diagnosis or therapy. cluster-randomized trials were of interest, only these articles with Many available treatments are eligible. Trials were included if they children and adolescents suffering either effective but yield potential wereTypes publishedof Participants in English or German. for undesirable adverse effects, or from gastrointestinal complaints as 10 – safe but might lack effectiveness. mentioned above were taken into – Daccount.ata Extraction and Management This may lead to conflicting advice, Only studies on children (0 12 years different prescribed treatments,7,11,​ and12​ of age) or adolescents (13 18 years high direct and indirect costs. ‍ of age) were included if patients In this context, a high prevalence suffered from gastrointestinal Extraction of data on methods, of complementary and alternative complaints such as diarrhea, patients (eg, age, sex, diagnosis), medicine (CAM) use can be observed– constipation, colic, IBS, inflammatory interventions (herbs, dose, etc), control interventions, and results among patients suffering from13 16 bowel diseases, and other disorders gastrointestinal disorders. ‍ ofTypes the ofgastrointestinal Interventions tract. was performed by 2 review authors Research suggests that parents (DA and RL) independently by often favor CAM products, such using an a priori-developed data as herbal medicine, in the belief Studies that compared herbal extraction form. Discrepancies were rechecked with a third reviewer (HC) they 17are natural and therefore medicines with treatment-as-usual safe. In addition to this, evidence or other active comparators, placebo, and discussed until consensus was suggests some parents may also be or no treatment were eligible. If Riskachieved. of Bias in Individual Studies dissatisfied or fear the side effects18 the herbal drug was applied only in of conventional medication. As a homeopathic potency or if the herb result, parents– often do not disclose is exclusively used in traditional By using the Cochrane risk of bias the use of CAM19 23to the attending Chinese medicine (so-called Chinese tool, the risk of bias of each included pediatrician. ‍‍ herbal medicine often includes study was assessed by 2 authors Downloaded from www.aappublications.org/news by guest on September 29, 2021 2 Anheyer et al (DA and HC) independently. This tool assesses risk of bias by using 7 criteria (rating: low, unclear, or high risk of bias): random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. Discrepancies were rechecked with a third reviewer and discussed until consensus was achieved. Trial authors were contacted for further details if necessary. Results Literature Search

Literature search retrieved 10083 nonduplicate records, of which 259 full texts were assessed for eligibility. Eighty-six of them were considered to be eligible for the whole field of herbal medicine in children and adolescents, whereas 173 full texts were excluded for the following reasons: they were not RCTs, the investigated herbs were exclusively FIGURE 1 used in traditional Chinese medicine, Flowchart of the results of the literature search. the herbal drug was applied only in homeopathic potency, or the study had no participants between 0 and M chamomilla adequate allocation concealment. (Diarrhoesan) containing apple 18 years exclusively. Finally, 14 32,33​ Researchers for 3 of the included pectin and . ‍ Both full-text articles involving a total of trials did not report blinding of studies demonstrated a significant 1927 participants suffering from patients and personnel, and 2 studies reduction in the duration of diarrhea gastrointestinal disorders were did not reveal adequate blinding of compared with placebo. Additionally, Sincludedtudy Characteristics in this review and (Fig 1). 32 outcome assessment. Three of the 14 Becker et al showed that the herbal Intervention Characteristics trials had high risk of attrition bias, compound significantly reduced and 2 were not free of suspected stool frequency in comparison with selective reporting. Because of placebo. Detailed characteristics of samples α 31 multiple primary outcomes without P erecta sizes, interventions, outcome Subbotina et al investigated the performing an -correction, a high assessments, and results are shown effectiveness of in treating risk of other bias has to be suspected Riskin Table of Bias 1. in Individual Studies children with diarrhea due to a Gastroenteritisfor 2 RCTs. rotavirus infection. The duration Diarrhea of diarrhea, abnormal stool, and The risk of biased judgment in hospitalization, as well as stool individual studies is shown in Figs 2 output was decreased significantly and 3. Researchers for 8 studies had Researchers in 4 studies with a compared with placebo. reported adequate random sequence total of 424 participants researched Researchers in another study generation, whereas for 6 RCTs the the efficacy of herbal medicine for observed carob bean juice as an randomization procedure remained the treatment of acute diarrhea add-on therapy compared30 with unclear. Researchers for only 5 in children. Two studies observed standard therapy alone. The of the included studies reported an herbal compound preparation duration of diarrhea, stool output, Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 139, number 6, June 2017 3 Results (d) weight) body weight) (mmol/L) (mmol/L (d) stool (d) hospitalization (d) (h) differences after therapy differences after therapy differences after therapy 1. Duration of diarrhea 2. Stool output (g/kg body 1. WHO-ORS intake (mL/kg 2. Serum sodium 3. Serum potassium 1. Duration of diarrhea 1. Duration of abnormal 2. Duration of 3. Stool output (mL/kg/d) 1. Duration of diarrhea 2. Stool frequency Significant group Significant group Significant group Primary outcome Secondary outcomes Primary outcome Secondary outcomes Primary outcome weight) body weight) (mmol/L) stool (d) hospitalization (d) (mL/kg/d) cramps 1. Duration of diarrhea (d) 2. Stool output (g/kg body 1. WHO-ORS intake (mL/kg 2. Weight gain in percent 3. Serum sodium (mmol/L) 4. Serum potassium 1. Duration of diarrhea (d) 1. Duration of abnormal 2. Duration of 3. Stool output (mL/kg/d) 4. Oral rehydration volume 1. Duration of diarrhea (h) 2. Stool frequency 3. Consistency of stool 1. Therapeutic response 2. General condition 3. Existence of abdominal 4. Efficacy Primary outcome Primary outcome Primary outcome Secondary outcomes Secondary outcomes Secondary outcomes regularly until diarrhea stopped daily until diarrhea ceased, or stool output was <10 mL/kg/d, stool consistency was normalized, and symptoms of dehydration were corrected day 3 and 5 of intervention Initial visit, then Initial visit, then Initial visit, and at weight and breast milk or cows ’ milk-yoghurt- mix weight; 3 drops placebo elixir per year of life, 3 times daily until discontinuation of diarrhea or maximum of 5 d same dosage WHO-ORS 20 mL/kg body WHO-ORS 20 mL/kg body Oralp ä don and placebo in Intervention(s) Control condition(s) Measurement(s) Outcome measure(s) mL/kg body weight and breast milk or cows ’ milk-yoghurt- mix weight; 3 drops P erecta elixir (1 part of dried root with 10 parts of 40% ethyl alcohol) per year of life, 3 times daily until discontinuation of diarrhea or maximum of 5 d Diarrhoesan (apple pectin, M chamomilla ) dosage: Diarrhoesan up to 40 – 80 mL/d depending on age; Oralp ä don within the first 24 h: 1 sachet after each stool over 5 d WHO-ORS and CBJ 20 Oralp ä don and mo age, median 33.02 ± 22.77 Control group 22.99 mo median 33.76 ± 23.5 mo 22.5 mo WHO-ORS 20 mL/kg body group age, 15 ± 13 mo 18 ± 14 mo acute diarrhea, N = 80; age: 4 – 48 mo rotavirus diarrhea, N = 40; age: 3 mo – 7 y acute diarrhea, N = 225; age: 6 mo – 6 y Study population Experimental Patients with Patients with Patients with 31 l 32 l  Characteristics of Included Studies 30

l 1 LE Subbotina et a Becker et a Gastroenteritis Diarrhea Ak ş it et a TAB Author

Downloaded from www.aappublications.org/news by guest on September 29, 2021 4 Anheyer et al Results reatment failure (h) rehydration differences after therapy 1. Duration of diarrhea differences after therapy 1. T 1. Intravenous Significant group Primary outcome Significant group Primary outcome

reatment failure, defined as a composite score of intravenous rehydration or hospitalization, subsequent unscheduled physician encounter, protracted symptoms or significant weight loss occurring within 7 d of enrollment and vomiting change 1. Duration of diarrhea (h) 1. Consistency of stool 2. Well-being 1. T 1. Intravenous rehydration 2.Hospitalization 3. Frequency of diarrhea 4. Percentage of weight Primary outcome Secondary outcomes Primary outcome Secondary outcomes Secondary outcomes parents: Initial, then 2 times/d until diarrhea ceased daily telephone assessment by parents for 7 d of intervention Initial visit, then sweetened pediatric electrolyte solution, in same dosage Placebo in same dosage Diary assessed by Apple-flavored, sucralose- Intervention(s) Control condition(s) Measurement(s) Outcome measure(s) dose bag, maximum dose 12 bags a day depending on age juice, 5 mL aliquots every 2 – 5 min up to 2 L, and preferred other liquids (juices or milk) Diarrhoesan 5 mL per Half-strength apple — age, median Control group — median group age, 28 ± 15.4 mo 29 ± 16.5 mo acute diarrhea, N = 79; age: 6 mo – 5.5 y gastroenteritis, N = 647; age: 6 – 60 mo Study population Experimental Patients with Patients with mild 33 l 34 l Continued 1 LE Dehydration Freedman et a De la Motte et a TAB Author

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 139, number 6, June 2017 5 o other N Results o. doses/d symptoms (defined as <9 h cumulative crying h/wk) the end of treatment (h/wk) placebo (mL/d) N differences after therapy differences for responses to treatment. results reported differences after therapy 1. Relief of colic 1. Cumulative crying at 2. Consumed emulsion/ 3. o significant group Significant group N Significant group Primary outcome Secondary outcomes

gitation o. doses per day (defined as <9 h cumulative crying h/wk) end of treatment (h/wk) placebo (mL/d) N 1. Responses to treatment 2. Daily episodes of colic 3. Crying time (h) 1. Milk regur 2. Vomiting 3. Diarrhea 4. Constipation 5. Drowsiness 1. Relief of colic symptoms 1. Cumulative crying at the 2. Consumed emulsion/ 3. Primary outcome Secondary outcomes Primary outcome Secondary outcomes at day 7 and day 17 of intervention parents. Diaries were entered for 21 d (7 before the trial, during the 7-d trial, 7 d after the trial). Visits before, during, and after intervention Initial visit, and Diary assessed by mg/kg body weight) polysorbate-80 in water in same dosage Simethicone drops (2.5 Emulsion of 0.4% Intervention(s) Control condition(s) Measurement(s) Outcome measure(s) (1 drop/kg body weight). fennel seed oil ( F vulgare ) and 0.4% polysorbate-80 in a minimum of water, 5 mL and a max of 20 mL up to 4 times a day Peppermint oil drops Emulsion of 0.1% — age, median Control group — median group age, 29.7 ± 8.2 d 30.5 ± 6.9 d infantile colic, N = 125; age: 2 – 12 wk infantile colic, N = 30; age: 8 – 56 d (m = 33 ± 11.1 d) Study population Experimental Patients with Patients with 36 Continued l 1 35 l LE et a Functional gastrointestinal disorders Infantile colic Alexandrovich Alves et a TAB Author

Downloaded from www.aappublications.org/news by guest on September 29, 2021 6 Anheyer et al Results o comparison of reatment responding min/d) compared with treatment as usual. N fennel tea to the other interventions was performed differences after therapy differences after therapy 1. Crying time (mean 1. T differences differences after therapy 1. Crying time (h) when differences after therapy 1. Elimination of colic 2. Colic improvement o significant group Significant group Significant group Primary outcome N Secondary outcomes Significant group Primary outcome Significant group reatment responding rating o secondary outcomes o. of night wakings 1. Crying time (mean min/d) 1. T 1. Gastrointestinal symptom 1. Crying time (h) N requiring parental response N o primary outcome defined Primary outcome Primary outcome Secondary outcomes Primary outcome Secondary outcomes 1. N 2. Elimination of colic 3. Colic improvement at day 14 of intervention and after intervention period (7 d). Diary assessed by parents, 7 d during the intervention and 14 d after intervention by parents, 7 d during the intervention by parents: 7 d with no therapy, and 7 d of treatment. Initial examination by pediatrician, and at day 7, and day 14 Initial visit, and Diary assessed Diaries assessed peanut oil in same dosage 25 min/d; grp. 2: 12% sucrose solution 2 times a day 2 mL; grp. 3: hydrolyzed formula; grp. 4: treatment as usual instant powder of glucose and natural flavors in same dose Placebo capsules with Placebo in same dosage Initial visit, Grp. 1: massage 2 times Placebo tea preparation: Intervention(s) Control condition(s) Measurement(s) Outcome measure(s) (pH-dependent peppermint oil 187 mg), 3 times/d 1 – 2 capsules depending on weight M chamomilla , officinalis ) 2 mL/kg (body weight) times a day 35 mL up to 150 mL ( M chamomilla , V officinalis , G glabra , F vulgare M officinalis ); every episode of colic, up to 150 mL/dose, not more than 3 times a day Colpermin capsules ColiMil ( F vulgare , Fennel tea ( F vulgare ) 3 Herbal tea preparation ± 0.71 — 1.97 ± 0.75 mo 1.97 2.29 ± 0.75 mo mo m = 2.28 ± 0.61 mo age, median Control group contr grp 2: contr grp 3: contr grp 1: contr grp 4: mo — median group age, 2.24 ± 0.69 21.1 ± 9.3 d 24.6 ± 7.6 d 4.2 ± 1.4 wk 4.4 ± 1.6 wk infantile colic, N = 175; age: 4 – 12 wk infantile colic, N = 93; age: 21 – 60 d infantile colic, N = 68; age: 2 – 8 wk irritable bowel syndrome, N = 42; age: (8 – 17 y) Total: m = 12 y Study population Experimental Patients with Patients with Patients with Patients with 39 l 38 37 l l Continued 40 l 1 LE Weizmann et a Arikan et a Savino et a Irritable bowel syndrome Kline et a TAB Author

Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 139, number 6, June 2017 7 Results umber abdominal pain episodes (min/d) week (min/d) N differences after therapy between both groups differences after therapy differences after therapy 1. 1. Duration of pain 2. Frequency of pain, per 3. Severity of pain 1. Duration of pain 2. Severity of pain o significant differences Significant group N Significant group Primary outcome Compared with Lactol umber abdominal pain constipation other associated gastrointestinal symptoms pain episodes stools hydrogen/methane production episodes N 1. Improvement of 1. Improvement of 1. 2. Severity of abdominal 3. Percentage of normal 1. Changes in breath 2. Gut permeability o primary outcome defined Primary outcome Secondary outcomes Primary outcome Secondary outcomes 1. Duration of pain (min/d)2. Frequency of pain, per week Significant group Compared with Placebo 3. Severity of pain N stool diary assessed by parents, and follow-up-visits 1, 2, 4 and 8 wk after enrollment measurement, 6 wk treatment period, final assessment within the last 2 wk of treatment period before, and after 4 wk intervention. Periodic visits during intervention period Initial visit, daily 2 wk baseline Questionnaire with electrolytes 16.8 g/d + 0.5 g/kg body weight same dosage mg, daily 30 min before breakfast or lunch; grp 2: Lactol tablets (150 million spores of Bacillus coagulans + Fructooligosaccharide), 3 times/d after meals Polyethylene glycol 3350 Maltodextrin powder in Grp 1: Folic acid tablet 1 Intervention(s) Control condition(s) Measurement(s) Outcome measure(s) fiber, Psyllium, and fiber, fructose powder 16.8 g/d + 0.5 g/kg body weight 6 – 12 g depending on age per day (pH-dependent peppermint oil 187 mg), 3 times/d 1 – 2 capsules depending on weight Mixture of Acacia Psyllium fiber powder, Psyllium fiber powder, Colpermin capsules 7.44 ± 2.44 y 7.42 ± 2.49 y age, median Control group contr grp 2: contr grp 1: median 6.5 ± 2.6 y 6.7 ± 2.8 y group age, 13.1 ± 0.4 y 13.5 ± 0.4 y 7.06 ± 2.38 y irritable bowel syndrome N = 103; age: 7 – 18 y functional abdominal pain, N = 120; age: 4 – 13 y chronic functional constipation, N = 100; age: 4 – 10 y Study population Experimental Patients with Patients with Patients with 43 l 41 l Continued 1 42 LE l a Shulman et a Functional abdominal pain Asgarshirazi et Constipation Quitadamo et a TAB Author rehydration solution; — , not applicable. Organization-oral Cbj, carob bean juice; contr: control; grp, group; m, median; max, maximum; WHO-ORS, World Health

Downloaded from www.aappublications.org/news by guest on September 29, 2021 8 Anheyer et al FIGURE 3 Risk of bias graph: presented as percentages across all included studies and generated with Review Manager 5 software (version 5.2; The Nordic Cochrane Centre, Copenhagen, Denmark).

F vulgare M chamomilla M officinalis encounter, and protracted symptoms (ColiMil) containing , or significant weight loss occurring , and could

within 7 days of enrollment reduce the crying time significantly38 when compared with a standard compared with placebo. However, rehydration solution. no significant group differences for 34 Freedman et al reported that 2 treatment response, daily episodes children were hyponatremic at the of colic, and crying time could be time of intravenous insertion (1 in shown for peppermint oil drops the apple juice group and 1 in the in comparison with usual36 care (Simethicone drops). FIGURE 2 usual care group). No other serious Risk of bias assessment: using the Cochrane Functionaladverse events Gastrointestinal were reported. Researchers for 4 of the 5 studies risk of bias tool and generated with Review Disorders Manager 5 software (version 5.2; The Nordic reported that no side– effects or Cochrane Centre, Copenhagen, Denmark). Infantile Colic adverse events were35 37, observed39​ during the study period,38 ​ ‍ ‍ ‍ whereas Savino et al reported side effects Researchers in 5 studies with a total such as vomiting, sleepiness, and and the intake of a standard of 491 participants investigated constipation. None of these side rehydration solution was decreased the efficacy of herbal medicine effects were severe, and there was significantly if carob bean juice was in infantsFoeniculum suffering37 vulgare from colic. no significant difference between given additionally. One study demonstrated that a the herbal compound preparation tea of could and placebo in the occurrence of side Researchers for only 2 of the 4 32,33​ significantly decrease the crying effects. studies reported adverse events,​ ‍ Irritable Bowel Syndrome time (hours) when compared with with a total of 12 adverse events M usual care, whereas an herbal being registered. None of these chamomilla Verbena officinalis tea preparation containing were regarded as related to the trial Glycyrrhiza glabra F vulgare Two RCTs with a total of 145 , , medication. Melissa officinalis participants were conducted to Dehydration due to Gastroenteritis , , and research herbal medicine for the was superior treatment of IBS in children and in elimination of colic and colic 34 adolescents. Although capsules of Freedman et al investigated the improvement in comparison with a 39 peppermint oil (Colpermin) did not effectiveness of half-strength apple placebo tea preparation. Similar show any significant differences juice as a rehydration strategy in 647 results were shown by Alexandrovich 40 35 F vulgare when compared with the placebo,​ children with mild gastroenteritis. et al for an emulsion of 0.1% of 41 psyllium fiber powder significantly The results revealed that apple fennel ( ) seed oil. After a reduced the number of abdominal juice intake provoked significantly 7-day trial, a significant improvement pain episodes in comparison with the fewer treatment failures, defined as in colic symptoms and cumulative placebo (maltodextrin powder). a composite score of intravenous crying time could be observed rehydration or hospitalization, when compared with placebo. Also, The authors of both trials reported subsequent unscheduled physician an herbal compound preparation that no side effects or adverse events Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 139, number 6, June 2017 9 P erecta were observed by investigators or infantile colic, IBS, and functional noted that few high-quality46 trials parentsFunctional during Abdominal the treatment Pain period. abdominal pain. M ,chamomilla carob wereStrengths identified and Weaknesses. bean juice, and an herbal compound preparation including 42 and apple pectin (Diarrhoesan) Asgarshirazi et al investigated There are several limitations to this were shown to significantly reduce the efficacy of peppermint oil in the systematic review. Although aligning the duration of symptoms in treatment of functional abdominal our methodology with guidelines children suffering from diarrhea. pain disorders. A total of 120 from the Cochrane Collaboration This review also demonstrated that participants were treated either with strengthens rigor overall and peppermint oil (Colpermin) can Colpermin capsules or probiotic decreases risk of bias, it also means decrease duration, frequency, and tablets, or folic acid tablets as the that early-stage, non-RCTs of herbal severity of pain in children suffering placebo. When compared with the medicines were not captured. from undifferentiated functional placebo, peppermint oil significantly Although this was the intent, it was abdominal pain, whereas Colpermin reduced the duration of pain designed to exclude trial designs that showed no effects in treating children (minutes/day), frequency of pain may give preliminary insights into an and adolescents with IBS exclusively. (episodes per week), and severity of understudied area and emerging field Furthermore, evidence was found pain. In comparison with probiotics, of research. Secondly, many RCTs for different fennel preparations (eg, peppermint oil significantly reduced that were included in this systematic oil, tea, herbal compound ColiMil) in the duration of pain (minutes/day) review were small trials with treating children with infantile colic. and the severity of pain. between 30 and 100 participants 42 This review also found that psyllium Asgarshirazi et al stated that and larger trials are warranted to fiber may be a useful adjunct in no adverse events or side effects further examine efficacy and safety of treating children with constipation occurred as a result of peppermint oil herbal medicine for gastrointestinal and in decreasing pain episodes in use and probiotics during the study disorders in the pediatric population. patients with IBS. However, research period.Constipation Thirdly, most of the studies revealed evaluating the efficacy and safety of no adverse events, calling into herbal medicine for gastrointestinal question the way that adverse events 43 disorders in children is in its infancy. information was collected and Quitadamo et al studied an herbal Because the number of included recorded. A number of studies did compound of acacia fiber and RCTs for the different herbs and not indicate whether information on psyllium fiber versus a solution of indications was small, future rigorous adverse events was collected. polyethylene glycol and electrolytes RCTs might change the existing Implications for Further Research in the treatment of constipation conclusions. in 100 children. Compliance Agreements With Previous Systematic Reviews rates were significantly higher in It is difficult to make a strong children treated with the solution of recommendation for the use of polyethylene glycol and electrolytes herbal medicine for gastrointestinal (96%) compared with children Two previously conducted disorders in children when the treated with the herbal compound systematic reviews failed to locate evidence base is only just emerging. (72%). No significant differences any systematic reviews on the use of Large-scale trials are needed to between both groups were observed herbal medicine for gastrointestinal44,45​ further investigate early positive in primary or secondary study disorders in children. ‍ A previous results presented here; however, outcomes. literature review of herbal medicine research in herbal medicine faces No serious side effects or adverse use in children included 90 clinical many challenges when compared events were observed by the authors studies, of which one-third were with the study of synthetic drugs. during the study period. conducted in China in children46 Many herbal medicines are not Discussion with respiratory disorders. standardized with batch-to-batch A further 18 studies were located and label-to-label variations because Summary of Evidence that investigated the use of herbal of various elements such as growing medicine for gastrointestinal conditions, manufacturing processes, disorders, however only 2 clinical and differing formulations. In

This analysis indicates an emerging studies of garlic for diarrhea were addition47 to this, there are many evidence base for the use of certain mentioned in the results. Although ethical and clinical hurdles herbal medicines for conditions the review found that RCTs are involved in studying the use of such as diarrhea, dehydration, feasible with children, the authors herbal medicine in children. Despite Downloaded from www.aappublications.org/news by guest on September 29, 2021 10 Anheyer et al these challenges, additional well- professionals could recommend and often not disclosed to a primary – designed trials are required to build the use of herbal medicines that health care professional, leading an adequate evidence base and give have been shown to be safe and to concerns about safety, herb accurate information on dosing effective as a first-line measure drug interactions49 and inadequate to assist clinical decision-making to parents who have expressed treatment. This revelation and ensure the safe use of herbal interestP erecta in trying CAM for their underscores the need to have open medicineImplications for children.for Clinical Practice children. Herbal medicines such and nonjudgmental conversations as (tormentil), carob bean with parents about the use of herbal juice, and Diarrhoesan for diarrhea; medicine to ensure safe, coordinated A recent study found that over peppermint oil (Colpermin) for patient care. two-thirds of children attending functional abdominal pain; fennel Abbreviations gastroenterology outpatient clinics preparations (eg, oil, tea, herbal at a tertiary pediatric hospital were compound ColiMil) for treating using complementary medicine infantile colic; and psyllium fiber can 48 CAM: complementary and alter- including herbal medicine. The vast be used as an adjunct while treating native medicine majority of parents surveyed (80%) constipation in children with IBS. IBS: irritable bowel syndrome felt that medical professionals should Currently, most herbal medicine 48 RCT: randomized controlled trial support the use of CAM. Medical used by children is parent initiated DOI: https://​doi.​org/​10.​1542/​peds.​2017-​0062 Accepted for publication Mar 22, 2017 Address correspondence to Dennis Anheyer, MA, BSc, Kliniken Essen-Mitte, Klinik für Naturheilkunde und Integrative Medizin, Knappschafts-Krankenhaus, Am Deimelsberg 34a, 45276 Essen, Germany. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2017 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose. FUNDING: This review was supported by a grant from the Karl and Veronica-Carstens Foundation and the Rut- and Klaus-Bahlsen Foundation. The funding sources had no influence on the design or conduct of the review; the collection, management, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript. POTENTIAL CONFLICT OF INTEREST: Dr Langhorst has received grants from Schwabe Pharma, Steigerwald and Repha; the other authors have indicated they have no potential conflicts of interest to disclose.

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Downloaded from www.aappublications.org/news by guest on September 29, 2021 PEDIATRICS Volume 139, number 6, June 2017 13 Herbal Medicines for Gastrointestinal Disorders in Children and Adolescents: A Systematic Review Dennis Anheyer, Jane Frawley, Anna Katharina Koch, Romy Lauche, Jost Langhorst, Gustav Dobos and Holger Cramer Pediatrics originally published online May 4, 2017;

Updated Information & including high resolution figures, can be found at: Services http://pediatrics.aappublications.org/content/early/2017/05/02/peds.2 017-0062 References This article cites 48 articles, 10 of which you can access for free at: http://pediatrics.aappublications.org/content/early/2017/05/02/peds.2 017-0062#BIBL Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Complementary & Integrative Medicine http://www.aappublications.org/cgi/collection/complementary_-_inte grative_medicine_sub Gastroenterology http://www.aappublications.org/cgi/collection/gastroenterology_sub Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.aappublications.org/site/misc/Permissions.xhtml Reprints Information about ordering reprints can be found online: http://www.aappublications.org/site/misc/reprints.xhtml

Downloaded from www.aappublications.org/news by guest on September 29, 2021 Herbal Medicines for Gastrointestinal Disorders in Children and Adolescents: A Systematic Review Dennis Anheyer, Jane Frawley, Anna Katharina Koch, Romy Lauche, Jost Langhorst, Gustav Dobos and Holger Cramer Pediatrics originally published online May 4, 2017;

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