Functional gastrointestinal disorders (FGIDs) include a series of digestive symptoms caused by a disturbance in the interactions of the gastrointestinal (GI) system and the brain that is arisen from a dysfunction in the sensory-motor and immune systems in the GI tract to the altered central nervous system processing [
The
These herbs’ essential oils contain phenolic monoterpenoids,
The present randomized double-blind clinical trial was conducted at Hormozgan University of Medical Sciences, Bandar Abbas, Iran, from November 2017 to April 2018. The study was done by allocation ratio 1 : 1 and parallel groups. This trial was also approved by the Ethics Committee of the university (Ethics committee reference number: HUMS.REC.1394.012) based on the guidelines of the International Conference on Harmonization and the ethical principles originating in the Declaration of Helsinki. All data and final manuscript were reviewed and approved by all authors. The trial was registered in the Iranian Clinical Trials Registry with trial ID number IRCT2016072629026N2.
The statistical population included all patients aged 15-60 years, enrolled in the Gastroenterology Clinic of Shahid Mohammadi Hospital of Bandar Abbas.
Inclusion criteria included the written consent and complete knowledge about the study; being diagnosed with FD based on the ROME III criteria as the presence of postprandial distress syndrome (PDS) (including postprandial fullness or early satiation) and epigastric pain syndrome (EPS) (including epigastric pain, or epigastric burning), for three months in the past six months; and dyspepsia symptoms with scores of 6 or higher on the 11-point Numerical Rating Scale (NRS) for more than 4 of the 14 days prior to registration were included in the study.
Exclusion criteria included the participants’ lack of consent to continue the study; taking antibiotics or nonsteroid anti-inflammatory drugs two weeks before the study; gastroesophageal reflux disease (heartburn, acid regurgitation); drug or alcohol abuse; the presence of gastroesophageal malignancy, chronic digestive diseases, and peptic ulcer disease based on history, physical examination, laboratory tests (e.g., white blood cell count, C reactive protein (CRP) or erythrocyte sedimentation rate (ESR)), and upper endoscopy; liver and kidney dysfunction based on laboratory tests; planned or current pregnancy; the history of a severe allergic reaction to medicinal plants; the history of upper gastrointestinal tract surgery; and serious illnesses like heart failure, diabetes and epilepsy, and previous or current significant psychiatric comorbidity [
Firstly, the gastroenterologist visited the patients, and the inclusion criteria were confirmed; then, participants were justified briefly about the research, and informed consent was obtained. They were then randomly divided into two equal groups of control and intervention, which received medical regimens A and B, respectively. Randomization was done by using a random allocation software-generated list and in a 1 : 1 ratio. Also, the randomization and medicine administration was done by someone other than the investigators. The medicines were put in similar cans, and the code of the medicinal regimen was labeled on each can. The code of medicine given to each patient and their clinical symptoms was recorded on the treatment of the evaluator’s personal information form (a trained medical student). The investigators, patients, and treatment assessors were not aware of the medicine regimens type. Regimen A was 20 mg omeprazole capsule once a day for two weeks, and regimen B was 250 mg soft-gel capsules containing pure essential oils of ZM (28.8%), AG (21.6%), and TA (21.6%), and sunflower oil (28%) as an excipient twice a day for two weeks. Also, for blinding the participants, aromatized sunflower oil soft-gel capsules twice a day and starch hard gel capsules once a day in the same shape, size, and color as placebo were given to control and intervention arms, respectively.
250 mg soft-gel capsules were produced in Minoo Pharmaceutical Company (Tehran, Iran). The essential oils and sunflower oil were produced in Barij Essence Pharmaceutical Company (Kashan, Iran). The method of determining the safe dosage and preparation of herbal soft-gel capsule is as detailed in our previous investigation [
The gas chromatography-mass spectrometry (GC-MS) analyses of essential oils were performed on an HP 5890 GC system coupled to a Quadrupole Mass Detector. The analysis method has been described in detail in previous studies [
Patients’ information, the severity of symptoms, and quality of life were recorded in a special form at the baseline, end, and two weeks after the end of the treatment. The daily severity of EPS and PDS in the week before the start and end of the intervention were scored using NRS from 0 (no symptoms) to 10 (the most severe symptoms), and the sufficient response to treatment as the primary outcome was defined as a mean NRS score ≤3 in seven days before the end of the intervention [
The secondary outcomes were the improvement rate in the PDS, EPS, Gastrointestinal Symptom Rating Scale (GSRS), and quality of life scores at the end and two weeks after the intervention. Also, safety and tolerability were assessed.
The questions on this questionnaire are scored on a 7-point Likert scale, ranging from “No discomfort at all” (0) to “Very severe discomfort” [
SF-36 is scored based on the total score, a score for each subscale, and a score for each of the physical and mental parts, according to instructions. Several grading scales are used for answering different items of this questionnaire, such as the 5-point Likert scale from excellent (100) to the poor (0) or yes (100) and no (0). Higher scores signify a better health status and vice versa [
Mild adverse events (nausea, diarrhea, constipation, abdominal pains causing awakening, taste disturbance, dry mouth, bitterness and unpleasant changes in the mouth taste, headache, skin redness, dizziness, and itching) and severe adverse events (gastrointestinal bleeding and severe allergic reactions) were also recorded to assess the safety of treatment regimens. Treatment was discontinued if severe adverse events occurred. In order to evaluate the safety, the laboratory tests (serum alanine aminotransferases and aspartate aminotransferases, alkaline phosphatase, total and direct bilirubin, random blood sugar, blood urea nitrogen, and creatinine) were performed at the start and after treatment. Patients were asked to keep their medication until the end of the study. To consumption, more than 80%, 60-80%, and less than 60% of prescribed medications were considered full, good, and poor compliance rates, respectively [
According to a pilot study done before this trial, the treatment rate of FD by this herbal medicine was obtained 70%. Also, determining the sample size, treatment rate with omeprazole in two weeks [
Figure
Flow chart illustrating the progress of patients through the study.
Overall, 112 FD patients were screened. A total of 78 individuals met eligibility criteria. However, 14 patients were unwilling to participate in the study, and, finally, 64 subjects (32 intervention, 32 control) were randomized. Demographic details and FD-related summary measures are shown in Table
Baseline characteristics and FD-related summary measures of randomized patients.
Baseline characteristics | Intervention group ( | Control group ( | |
---|---|---|---|
Age range, year [mean (± SD)] | 18-55 [32.5 (10.2)] | 19-50 [34.5 (9.3)] | 0.41 |
Females, | 19 (59.4%) | 20 (62.5%) | 0.50 |
BMI, kg/m2, | 0.51 | ||
Bothersome symptoms | |||
EPS | 21 (65.6%) | 22 (68.7%) | |
PDS | 25 (78.1%) | 23 (71.8%) |
BMI: body mass index; EPS: epigastric pain syndrome; PDS: postprandial distress syndrome; SD: standard deviation.
During the intervention, four patients were excluded from the study, because no efficacy assessment was performed after the initiation of treatment; one from the control group and three of the intervention group due to lack of cooperation. Lack of cooperation was considered as not completing the daily checklist of symptoms severity or not visiting after treatment. Thus, the statistical analysis of efficacy based on the ITT principle was performed with 60 patients (29 in the intervention group and 31 in the control group). Also, one patient of the intervention group and two patients in the control arm did not return for reassessment after the first assessment. In these cases, missing values were substituted by the mean imputation method. As a result, 89% of patients (28 in the intervention group and 29 in the control group) finished the study.
The number of patients with PDS and EPS was 23 and 19 in the intervention group and 22 and 22 in the control group, respectively. The mean scores of PDS and EPS in the week before the intervention were
At the end of the trial, the sufficient response rates based on PDS and EPS scores ≤3 were 78.3% (18/23) and 73.7% (14/19) in the intervention group and 36.4% (8/22) and 40.9% (9/22) in the control group. According to these findings, the sufficient response rate based on PDS (
The improvement of EPS, PDS, total GSRS, GSRS Dyspepsia, and GSRS Pain scores compared to baseline in inner group comparison using paired sample
The mean score of PDS and EPS. Intention-to-treat population. EPS: epigastric pain syndrome; PDS: postprandial distress syndrome; Mean CBTW2: mean change baseline to week 2; Mean C2WAT: mean change 2 week after treatment;
The mean score of total GSRS and subscales of GSRS Pain and GSRS Dyspepsia at the end and two weeks later from the end of the trial was significantly lower in the intervention group (Table
The mean score of GSRS scale and subscales of GSRS Dyspepsia and GSRS Pain. Intention-to-treat population.
Scale | Group | Mean baseline (±s.d.) | Mean week 2 (±s.d.) | Mean CBTW2 (±s.d.) | Mean week 4 (±s.d.) | Mean C2WAT (±s.d.) | |
---|---|---|---|---|---|---|---|
GSRS | Control ( | 42.3 (7) | 0.17 | 22 (9.9)¶ | 20.3) 7) | 29 (13.5) | 7.7 (6.3) |
Intervention ( | 44.5 (7.4) | 9.4 (4.2) | 35.1 (9.9) | 13.6 (5.7) | 4.1 (4.3) | ||
GSRS Dyspepsia | Control ( | 17.9 (3.2) | 0.88 | 7.2 (4)¶ | 10.6 (4.6) | 10.1 (5.8) | 3.4 (3.6) |
Intervention ( | 18.4 (2.1) | 3.5) 2.4) | 14.8) 3.1) | 4.7 (3.1) | 1.2 (1.9) | ||
GSRS Pain | Control ( | 12.2) 2.7) | 0.86 | 5.1 (3.5)¶ | 7 (3.9) | 7 (5.5) | 3.1 (3.2) |
Intervention ( | 12.1 (2.2) | 2.4 (1.9) | 9.7 (2.7) | 2.9 (2.4) | 1.5 (2) |
Regarding the improvement of the posttreatment EPS, PDS, and GSRS scores, the improvement chance in the intervention group was 27%, 30%, and 27% higher than the control group, respectively (OR 1.27, CI 95% (1.04-1.56),
About the scales of SF-36, SF-36PH, and SF-36MH, the mean score of these scales at the end and two weeks later from the end of the trial and its mean increase after treatment was higher than the intervention group; these differences were statistically significant (Table
The mean score of SF-36, SF-36PH, and SF-36MH. Intention-to-treat population.
Scale | Group | Mean baseline (±s.d.) | Mean week 2 (±s.d.) | Mean CBTW2 (±s.d.) | Mean week 4 (±s.d.) | Mean C2WAT (±s.d.) | |
---|---|---|---|---|---|---|---|
SF-36 | Control ( | 78.4 (7.1) | 0.85 | 89.1 (3.3) | 11.1 (6.4) | 85.7 (5) | 4.3 (3.8) |
Intervention ( | 76.8 (8.1) | 92.3 (2.7) | 15.5 (6.3 | 90.6 (3.7) | 1.6 (2.2) | ||
SF-36PH | Control ( | 78.3 (5.8) | 0.35 | 88.5 (4.1) | 10.3 (7) | 85.2 (7.4) | 3.4 (5.1) |
Intervention ( | 76.5 (6.6) | 92 (3.3) | 15.6 (6.7) | 91 (3) | 0.8 (2.2) | ||
SF-36MH | Control ( | 78.4 (9.2) | 0.63 | 88.9 (5.4) | 10.5 (7) | 84.4 (8) | 4.6 (3.9) |
Intervention ( | 76.7 (10.3) | 92 (4.2) | 15.4 (6.8) | 90.2 (5.2) | 1.5 (2.8) |
The results of the GC-Mass analysis of essential oils are listed in Table
Composition of and percentage of each compound.
EO compounds | ZM % | TA % | AG % | RI |
---|---|---|---|---|
2.42 | 0.24 | 1.10 | 931 | |
— | 1.48 | 0.80 | 980 | |
Myrcene | 1.53 | 0.46 | — | 986 |
— | — | 15.76 | 1008 | |
8.64 | 21.67 | 0.89 | 1021 | |
Limonene | — | — | 16.85 | 1032 |
— | — | 3.32 | 1037 | |
12.27 | 20.31 | — | 1055 | |
Linalool | 3.52 | — | — | 1096 |
Dill ether | — | — | 5.29 | 1190 |
Trans dihydrocarvone | — | — | 8.34 | 1205 |
Carvacrol methyl ether | 1.12 | — | — | 1240 |
D-Carvone | — | — | 33.18 | 1247 |
Thymol | 30.34 | 50.26 | — | 1292 |
Carvacrol | 28.84 | 1.34 | — | 1304 |
Dill apiol | — | — | 6.80 | 1628 |
EO: essential oil; ZM: Zataria multiflora Boiss; TA: Trachyspermum ammi L.; AG: Anethum graveolens L; RI: the retention index of compounds on HP-5column.
In terms of minor adverse events, one case of unpleasant mouth taste (3.12%) and one case of epigastric pain (3.12%) were observed in the intervention group at the beginning of the trial. Postintervention laboratory tests showed no disorder in patients. In control and intervention groups, medicine compliance was more than 80% (full compliance) in 90.6% and 87.5% of patients, respectively.
The present research aimed to compare the efficacy of a novel herbal medication consisting of ZM, AG, and TA essential oils with omeprazole to improve the GI symptoms of patients with FD. According to the results, the improvement of EPS, PDS, total GSRS, GSRS Dyspepsia, and GSRS Pain scores compared to baseline in inner group comparison in both omeprazole and herbal medication groups were statistically significant (
Concerning the sufficient response rate with omeprazole, our study results are closer to those of the studies, as mentioned above. However, although the results of these studies indicate that omeprazole is more effective than other treatments in the treatment of FD, according to the results of our study, the sufficient response rate based on PDS (
In our study, the superior symptom relief with this herbal medication compared to omeprazole in the treatment of FD may be due to the multiple properties of these essential oils and different mechanisms of FD [
On the other hand, in addition to total GSRS, the mean reduction in subscales of GSRS Pain (stomachache, hunger pain, and nausea) and GSRS Dyspepsia (borborygmus, abdominal distention, eructation, and increased flatus) after the trial was considerably higher in the intervention arm than the control group. Anticholinergic, antispasmodics, and antibiotics medications are used to treat intestinal symptoms of FGIDs such as diarrhea, abdominal cramps, and symptoms associated with gas retention such as bloating, abdominal distension, and pain [
It seems this herbal combination may play a significant role in the treatment of FD that may arise from multiple mechanisms of action of these medicinal plants in FD other than an antisecretory property. However, further investigations are necessary to unveil the effects of medicinal plants on FD.
The short duration of treatment and follow-up were the limitations of our study. The adverse events and compliance of this novel herbal medication in long-term use need further investigation. Also, it is considered that FD is usually a chronic disease, and discontinuing the intervention may lead to the recurrence of the symptoms. Therefore, there is a need for a longer follow-up duration. So, due to mentioned and other limitations such as low sample size and single-center design of our study, a larger multicenter trial with a longer follow-up duration is needed to confirm this trial’s results.
In the present study, this herbal compound significantly improved FD symptoms and other intestinal symptoms more effectively than omeprazole’s daily use. It can be attributed to the various properties of the plants used in this study. Therefore, this herbal medicine can be considered as an alternative treatment for FD.
Functional dyspepsia FGIDs
Postprandial distress syndrome
Epigastric pain syndrome
Gastrointestinal Symptom Rating Scale
Functional gastrointestinal disorders
Gastrointestinal
Numerical Rating Scale
36-Item Short-Form Health Survey
Gas chromatography-mass spectrometry
Gas chromatography-flame ionization detector
The National Institute of Standards and Technology
Odds ratio
Intention-to-treat
Transient receptor potential
5-Hydroxytryptamine
Transient receptor potential ankyrin-1.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
This herbal medicine is registered in the Patent Cooperation Treaty (PCT) with the Application number PCT/IB2019/056773.
The authors declare that there is no conflict of interest regarding the publication of this paper.
We are sincerely thankful to Mohsen Azad for statistical analysis, Saber Ghasemi, Fatemeh Mosaferi, Fatemeh Hendijani, and Vice-Chancellery for Research, Hormozgan University of Medical Sciences. This study was funded by the Hormozgan Province Science & Technology Park with grant number 93/3/1986.
GC-FID analysis for the quantization of thymol, carvacrol, and D-carvone in essential oils.