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Treatment of irritable bowel syndrome using a selected herbal combination of iraqi folk medicines
Journal of Ethnopharmacology 148 (2013) 1008–1012
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Ethnopharmacological communication
Treatment of irritable bowel syndrome using a selected herbal combination of iraqi folk medicines Ahmed Salih Sahib n Department of Pharmacology, Al-Kindy College of Medicine, University of Baghdad, Baghdad, Iraq
art ic l e i nf o
a b s t r a c t
Article history: Received 9 September 2012 Received in revised form 4 May 2013 Accepted 6 May 2013 Available online 23 May 2013
Ethnopharmacological relevance: Mentha longifolia, Cyperus rotundus and Zingiber officinale are widely used in Iraqi traditional medicine for the treatment of multiple gastrointestinal diseases. The aim of this study was to examine the effectiveness of a combination of three herbal agents that are widely used in folk medicine in Iraq for the treatment of patients with irritable bowel syndrome (IBS). Materials and methods: A prospective randomised clinical study was carried out on 40 patients of both sexes between 25 and 60 years of age who had been diagnosed with IBS for 5–10 years. The patients were allocated to one of two groups, each consisting of 20 patients. Group A was treated with mebeverine, and Group B was treated with a capsule containing a combination of the following three herbs prepared as fine powders: Mentha longifolia, Cyperus rotundus and Zingiber officinale. IBS symptoms were assessed before and after 8 weeks of treatment. Results: Treatment of IBS patients with the herbal combination resulted in improvements in all of their IBS symptoms after 8 weeks, as revealed by increase in their individual symptom scores and in their mean total improvement percentages. These results were comparable to those produced by the standard agent mebeverine. Conclusion: Patients with IBS showed significant improvements in their IBS symptoms after 8-weeks of treatment with the herbal combination and did not report any adverse effects during their treatment. These results support the efficacy and safety of the herbal combination for the treatment of IBS. & 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Irritable bowel syndrome Folk Medicine Herbal Medicine
1. Introduction Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder. It is characterised by chronic abdominal pain or discomfort and altered bowel function. The symptombased Rome III criteria for the diagnosis of IBS include recurrent abdominal pain or discomfort for, at least 3 days per month in the past 3 months, and at least two of the following: improvement of pain with defecation, onset of pain that is associated with a change in the frequency of stool, or onset of pain that is associated with a change in the form (appearance) of stool (Longstreth et al., 2006). With an estimated prevalence of 14–24% in women and 5–19% in men, IBS is a common reason for seeking medical care (Andrews et al., 2005). It accounts for 12% of visits to primary care physicians and 28% of visits to gastroenterologists (Dean et al., 2005). In addition, IBS is associated with significantly impaired quality of life and significantly increased economic costs (Chang, 2004). Despite recent advances in the treatment of IBS, the pathophysiology of IBS is incompletely understood (Mathew and Bhatia, 2009). Alterations in neurohormonal function, psychological factors,
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bacterial overgrowth, genetic factors, changes in gut motility, visceral hypersensitivity, and immune system changes are currently believed to influence the pathogenesis of IBS (Longstreth et al., 2005). Patients can be divided into three IBS subgroups: those with constipation, those with diarrhoea, and those with alternating constipation and diarrhoea (Mearin et al., 2003). Because of its complex pathogenesis, a drug that treats all of the underlying abnormalities of IBS has not been identified. The use of dietary fibres, laxatives, antidiarrheal agents, and antispasmodic agents as first line therapies has been limited owing to their marginal therapeutic benefits, and side effects. Antidepressants have proved to be efficacious for improving symptoms and psychological well-being. However, their use has been limited by side effects and poor acceptance by patients. Modulators of serotonin receptors have recently been developed and initially showed promising therapeutic effects (Lacy et al., 2009). Over the past 2 decades, there has been a focus on smooth muscle relaxants (commonly called antispasmodics) for the treatment of IBS. Mebeverine is a commonly prescribed drug that has been used successfully for many years for the management of IBS. Mebeverine is a musculotropic agent that has antispasmodic activity and regulatory effects on bowel function (Talley, 2001). During oral administration of doses of 135–270 mg three times daily, mebeverine does not cause anticholinergic side effects such as dry mouth, blurred vision,
A.S. Sahib / Journal of Ethnopharmacology 148 (2013) 1008–1012
or impaired micturation. The incidence of side effects caused by mebeverine is no higher than that produced by treatment with a placebo (Poynard et al., 1994). Because of the lack of a cure for IBS and the adverse effects of medications used to treat this disorder, many patients consider conventional IBS treatment to be disappointing and often turn to complementary therapies. The choice to use natural rather than chemical therapies is appealing because many patients assume that natural products are safe and that they do not cause adverse effects. Additionally, because technology has supplanted bedside manner, the deteriorating relationship between patients and physicians also encourage the use of complementary and alternative medicine, giving patients a greater sense of autonomy in their care. Because of the substantial impact of complementary and alternative medicine on both individual patients and society, it is crucial for health care providers to gain a better understanding of the potential benefits and pitfalls of complementary and alternative medicine (Tillisch, 2006; Stake-Nilsson et al., 2012). Herbal medicines have been used in Asia for a long time, and, an increasing number of IBS patients in the West are beginning to take complementary and alternative medicines, most frequently herbal remedies (Magge and Lembo, 2011). One important herbal agent that is widely used by IBS patients is peppermint oil, an oil extract of the Mentha piperita Linnaeus plant that has been used to treat upset stomach for thousands of years. Peppermint oil has been shown to relax intestinal smooth muscle cells by inhibiting calcium channels (Kligler and Chaudhary, 2007). Short term trials have suggested that the daily use of 3–6 enteric coated capsules containing 0.2–0.4 mL of peppermint oil improved IBS symptoms (Cappello et al., 2007). The major advantage of peppermint oil for the treatment of IBS is its safety profile; common side effects include heart-burn and a perianal burning sensation (Kline et al., 2001). The active ingredient in peppermint oil is menthol (C10H20O) a terpenoid that is found in the essential oils of members of the mint family (Mentha spp.), including Mentha piperita and Mentha longifolia (Al-Bayati, 2009). Mentha longifolia is an extremely variable species with a widespread distribution in Iraq. In Iraqi folk medicine, the leaves and stems of Mentha longifolia species are frequently used in herbal teas or as additives in spice mixtures. As a folk remedy Mentha longifolia is used to treat nausea, and flatulence, and it is used as an anti-inflammatory, carminative, analgesic, and antispasmodic agent (Al-Rawi and Chakravarty,1988). Cyperus rotundus is another traditional herbal medicine that grows naturally in Iraq. It is widely used as an analgesic, sedative, and antispasmodic agent and for the treatment of stomach disorders and diarrhoea (Zhu et al., 1997). The tuber part of Cyperus rotundus is widely used as a folk medicine, especially by older women, for its carminative, antispasmodic, analgesic anti-
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diarrheal properties. Previous phytochemical studies have shown that the major chemical components of this herb are essential oils, flavonoids, terpenoids, and mono- and sesquiterpenes (Nima et al., 2008). Ginger was also used as an herbal agent in this study. Ginger (Zingiber officinale, Zingiberaceae) has several ethnomedicinal and nutritional attributes, and is used extensively throughout the world as a spice, a flavouring agent and an herbal remedy (Gaurav et al., 2011). In Iraq, this herb is imported from other countries and is commonly used as a food additive and a spice. It is also used as a treatment for several different conditions, particularly those associated with digestive problems such as dyspepsia, flatulence, nausea and abdominal pain. Only recently has this plant been cultivated in Iraq (AL-Bayaty et al., 2006). Choosing the appropriate outcome measures and therapeutic regimens for complementary and alternative medicine studies requires a good understanding of the expected role of a given therapy in the treatment of a gastrointestinal disorder (Tillisch, 2006). For example for the treatment of IBS, adminstration of peppermint may be useful for its muscle relaxant effect. Cyprus rotundus administration may be useful for its antimicrobial effect, and administration of ginger may be useful for its antiflatulent effect. In this way, the multiple manifestations of IBS can be specifically targeted using different herbal agents. The aim of this study was to examine the effectiveness of a combination of three herbal agents, Mentha longifolia, Cyperus rotundus and Zingiber officinale, in their powder form, for the treatment of patients with IBS.
2. Materials and methods This prospective randomised clinical study was carried out on 40 patients of both sexes between 25 and 60 years of age who had been diagnosed with IBS for 5–10 years, and who had visited the outpatient clinic at the Al-Kindy College of Medicine during a 6month period. The study followed the guidelines outlined in the Declarations of Helsinki and Tokyo for the ethical use of human subject in research and was approved by the scientific and ethical committees at Al-Kindy College of Medicine. All patients provided informed consent. The patients that participated in this study were allocated to one of two groups: 1. Group A included 20 patients of both sexes treated with tablets containing 135 mg of mebeverine three times daily for 8 weeks. Mebeverine (tradename Colospasmin Forte, 135 mg tablet) was obtained from EIPICO, Egypt. 2. Group B included 20 patients of both sexes treated with a capsule containing a combination of the following three herbs
Table 1 Effects of treatment with 135 mg of mebeverine (Group A, n¼ 20), three times daily, on the distribution of symptom severity in IBS patients. Symptom
Mild
Moderate
Pre Pain severity Pain frequency Stool frequency Stool consistency Abdominal distension Incomplete evacuation Urgency Passing of mucus Mean
5 4 7 6 5 5 4 6 5.25
Post (25%) (20%) (35%) (30%) (25%) (25%) (20%) (30%) (26.25%)
1 2 5 4 3 4 3 4 3.25
(5%) (10%) (1%) (20%) (15%) (20%) (15%) (20%) (16.25%)a
Results represent a percentage of the total number of IBS patients. a
Denotes a statistically significant change (P≤0.05) in symptom severity.
Severe
Pre
Post
9 (45%) 8 (40%) 8 (40%) 7 (35%) 9(45%) 8 (40%) 7 (35%) 8 (40%) 8 (40%)
4 3 3 2 2 1 3 3 2.63
(20%) (15%) (15%) (10%) (10%) (5%) (15%) (15%) (13.12%)a
Pre
Post
6 (30%) 8 (40%) 5(25%) 7 (35%) 6 (30%) 7 (35%) 9(45%) 6 (30%) 6.75 (33.75%)
1 1 0 1 0 0 1 1 0.625
(5%) (5%) (0%) (5%) (0%) (0%) (5%) (5%) (3.13%)a
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prepared as fine powders: leaves part of Mentha longifolia (150 mg), tubers part of Cyperus rotundus (150 mg) and tubers part of Zingiber officinale (150 mg). The capsules were taken three times daily 1 h after meal for 8 weeks. The herbal agents were obtained from a local market and approved by the National Centre of Herbal Medicine at the Ministry of Health in Iraq.
The inclusion criteria were as follows: the patients fulfilled Rome III's diagnostic criteria for IBS, and the patients did not suffer from endocrine illness or structural organic gastrointestinal abnormalities, such as inflammatory bowel disease (Crohn's disease and ulcerative colitis), diverticular disease, colorectal carcinoma, intestinal obstruction, peptic ulcer disorders, or biliary tract disorders. Women who were breast feeding or pregnant, patients with chronic cardiovascular disease and patients with thromboembolic disease were excluded from the study. A full history was taken from each patient. Each patient was also subjected to a general and systemic physical examination that included a thorough examination of the abdomen and abdominal ultrasound to exclude biliary tract. The presence of gases causing distension of the colon, which is suggestive of IBS, was documented. All patients underwent a flexible sigmoidoscopic examination to exclude inflammatory bowel diseases, colorectal carcinoma, and diverticular diseases. Patients follow up occurred at 8 weeks interval. The medications were taken for the first time by the patients during the visit. Thereafter, patients were told to call the doctor by phone as needed. Contact information was collected from all patients, and patients were contacted periodically to ensure that medications were been taken as prescribed. Patient examinations were performed, and histories were taken by consulting physicians at the consulting clinic at the Al-Kindy College of Medicine.
Data were collected using a questionnaire that evaluated the presence of IBS symptoms based on the Rome III criteria for the diagnosis of IBS. The following symptoms were evaluated: pain severity, pain frequency, stool frequency, stool consistency, abdominal distension, incomplete evacuation, urgency and passing of mucus. Changes in symptoms following treatment were scored as follows: symptom improvement was scored as plus one (+1), no improvement was scored as zero (0), and worsening of a symptom was scored as minus one (−1). Descriptive analyses are summarised as percentages. Student's t-test was used to determine the significance of the results. A P-value of ≤0.05 was considered to be statistically significant.
3. Results Table 1 shows the severity distribution of the IBS symptoms studied in group A (mebeverine). The severity distribution as a mean percentage of total was as follows: 26.25% of cases were mild, 40% were moderate and 33.75% were severe. Following treatment with 135 mg of mebeverine three times daily for 8 weeks, the mean symptom severity significantly (P≤0.05) reduced this per cent by 10% in mild cases, 26.88% in moderate cases and by 30.62% in severe cases Fig. 1. The results presented in Fig. 1 clearly show that the reduction in the symptom severity profile of IBS patients treated with mebeverine was greater among those patients initially classified as having severe symptoms, compared to those patients initially classified as having moderate or mild symptoms. Treatment with the herbal combination capsules, taken three times daily for 8 weeks, also significantly (P≤0.05) reduced the mean symptom severity in patients initially classified as having mild, moderate or severe IBS symptoms, by 17.5%, 28.75% and 26.87%, respectively folds for the categories mild, moderate and severe respectively (Table 2, Fig. 2).
26.88
30
40
30.62
% Reduction
% Reduction
40
20 10
10 0
30 20
Moderate
Severe
Fig. 1. Effects of mebeverine on the severity profile of IBS symptoms.
26.87
Moderate
Severe
17.5
10 0
Mild
28.75
Mild
Fig. 2. Effects of the herbal combination on severity profile of IBS symptoms.
Table 2 Effects of treatment with the herbal combination capsule (Group B, n¼ 20), taken three times daily, on the distribution of symptom severity in IBS patients. Symptom
Pain severity Pain frequency Stool frequency Stool consistency Abdominal distension Incomplete evacuation Urgency Passing of mucus Mean
Mild
Moderate
Pre
Post
7 (35%) 5 (25%) 7 (35%) 8 (40%) 6 (30%) 5(25%) 5 (25%) 7 (35%) 6.25 (31.25%)
4 3 4 3 2 2 3 1 2.75
(20%) (15%) (20%) (15%) (10%) (10%) (15%) (5%) (13.75%)a
Results represent a percentage of the total number of IBS patients. a
Denotes a statistically significant change (P≤0.05) in symptom severity.
Severe
Pre
Post
8 (40%) 10(50%) 9 (45%) 7 (35%) 8 (40%) 7 (35%) 7 (35%) 8 (40%) 8 (40%)
2 3 3 2 2 2 1 3 2.25
(10%) (15%) (15%) (10%) (10%) (10%) (5%) (15%) (11.25%)a
Pre
Post
5(25%) 5(25%) 4 (20%) 5 (25%) 6 (30%) 8 (40%) 8 (40%) 5 (25%) 5.75 (28.75%)
0 1 0 1 0 0 0 1 0.38
(0%) (5%) (0%) (5%) (0%) (0%) (0%) (5%) (1.88%)a
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4. Discussion In folk medicine, various drugs are used alone or in combination forms with considerable success to treat different types of conditions. Although many of these drugs have been in use for a long time, and their medicinal applications and general safety are well-known, in many cases, their use as therapeutic agent has not been evaluated using standard methodologies. Scientific studies are therefore required to assess their safety and efficacy (Shen and Nahas, 2009). Because of low levels of satisfaction that have been reported for current treatments of IBS (Thompson et al., 2000), the adverse effects that are associated with the medications that are used, and the lack of a cure for this disorder, 50% of patients with IBS worldwide have turned to complementary and alternative therapies, and to herbal medicines in particular, to treat their IBS (Hussain and Quigley, 2006). Peppermint oil has been used to treat many gastrointestinal disorders for a long time. It has been used primarily for its antispasmodic properties (Liu et al., 1997). The therapeutic benefit of peppermint oil is supported by two meta-analyses; the first meta-analysis reviewed five clinical trials that suggested its efficacy (Pittler and Ernst, 1998), and the second meta-analysis reviewed four small trials and found overall symptom improvement with peppermint oil (Spanier et al., 2003). It is well known that the principal active ingredient in peppermint oil is menthol, a cyclic monoterpene that relaxes smooth muscle by blocking calcium influx (Hills and Aaronson, 1991). Menthol is found in
the essential oils of all members of the mint family (Mentha spp.), including peppermint (Mentha piperita) and horse mint (Mentha longifolia); these mint species are highly distributed as wild herbs in Iraq (Al-Bayati, 2009). In this study, a fine powder derived from crude Mentha longifolia and encapsulated with other herbs was used for the treatment of IBS symptoms; this herb may have contributed, in part, to the improvements in IBS symptoms that were observed. Cyperus rotundus is another herbal agent that was used in this study. Although there is a strong precedence for the use of Cyperus rotundus to treat various digestive tract disorders in folk medicine (Jagtap et al., 2004), there is no evidence in the scientific literature to support the use of Cyperus rotundus to treat IBS. However, Uddin et al. (2006) have shown that when administered orally, the methanolic extract from Cyperus rotundus rhizomes has significant antidiarrheal activity in experimental animals. It is through its antidiarrheal action that Cyperus rotundus might improve symptoms in IBS patients that suffer from diarrhoea. Moreover, because IBS is associated with bacterial overgrowth (Di Stefano et al., 2000), the antibacterial action of Cyperus rotundus on enteric bacteria (Kilani et al., 2008) might account for the observed improvements in abdominal distension and pain resulting from abnormal intestinal gas production as well as the observed improvement in other symptoms, such as incomplete evacuation, stool frequency and stool consistency (Nobaek et al., 2000). The third herbal component used in this study was ginger. Ginger is used to treat many gastrointestinal related illnesses, including nausea, vomiting and motion sickness, and is used as a
Improvement percent
Table 3 shows the percentage improvement of the IBS symptom scores after 8 weeks of administration of the agents tested. In both groups A and B, the amount of improvement was different for each symptom studied. Overall, symptom improvement was good, and in no patients did IBS symptoms worsen. The mean of the total improvement percentage in patients treated with mebeverine (group A) was 66.88%. The mean total improvement percentage 3.12% lower than the 70% mean total improvement that was observed in patients treated with the herbal combination (group B). This difference is not statistically significant (Fig 3). These data demonstrate the effectiveness of the herbal combination used in this study for IBS. The herbal combination significantly reduced the incidence and severity of all IBS symptoms to a level that was comparable to that produced by the standard agent mebeverine. Additionally, the herbal combination was not associated with the worsening of any of the IBS symptoms studied, nor were any side effects reported during the study. These results support the safety and efficacy of the agents studied.
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90
Group A
80
Group B
70 60 50 40 30 20 10 0
Fig. 3. Improvement of IBS symptoms after 8 weeks of treatment with mebeverine (Group A) or the herbal combination (Group B).
Table 3 Improvements in the symptoms of IBS patients after 8 weeks of treatment. Symptoms
Pain severity Pain frequency Stool frequency Stool consistency Abdominal distension Incomplete evacuation Urgency Passing of Mucous Mean of total per cent
Group A, n ¼20
Group B, n¼20
+1
0
−1
+1
0
−1
14(70%) 14(70%) 12(60%) 12(60%) 15(75%) 15(75%) 13(65%) 12(60%) 66.88%
6(30%) 6(30%) 8(40%) 8(40%) 5(25%) 5(25%) 7(35%) 8(40%) 33.12%
0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0%
14(70%) 13(65%) 13(65%) 13(65%) 16(80%) 14(70%) 14(70%) 15(75%) 70%
6(30%) 7(35%) 7(35%) 7(35%) 4(20%) 6(30%) 6(30%) 5(25%) 30%
0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0%
Group A was treated with mebevrine; and Group B was treated with the herbal combination. Results represent the percentage of the total number of IBS patients; (+1) denotes symptom improvement, (0) denotes no improvement of symptom, and (−1) denotes symptom worsening. * Denotes a statistically significant change (P≤0.05) in symptom severity.
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carminative and antiulcer agent (White, 2007). Very few randomised clinical trials in humans have evaluated the use of ginger as a carminative agent or as an ulcer remedy. In one study, the efficacy of ginger for the treatment of functional dyspepsia was evaluated in 11 patients in a randomised double-blind manner. After an 8-h fast, the patients ingested three capsules containing ginger (1.2 g total) or placebo, followed after 1 h by 500 mL of lownutrient soup. This study showed that ginger stimulates gastric emptying and antral contractions in patients with functional dyspepsia (Hu et al., 2011). Although complementary and alternative medicine is commonly used to treat IBS, no clinical trials have been conducted to date to evaluate the efficacy of ginger for the treatment of IBS. One study did evaluate the use and economic cost of complementary and alternative medicines to treat functional bowel disorder. This study showed that ginger root and ginger/tea were useful in 14.8% of the IBS patients studied. However, the clinical setting in which this study was conducted is unclear (Van Tilburg et al., 2008). The results of this study clearly show that administration of the herbal combination of Mentha longifolia, Cyperus rotundus and Zingiber officinale results in an improvement in individual IBS symptoms and in IBS symptoms overall. Calculation of the percentage of total improvement scores revealed that the herbal combination is superior to the standard pharmacological agent mebeverine for the treatment of IBS (Darvish-Damavandi et al., 2010). The results of this study show that the herbal combination is well tolerated by all patients; no side effects were reported during the study by patients taking the herbal combination. Moreover, patients requested additional capsules containing this herbal combination following the conclusion of the study, which supports its efficacy, safety and tolerability. In conclusion, this study showed that patients with IBS may benefit from 8-weeks of treatment with a capsule containing a herbal combination of powders derived from Mentha longifolia, Cyperus rotundus and Zingiber officinale. The improvement in IBS symptoms with this herbal combination was comparable to that of the standard pharmacological agent mebeverine, and no adverse effects were reported during the course of the study. These results support the efficacy and safety of the herbal combination to treat IBS.
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Journal of Ethnopharmacology journal homepage: www.elsevier.com/locate/jep
Ethnopharmacological communication
Treatment of irritable bowel syndrome using a selected herbal combination of iraqi folk medicines Ahmed Salih Sahib n Department of Pharmacology, Al-Kindy College of Medicine, University of Baghdad, Baghdad, Iraq
art ic l e i nf o
a b s t r a c t
Article history: Received 9 September 2012 Received in revised form 4 May 2013 Accepted 6 May 2013 Available online 23 May 2013
Ethnopharmacological relevance: Mentha longifolia, Cyperus rotundus and Zingiber officinale are widely used in Iraqi traditional medicine for the treatment of multiple gastrointestinal diseases. The aim of this study was to examine the effectiveness of a combination of three herbal agents that are widely used in folk medicine in Iraq for the treatment of patients with irritable bowel syndrome (IBS). Materials and methods: A prospective randomised clinical study was carried out on 40 patients of both sexes between 25 and 60 years of age who had been diagnosed with IBS for 5–10 years. The patients were allocated to one of two groups, each consisting of 20 patients. Group A was treated with mebeverine, and Group B was treated with a capsule containing a combination of the following three herbs prepared as fine powders: Mentha longifolia, Cyperus rotundus and Zingiber officinale. IBS symptoms were assessed before and after 8 weeks of treatment. Results: Treatment of IBS patients with the herbal combination resulted in improvements in all of their IBS symptoms after 8 weeks, as revealed by increase in their individual symptom scores and in their mean total improvement percentages. These results were comparable to those produced by the standard agent mebeverine. Conclusion: Patients with IBS showed significant improvements in their IBS symptoms after 8-weeks of treatment with the herbal combination and did not report any adverse effects during their treatment. These results support the efficacy and safety of the herbal combination for the treatment of IBS. & 2013 Elsevier Ireland Ltd. All rights reserved.
Keywords: Irritable bowel syndrome Folk Medicine Herbal Medicine
1. Introduction Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder. It is characterised by chronic abdominal pain or discomfort and altered bowel function. The symptombased Rome III criteria for the diagnosis of IBS include recurrent abdominal pain or discomfort for, at least 3 days per month in the past 3 months, and at least two of the following: improvement of pain with defecation, onset of pain that is associated with a change in the frequency of stool, or onset of pain that is associated with a change in the form (appearance) of stool (Longstreth et al., 2006). With an estimated prevalence of 14–24% in women and 5–19% in men, IBS is a common reason for seeking medical care (Andrews et al., 2005). It accounts for 12% of visits to primary care physicians and 28% of visits to gastroenterologists (Dean et al., 2005). In addition, IBS is associated with significantly impaired quality of life and significantly increased economic costs (Chang, 2004). Despite recent advances in the treatment of IBS, the pathophysiology of IBS is incompletely understood (Mathew and Bhatia, 2009). Alterations in neurohormonal function, psychological factors,
n
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bacterial overgrowth, genetic factors, changes in gut motility, visceral hypersensitivity, and immune system changes are currently believed to influence the pathogenesis of IBS (Longstreth et al., 2005). Patients can be divided into three IBS subgroups: those with constipation, those with diarrhoea, and those with alternating constipation and diarrhoea (Mearin et al., 2003). Because of its complex pathogenesis, a drug that treats all of the underlying abnormalities of IBS has not been identified. The use of dietary fibres, laxatives, antidiarrheal agents, and antispasmodic agents as first line therapies has been limited owing to their marginal therapeutic benefits, and side effects. Antidepressants have proved to be efficacious for improving symptoms and psychological well-being. However, their use has been limited by side effects and poor acceptance by patients. Modulators of serotonin receptors have recently been developed and initially showed promising therapeutic effects (Lacy et al., 2009). Over the past 2 decades, there has been a focus on smooth muscle relaxants (commonly called antispasmodics) for the treatment of IBS. Mebeverine is a commonly prescribed drug that has been used successfully for many years for the management of IBS. Mebeverine is a musculotropic agent that has antispasmodic activity and regulatory effects on bowel function (Talley, 2001). During oral administration of doses of 135–270 mg three times daily, mebeverine does not cause anticholinergic side effects such as dry mouth, blurred vision,
A.S. Sahib / Journal of Ethnopharmacology 148 (2013) 1008–1012
or impaired micturation. The incidence of side effects caused by mebeverine is no higher than that produced by treatment with a placebo (Poynard et al., 1994). Because of the lack of a cure for IBS and the adverse effects of medications used to treat this disorder, many patients consider conventional IBS treatment to be disappointing and often turn to complementary therapies. The choice to use natural rather than chemical therapies is appealing because many patients assume that natural products are safe and that they do not cause adverse effects. Additionally, because technology has supplanted bedside manner, the deteriorating relationship between patients and physicians also encourage the use of complementary and alternative medicine, giving patients a greater sense of autonomy in their care. Because of the substantial impact of complementary and alternative medicine on both individual patients and society, it is crucial for health care providers to gain a better understanding of the potential benefits and pitfalls of complementary and alternative medicine (Tillisch, 2006; Stake-Nilsson et al., 2012). Herbal medicines have been used in Asia for a long time, and, an increasing number of IBS patients in the West are beginning to take complementary and alternative medicines, most frequently herbal remedies (Magge and Lembo, 2011). One important herbal agent that is widely used by IBS patients is peppermint oil, an oil extract of the Mentha piperita Linnaeus plant that has been used to treat upset stomach for thousands of years. Peppermint oil has been shown to relax intestinal smooth muscle cells by inhibiting calcium channels (Kligler and Chaudhary, 2007). Short term trials have suggested that the daily use of 3–6 enteric coated capsules containing 0.2–0.4 mL of peppermint oil improved IBS symptoms (Cappello et al., 2007). The major advantage of peppermint oil for the treatment of IBS is its safety profile; common side effects include heart-burn and a perianal burning sensation (Kline et al., 2001). The active ingredient in peppermint oil is menthol (C10H20O) a terpenoid that is found in the essential oils of members of the mint family (Mentha spp.), including Mentha piperita and Mentha longifolia (Al-Bayati, 2009). Mentha longifolia is an extremely variable species with a widespread distribution in Iraq. In Iraqi folk medicine, the leaves and stems of Mentha longifolia species are frequently used in herbal teas or as additives in spice mixtures. As a folk remedy Mentha longifolia is used to treat nausea, and flatulence, and it is used as an anti-inflammatory, carminative, analgesic, and antispasmodic agent (Al-Rawi and Chakravarty,1988). Cyperus rotundus is another traditional herbal medicine that grows naturally in Iraq. It is widely used as an analgesic, sedative, and antispasmodic agent and for the treatment of stomach disorders and diarrhoea (Zhu et al., 1997). The tuber part of Cyperus rotundus is widely used as a folk medicine, especially by older women, for its carminative, antispasmodic, analgesic anti-
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diarrheal properties. Previous phytochemical studies have shown that the major chemical components of this herb are essential oils, flavonoids, terpenoids, and mono- and sesquiterpenes (Nima et al., 2008). Ginger was also used as an herbal agent in this study. Ginger (Zingiber officinale, Zingiberaceae) has several ethnomedicinal and nutritional attributes, and is used extensively throughout the world as a spice, a flavouring agent and an herbal remedy (Gaurav et al., 2011). In Iraq, this herb is imported from other countries and is commonly used as a food additive and a spice. It is also used as a treatment for several different conditions, particularly those associated with digestive problems such as dyspepsia, flatulence, nausea and abdominal pain. Only recently has this plant been cultivated in Iraq (AL-Bayaty et al., 2006). Choosing the appropriate outcome measures and therapeutic regimens for complementary and alternative medicine studies requires a good understanding of the expected role of a given therapy in the treatment of a gastrointestinal disorder (Tillisch, 2006). For example for the treatment of IBS, adminstration of peppermint may be useful for its muscle relaxant effect. Cyprus rotundus administration may be useful for its antimicrobial effect, and administration of ginger may be useful for its antiflatulent effect. In this way, the multiple manifestations of IBS can be specifically targeted using different herbal agents. The aim of this study was to examine the effectiveness of a combination of three herbal agents, Mentha longifolia, Cyperus rotundus and Zingiber officinale, in their powder form, for the treatment of patients with IBS.
2. Materials and methods This prospective randomised clinical study was carried out on 40 patients of both sexes between 25 and 60 years of age who had been diagnosed with IBS for 5–10 years, and who had visited the outpatient clinic at the Al-Kindy College of Medicine during a 6month period. The study followed the guidelines outlined in the Declarations of Helsinki and Tokyo for the ethical use of human subject in research and was approved by the scientific and ethical committees at Al-Kindy College of Medicine. All patients provided informed consent. The patients that participated in this study were allocated to one of two groups: 1. Group A included 20 patients of both sexes treated with tablets containing 135 mg of mebeverine three times daily for 8 weeks. Mebeverine (tradename Colospasmin Forte, 135 mg tablet) was obtained from EIPICO, Egypt. 2. Group B included 20 patients of both sexes treated with a capsule containing a combination of the following three herbs
Table 1 Effects of treatment with 135 mg of mebeverine (Group A, n¼ 20), three times daily, on the distribution of symptom severity in IBS patients. Symptom
Mild
Moderate
Pre Pain severity Pain frequency Stool frequency Stool consistency Abdominal distension Incomplete evacuation Urgency Passing of mucus Mean
5 4 7 6 5 5 4 6 5.25
Post (25%) (20%) (35%) (30%) (25%) (25%) (20%) (30%) (26.25%)
1 2 5 4 3 4 3 4 3.25
(5%) (10%) (1%) (20%) (15%) (20%) (15%) (20%) (16.25%)a
Results represent a percentage of the total number of IBS patients. a
Denotes a statistically significant change (P≤0.05) in symptom severity.
Severe
Pre
Post
9 (45%) 8 (40%) 8 (40%) 7 (35%) 9(45%) 8 (40%) 7 (35%) 8 (40%) 8 (40%)
4 3 3 2 2 1 3 3 2.63
(20%) (15%) (15%) (10%) (10%) (5%) (15%) (15%) (13.12%)a
Pre
Post
6 (30%) 8 (40%) 5(25%) 7 (35%) 6 (30%) 7 (35%) 9(45%) 6 (30%) 6.75 (33.75%)
1 1 0 1 0 0 1 1 0.625
(5%) (5%) (0%) (5%) (0%) (0%) (5%) (5%) (3.13%)a
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prepared as fine powders: leaves part of Mentha longifolia (150 mg), tubers part of Cyperus rotundus (150 mg) and tubers part of Zingiber officinale (150 mg). The capsules were taken three times daily 1 h after meal for 8 weeks. The herbal agents were obtained from a local market and approved by the National Centre of Herbal Medicine at the Ministry of Health in Iraq.
The inclusion criteria were as follows: the patients fulfilled Rome III's diagnostic criteria for IBS, and the patients did not suffer from endocrine illness or structural organic gastrointestinal abnormalities, such as inflammatory bowel disease (Crohn's disease and ulcerative colitis), diverticular disease, colorectal carcinoma, intestinal obstruction, peptic ulcer disorders, or biliary tract disorders. Women who were breast feeding or pregnant, patients with chronic cardiovascular disease and patients with thromboembolic disease were excluded from the study. A full history was taken from each patient. Each patient was also subjected to a general and systemic physical examination that included a thorough examination of the abdomen and abdominal ultrasound to exclude biliary tract. The presence of gases causing distension of the colon, which is suggestive of IBS, was documented. All patients underwent a flexible sigmoidoscopic examination to exclude inflammatory bowel diseases, colorectal carcinoma, and diverticular diseases. Patients follow up occurred at 8 weeks interval. The medications were taken for the first time by the patients during the visit. Thereafter, patients were told to call the doctor by phone as needed. Contact information was collected from all patients, and patients were contacted periodically to ensure that medications were been taken as prescribed. Patient examinations were performed, and histories were taken by consulting physicians at the consulting clinic at the Al-Kindy College of Medicine.
Data were collected using a questionnaire that evaluated the presence of IBS symptoms based on the Rome III criteria for the diagnosis of IBS. The following symptoms were evaluated: pain severity, pain frequency, stool frequency, stool consistency, abdominal distension, incomplete evacuation, urgency and passing of mucus. Changes in symptoms following treatment were scored as follows: symptom improvement was scored as plus one (+1), no improvement was scored as zero (0), and worsening of a symptom was scored as minus one (−1). Descriptive analyses are summarised as percentages. Student's t-test was used to determine the significance of the results. A P-value of ≤0.05 was considered to be statistically significant.
3. Results Table 1 shows the severity distribution of the IBS symptoms studied in group A (mebeverine). The severity distribution as a mean percentage of total was as follows: 26.25% of cases were mild, 40% were moderate and 33.75% were severe. Following treatment with 135 mg of mebeverine three times daily for 8 weeks, the mean symptom severity significantly (P≤0.05) reduced this per cent by 10% in mild cases, 26.88% in moderate cases and by 30.62% in severe cases Fig. 1. The results presented in Fig. 1 clearly show that the reduction in the symptom severity profile of IBS patients treated with mebeverine was greater among those patients initially classified as having severe symptoms, compared to those patients initially classified as having moderate or mild symptoms. Treatment with the herbal combination capsules, taken three times daily for 8 weeks, also significantly (P≤0.05) reduced the mean symptom severity in patients initially classified as having mild, moderate or severe IBS symptoms, by 17.5%, 28.75% and 26.87%, respectively folds for the categories mild, moderate and severe respectively (Table 2, Fig. 2).
26.88
30
40
30.62
% Reduction
% Reduction
40
20 10
10 0
30 20
Moderate
Severe
Fig. 1. Effects of mebeverine on the severity profile of IBS symptoms.
26.87
Moderate
Severe
17.5
10 0
Mild
28.75
Mild
Fig. 2. Effects of the herbal combination on severity profile of IBS symptoms.
Table 2 Effects of treatment with the herbal combination capsule (Group B, n¼ 20), taken three times daily, on the distribution of symptom severity in IBS patients. Symptom
Pain severity Pain frequency Stool frequency Stool consistency Abdominal distension Incomplete evacuation Urgency Passing of mucus Mean
Mild
Moderate
Pre
Post
7 (35%) 5 (25%) 7 (35%) 8 (40%) 6 (30%) 5(25%) 5 (25%) 7 (35%) 6.25 (31.25%)
4 3 4 3 2 2 3 1 2.75
(20%) (15%) (20%) (15%) (10%) (10%) (15%) (5%) (13.75%)a
Results represent a percentage of the total number of IBS patients. a
Denotes a statistically significant change (P≤0.05) in symptom severity.
Severe
Pre
Post
8 (40%) 10(50%) 9 (45%) 7 (35%) 8 (40%) 7 (35%) 7 (35%) 8 (40%) 8 (40%)
2 3 3 2 2 2 1 3 2.25
(10%) (15%) (15%) (10%) (10%) (10%) (5%) (15%) (11.25%)a
Pre
Post
5(25%) 5(25%) 4 (20%) 5 (25%) 6 (30%) 8 (40%) 8 (40%) 5 (25%) 5.75 (28.75%)
0 1 0 1 0 0 0 1 0.38
(0%) (5%) (0%) (5%) (0%) (0%) (0%) (5%) (1.88%)a
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4. Discussion In folk medicine, various drugs are used alone or in combination forms with considerable success to treat different types of conditions. Although many of these drugs have been in use for a long time, and their medicinal applications and general safety are well-known, in many cases, their use as therapeutic agent has not been evaluated using standard methodologies. Scientific studies are therefore required to assess their safety and efficacy (Shen and Nahas, 2009). Because of low levels of satisfaction that have been reported for current treatments of IBS (Thompson et al., 2000), the adverse effects that are associated with the medications that are used, and the lack of a cure for this disorder, 50% of patients with IBS worldwide have turned to complementary and alternative therapies, and to herbal medicines in particular, to treat their IBS (Hussain and Quigley, 2006). Peppermint oil has been used to treat many gastrointestinal disorders for a long time. It has been used primarily for its antispasmodic properties (Liu et al., 1997). The therapeutic benefit of peppermint oil is supported by two meta-analyses; the first meta-analysis reviewed five clinical trials that suggested its efficacy (Pittler and Ernst, 1998), and the second meta-analysis reviewed four small trials and found overall symptom improvement with peppermint oil (Spanier et al., 2003). It is well known that the principal active ingredient in peppermint oil is menthol, a cyclic monoterpene that relaxes smooth muscle by blocking calcium influx (Hills and Aaronson, 1991). Menthol is found in
the essential oils of all members of the mint family (Mentha spp.), including peppermint (Mentha piperita) and horse mint (Mentha longifolia); these mint species are highly distributed as wild herbs in Iraq (Al-Bayati, 2009). In this study, a fine powder derived from crude Mentha longifolia and encapsulated with other herbs was used for the treatment of IBS symptoms; this herb may have contributed, in part, to the improvements in IBS symptoms that were observed. Cyperus rotundus is another herbal agent that was used in this study. Although there is a strong precedence for the use of Cyperus rotundus to treat various digestive tract disorders in folk medicine (Jagtap et al., 2004), there is no evidence in the scientific literature to support the use of Cyperus rotundus to treat IBS. However, Uddin et al. (2006) have shown that when administered orally, the methanolic extract from Cyperus rotundus rhizomes has significant antidiarrheal activity in experimental animals. It is through its antidiarrheal action that Cyperus rotundus might improve symptoms in IBS patients that suffer from diarrhoea. Moreover, because IBS is associated with bacterial overgrowth (Di Stefano et al., 2000), the antibacterial action of Cyperus rotundus on enteric bacteria (Kilani et al., 2008) might account for the observed improvements in abdominal distension and pain resulting from abnormal intestinal gas production as well as the observed improvement in other symptoms, such as incomplete evacuation, stool frequency and stool consistency (Nobaek et al., 2000). The third herbal component used in this study was ginger. Ginger is used to treat many gastrointestinal related illnesses, including nausea, vomiting and motion sickness, and is used as a
Improvement percent
Table 3 shows the percentage improvement of the IBS symptom scores after 8 weeks of administration of the agents tested. In both groups A and B, the amount of improvement was different for each symptom studied. Overall, symptom improvement was good, and in no patients did IBS symptoms worsen. The mean of the total improvement percentage in patients treated with mebeverine (group A) was 66.88%. The mean total improvement percentage 3.12% lower than the 70% mean total improvement that was observed in patients treated with the herbal combination (group B). This difference is not statistically significant (Fig 3). These data demonstrate the effectiveness of the herbal combination used in this study for IBS. The herbal combination significantly reduced the incidence and severity of all IBS symptoms to a level that was comparable to that produced by the standard agent mebeverine. Additionally, the herbal combination was not associated with the worsening of any of the IBS symptoms studied, nor were any side effects reported during the study. These results support the safety and efficacy of the agents studied.
1011
90
Group A
80
Group B
70 60 50 40 30 20 10 0
Fig. 3. Improvement of IBS symptoms after 8 weeks of treatment with mebeverine (Group A) or the herbal combination (Group B).
Table 3 Improvements in the symptoms of IBS patients after 8 weeks of treatment. Symptoms
Pain severity Pain frequency Stool frequency Stool consistency Abdominal distension Incomplete evacuation Urgency Passing of Mucous Mean of total per cent
Group A, n ¼20
Group B, n¼20
+1
0
−1
+1
0
−1
14(70%) 14(70%) 12(60%) 12(60%) 15(75%) 15(75%) 13(65%) 12(60%) 66.88%
6(30%) 6(30%) 8(40%) 8(40%) 5(25%) 5(25%) 7(35%) 8(40%) 33.12%
0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0%
14(70%) 13(65%) 13(65%) 13(65%) 16(80%) 14(70%) 14(70%) 15(75%) 70%
6(30%) 7(35%) 7(35%) 7(35%) 4(20%) 6(30%) 6(30%) 5(25%) 30%
0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0(0.0%) 0.0%
Group A was treated with mebevrine; and Group B was treated with the herbal combination. Results represent the percentage of the total number of IBS patients; (+1) denotes symptom improvement, (0) denotes no improvement of symptom, and (−1) denotes symptom worsening. * Denotes a statistically significant change (P≤0.05) in symptom severity.
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carminative and antiulcer agent (White, 2007). Very few randomised clinical trials in humans have evaluated the use of ginger as a carminative agent or as an ulcer remedy. In one study, the efficacy of ginger for the treatment of functional dyspepsia was evaluated in 11 patients in a randomised double-blind manner. After an 8-h fast, the patients ingested three capsules containing ginger (1.2 g total) or placebo, followed after 1 h by 500 mL of lownutrient soup. This study showed that ginger stimulates gastric emptying and antral contractions in patients with functional dyspepsia (Hu et al., 2011). Although complementary and alternative medicine is commonly used to treat IBS, no clinical trials have been conducted to date to evaluate the efficacy of ginger for the treatment of IBS. One study did evaluate the use and economic cost of complementary and alternative medicines to treat functional bowel disorder. This study showed that ginger root and ginger/tea were useful in 14.8% of the IBS patients studied. However, the clinical setting in which this study was conducted is unclear (Van Tilburg et al., 2008). The results of this study clearly show that administration of the herbal combination of Mentha longifolia, Cyperus rotundus and Zingiber officinale results in an improvement in individual IBS symptoms and in IBS symptoms overall. Calculation of the percentage of total improvement scores revealed that the herbal combination is superior to the standard pharmacological agent mebeverine for the treatment of IBS (Darvish-Damavandi et al., 2010). The results of this study show that the herbal combination is well tolerated by all patients; no side effects were reported during the study by patients taking the herbal combination. Moreover, patients requested additional capsules containing this herbal combination following the conclusion of the study, which supports its efficacy, safety and tolerability. In conclusion, this study showed that patients with IBS may benefit from 8-weeks of treatment with a capsule containing a herbal combination of powders derived from Mentha longifolia, Cyperus rotundus and Zingiber officinale. The improvement in IBS symptoms with this herbal combination was comparable to that of the standard pharmacological agent mebeverine, and no adverse effects were reported during the course of the study. These results support the efficacy and safety of the herbal combination to treat IBS.
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