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J Arch Mil Med. 2015 August; 3(3): e30057. DOI: 10.5812/jamm.30057 Published online 2015 August 24. Assessment of Consensus-Based Pharmacological Therapies in Irritable Seyed Reza Abtahi 1,*; Parvin Zareian 11Department of Physiology and Pharmacology, School of Medicine, AJA University of Medical Sciences, Tehran, IR Iran*Corresponding author: Seyed Reza Abtahi, Department of Physiology and Pharmacology, School of Medicine, AJA University of Medical Sciences, Tehran, IR Iran. Tel: +98-2188337909, Received: May 18, 2015; Revised: May 26, 2015; Accepted: June 8, 2015
Context: The irritable bowel syndrome (IBS) is a symptom-based gastrointestinal (GI) disease with the presence of symptoms such as
abdominal pain and abnormal intestinal activities. It is a frequent GI problem encountered by physicians. The purpose of this paper was to review and assess some of the current and emerging pharmacological therapies for this syndrome.
Evidence Acquisition: In the present study, data on the IBS were principally collected via Google Scholar and PubMed, followed by articles
in journals and libraries.
Results: The pathophysiology of the IBS has yet to be fully elucidated. Global medical attempts, including pharmacological therapy and
herbal remedies, aim at curing and/or subsiding pain, flatulence, diarrhea, and constipation.
Conclusions: There is a need for new drugs in the setting of pharmacological therapy for the IBS. A new medical approach should include
both novel and traditional drugs in order to reach to a desirable outcome for patients and improve their quality of life.
Keywords: Diagnosis; Irritable Bowel Syndrome; Physiopathology; Pharmacotherapy 1. Context
The irritable bowel syndrome (IBS) is a functional gas- organic disease (7). The Manning criteria were improved trointestinal (GI) tract disturbance affecting a consider- and published as the Rome I criteria in 1990. These new able portion of the general population and is responsible criteria were more detailed and contained more useful for a large number of visits to physicians. The salient definitions of the syndrome (8). A decade later, the Rome characteristic of the IBS is recurrent abdominal pain/ I criteria were revised and upgraded into the Rome II discomfort with a concurrent disturbance in defecation criteria in order to suggest a relation between pain and (1). The IBS encompasses a wide array of physiological stool consistency (8, 9). Ultimately, the Rome III criteria and psychological signs and symptoms which affect the were presented in 2006 (10). The Rome III is a precise and cerebro-intestinal regulation, GI tract activity, and viscer- more specified modification of the Rome II criteria. In the al perception (1, 2). The symptoms include altered bowel Rome III, pain must be confirmed at least 3 days a month habits, without any organic pathology (3). Considerable in the previous 3 months (10). Hence, it is now possible to evidence suggests that most patients with the IBS appear determine the exact prevalence and incidence of the IBS to have an enhanced perception of the overdistension of in accordance with the Rome criteria and forge compat- their rectum. This visceral hypersensitivity is presented ibility in the studies conducted in this field. by an increased intensity of sensations, intolerable intes- The IBS exerts a negative influence on the lifestyle and tinal pain, and/or propagated viscerosomatic referral in daily activity of many of its sufferers (11-14), but it is still comparison to healthy subjects (4). Patients with the IBS not clear whether it increases the patients' mortality and demonstrate a number of other symptoms such as back morbidity. What is clear, however, is that this syndrome pain, migraine headaches, epigastric pain, dyspareunia, places a substantial financial burden on health care sys- and myalgia compatible with the possibility of central tems. The diagnosis of the IBS is made based on the crite- pain hypersensitivity mechanisms (5).
ria and exclusion of organic disease (10% - 15%) (11). The IBS The IBS is a common gastrointestinal disease respon- was once thought to be common in females exacerbated sible for the patients' referral to GI tract specialists (6). by anxiety and depression. Recent statistical analyses The first symptom-based criteria for the evaluation of have, nonetheless, suggested that the female gender is the IBS were presented in 1978 by Manning et al. (7). The no longer a risk factor (15).
Manning criteria classified patients with abdominal The prevalence of the IBS is on the increase in devel- pain on the basis of whether or not they suffered from oped and particularly in developing countries. Pharma- Copyright 2015, AJA University of Medical Sciences. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommer- cial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited.
Abtahi SR et al. cological agents are used widely in all countries; some of havior approximately once a year (20, 21), and some suf- these agents have proved their efficacy, while others have fer from gastric emptying, especially of solid foods (24- achieved partial clinical benefits (16). A review of psycho- 26), which is particularly considerable in patients with logical factors in patients who respond to specific psy- constipation (27, 28). Furthermore, emotional status and chological treatment plays a key role in their follow-up anxiety attenuate the contractility of the stomach and (17). To ensure simplicity, the present study does not delve lead to delayed emptying in comparison with healthy into the details of statistical procedures.
individuals (29). The peristaltic activity of the small in- testine is faster in the IBS-D than in the other two types 2. Evidence Acquisition
(30). Colonic distension (an intestino-intestinal inhibi- tory reflex that decreases duodenal motility) is impaired (31). Disturbed contractile activity is responsible for these 2.1. Methodology clinical features (32, 33). In these patients, postprandial The databases drawn upon for data acquisition in the peristaltic hyperactivity and propagated motor response present study were Google Scholar, PubMed, and librar- are more severe than those in healthy individuals (34-37).
ies and journals of the medical universities of the Islamic Republic of Iran as well as AJAUMS. The focus, however, 3.3. Bloating was on the data published in the English language in the Abdominal pain and abnormal gas handling as a result last 25 years, and in particular the past 10 years.
of gas retention are very common. Abnormal contrac- tile activity, accompanied by visceral hypersensitivity, is 3. Results
more important than abdominal distention due to intes- tinal gas (33). It has been reported that patients suffering 3.1. Clinical Manifestation of Irritable Bowel Syn- from bloating have disturbed transit of extrinsic excess gas, which exacerbates their symptoms (25). Nutrition, physical activity, and body posture are factors that may The cardinal manifestations of the IBS consist of con- alleviate this problem (38-42).
tinuous or relapsing abdominal pain and/or bloating, ac- Ninety-six per cent of individuals suffer from abdomi- companied by change in defecation behavior, in the lack nal gas retention, which is more frequent in women (43). of constitutional disorders probable to assess for these However, this is not considered a differentiated character symptoms. Subjects are observed for over 6 months to but an important feature of the syndrome (10). The pa- evaluate the presence of other diseases such as temporary tients tend to complain of a diurnal starting of abdomi- infections or the GI tract malignancy, which are detected nal gas excess, especially postprandial, which usually approximately within 6 months of symptom onset (18-20).
subsides or is relieved by the evening, which helps to de- Based on the predominant defecation pattern, the IBS termine the differential diagnosis of abdominal swelling is sub-classified to diarrhea predominant (IBS-D) and such as an ovarian cyst or ascites (44, 45). Distension is constipation predominant (IBS-C). Additionally, a mixed only consistent with bloating in the IBS-C patients (60%) bowel pattern (IBS-M) with both loose and hard stool is in comparison with the IBS-D patients (40%) (45).
noted (18-20).
According to the Rome III criteria, the main manifesta- 3.4. Serotonin (5-HT) Role in Motility and Secretion tions of the IBS are abdominal discomfort, which is obvi- ously related to intestinal dysfunction and is alleviated by defecation, and alteration in stool frequency or con- It is obvious that serotonin functions as a crucial neu- sistency. The most common clinical features are bloating, rotransmitter in the GI tract and participates in the abnormal stool form and frequency, abdominal cramp, pathophysiological status of the IBS. Serotonin modu- and mucus in feces. The patients tend to complain of the lates the GI autonomic nervous system, which influences intervals of remission and the exacerbation of the symp- the enhancement or inhibition of the GI secretion and toms (21, 22).
motility. Abnormality in the serotonin signaling path- way gives rise to various annoying features of the disease 3.2. Abnormal Esophageal, Gastric, Small Intesti- (46). Serotonin excess is consistent with the IBS-D, and nal, and Colonic Motility the inadequate secretion of serotonin is an important factor in the manifestation of the IBS-C. What confirms Large and small intestine activity is widely studied in this hypothesis is that the postprandial blood levels of the IBS. There are some reports on the esophagus and serotonin in individuals with the IBS-D are elevated. In stomach motility dysfunction. These malfunctions de- addition, the platelet-depleted plasma 5-HT levels are crease the lower esophageal sphincter pressure and lead elevated before and after meals. The tissue level of 5-hy- to abnormal contraction activity (23). Abnormal colon droxyindoleacetic acid (5-HIAA)/5-HT ratio is attenuated activity is known as the spastic and irritable colon (8). in individuals with the IBS-C, and there is a remarkable Twenty per cent of individuals alter their defecation be- deficit in high plasma 5-HT fed levels in individuals with J Arch Mil Med. 2015;3(3):e30057

Abtahi SR et al. the IBS-C (46). Serotonin is gathered in the special cells larly specialized for the management of this syndrome (enterochromaffin cells) of the GI system and plays a cru- in recent years. Therapeutic protocols recommend that cial role in the contractile activity, visceral sensitivity, and the patient's predominant complaint such as pain, con- gut secretion (47). stipation, and diarrhea be addressed first and foremost. For the treatment of the symptoms of the IBS-D in fe- Multiple drugs are used for the management of this syn- males, the 5-HT3 antagonists are used widely. Ischemic drome, albeit with low effect on subsiding pain and gas colitis is an untoward effect and limits the prescription of retention. Therapeutic goals emphasize on the control these agents. Moreover, the 5-HT4 agonists have been ap- of the autonomic nervous system in the GI tract in order proved for use in the management of the IBS-C in women to improve bowel habits following the relaxation of the as well as in the other constipation categories.
smooth muscle cells. This intervention attenuates the Serotonin is responsible for visceral hypersensitivity visceral noxious perception signaling. In the motility dys- and contractile activity, and also participates in the mod- function of the GI tract, increasing or decreasing intesti- ulation of the GI tract secretion and absorption (48, 49). nal contractile activity is crucial (36, 50, 51). The chemical It has been suggested that the 5-HT4 receptor agonists structures of some agents are depicted in Figure 1.
enhance the release of water and electrolytes in the small intestine (49).
3.6. Drugs Acting on Central Nervous System 3.5. Consensus-Based Pharmacological Treatment Some drugs function within the central nervous system for Irritable Bowel Syndrome (CNS). Dextofisopam is an R-enantiomer of tofisopam that binds to a specific site of the gamma-aminobutyric The pharmacological management of the IBS, albeit cru- acid (GABA) receptors, inhibiting nerve signaling, and its cial, presents the prescriber with a major therapeutic di- advantages in the management of the IBS-D have been lemma. There have been no highly specific drugs particu- previously approved (52).
Figure 1. Chemical Structures of Some Agents
J Arch Mil Med. 2015;3(3):e30057 Abtahi SR et al. 3.7. Kappa (κ)-Opioid Receptor Agonists the United States food and drug administration (FDA). Visceral pain control in the GI system is a target for drug This drug is recommended for female patients who suf- prescription. Peripheral κ-opioid receptor agonists block fer from the relapsing symptoms of the IBS-D (67), and a the signaling of the afferent pain perception from the in- meta-analysis study has demonstrated its advantages in testines with no untoward effects such as dependency and females with the IBS-D (68, 69). Alosetron is more effec- constipation, which are observed in μ opioid agonists. tive than placebo in relieving visceral hypersensitivity Kappa receptors are distributed in the stomach, large and improving abnormal defecation behavior, stool con- intestine, and cerebrum (53, 54). Asimadoline, a selective sistency, and colonic spasm; nevertheless, the drug is ab- κ-opioid receptor agonist, possesses a low blood-brain solutely contraindicated in constipation (68-70). Cilanse- barrier penetration potency and a negligible concentra- tron is a newer similar agent for the management of the tion level in the CNS. Its analgesic effect is modulated IBS-D and is prescribed for 3 to 6 months to treat noxious by the attenuation of nerve excitement (55, 56). Many visceral perception and disturbed bowel habits in all pa- human studies have shown that asimadoline decreases tients (67, 71). The 5-HT4 receptor agonists modulate the intestinal pain perception with no serious side effects visceral afferent function. The probable mechanism is (53-57). The potential and favorable role of the drug in the the release of acetylcholine via the presynaptic 5-HT4 re- management of the IBS has led to further research (57), ceptor on the cholinergic neurons. Tegaserod is a strong, and statistical studies have shown defined and promis- bearable aminoguanidine indole selective partial ago- ing advantages in the control of visceral noxious percep- nist at the 5-HT4 receptor and has been approved for the tion and disturbed bowel habits in the D-IBS (58).
management of the IBS-C (72). This agent has been evalu- ated in well-extended studies (16, 72) and has prokinetic effects in the small and large intestines (72-74). Tegaserod 3.8. Antispasmodic Drugs accelerates the upper and lower intestine contractile ac- Anticholinergic agents inhibit the muscarinic recep- tivity, induces prokinetic effects on the stomach, enhanc- tors in the GI tract, decelerating the propagated contrac- es bowel secretion, and improves constipation in women tile activities before and after meals, particularly in the with the IBS-C (75). The advantages are those associated IBS-D (36). The efficacy of antispasmodic agents has been with defecation frequency (76). Some studies have shown evaluated by several meta-analyses (59-62). that this drug enhances the quality of life (72, 74). The Hyoscine, peppermint oil, and cimetropium are an- most common untoward effect of tegaserod (6 mg twice tispasmodic and relax the smooth muscle cells of the daily) is predictably diarrhea (77). Prucalopride is a newer GI system (anticholinergic). Colonic spasm is a noxious 5-HT4 receptor agonist and has acceptable advantages in symptom and a target of antispasmodic gents (63).
the management of the IBS-C. In Europe, this drug is rec- The nonspecific antagonists of the muscarinic recep- ommended for the treatment of recurrent constipation tor are dicyclomine and hyoscyamine (tertiary amines) in females (78).
as well as glycopyrrolate (quaternary ammonium com- pound) and methscopolamine. The low lipid solubility of 3.10. 5-HT4 Receptor Agonists/5-HT3 Receptor An- the latter two compounds decreases the brain-blood bar- rier passage and lessens the CNS untoward effects such as drowsiness and nervousness (64).
Renzapride is a mixed serotonin receptor agonist/an- Mebeverine is a musculotropic antispasmodic agent tagonist. It may be more effective than a single agent and and a derivative of hydroxybenzamide. It has a direct ef- is prescribed for the therapeutic management of the IBS- fect on smooth muscle cells and blocks Na+, K+, and Ca2+ C. This drug facilitates motility thanks to its 5-HT4 recep- channels (64). Mebeverine has no serious side effects and tor agonist mechanism, although its efficacy in the treat- is used before meals. The efficacy of the drug in compari- ment of the IBS has yet to be documented (79).
son with placebo has been confirmed (64). 3.11. Aminobutyric Acid Analogue 3.9. 5-HT3 Receptor Antagonists Pregabalin is a novel, second-generation γ-aminobutyric acid (GABA) analog (α2δ ligand). It attenuates nerve ac- The 5-HT3 receptor acts in the sensitization of the spi- tion potential and blocks the release of excitatory neu- nal sensory neurons, nausea stimulating vagal nerve, rotransmitters associated with depolarization-induced and peristaltic reflexes (49, 65). Alosetron is a potent calcium influx (80, 81). The effectiveness of pregabalin in 5-HT3 receptor antagonist and is more effective than an- the management of pain with different origins has been tispasmodic agents (49). It inhibits basal secretion in the demonstrated (80, 81).
healthy jejunum (66) and is prescribed to improve the quality of life in the IBS-D females (67). Ischemic colitis 3.12. Drugs Affecting Chloride Channels in Gastro- and constipation are the untoward effects of alosetron, intestinal Tract and they resulted in the withdrawal of this drug from the market in 2000. Alosetron was reintroduced in 2002 by Some agents act on the chloride channels by activating J Arch Mil Med. 2015;3(3):e30057 Abtahi SR et al. or inhibiting the efflux of chloride ions into the lumen peripheral anticholinergic and non-SSRI effects. TCAs are of the GI tract. This phenomenon results in the mainte- prescribed in a various neurotic and visceral pain (89). nance of isoelectric equilibrium and isotonic environ- The drugs may change pain perception (90), especially ment by moving water in the GI tract lumen and sodium during severe stress (93), in addition to their antidepres- efflux subsequently. Accelerated intestinal secretion and sant or antianxiety effects (90). Many studies have shown excess fluid volume provide a new opportunity for the that low-dose TCAs effectively decrease symptoms. Ami- management of the patients suffering from prolonged triptyline, trimipramine, desipramine, clomipramine, constipation and the IBS-C (82, 83).
and doxepin possess the pharmacological efficacy and potency to relieve pain. Mianserin is an SSRI and has simi- 3.13. Activators lar effects. The initial analgesic effects of these drugs have led to the continuous use of these agents in individu- Lubiprostone activates the chloride ions channels. The als with the IBS-D (94). The untoward effects of TCAs are FDA recommends this agent for the management of the parasympatholytic symptoms such as constipation and IBS-C in females (82, 83). In addition, linaclotide is anoth- blared vision, observed in 30% of subjects (90). These un- er activator of the chloride ions channels and functions toward effects often lead to drug discontinuation; it is, as a guanylate cyclase-C agonist. This agent is an activa- therefore, essential that prescribers counsel the patients tor of the cystic fibrosis transmembrane regulator (CFTR) about these side effects and explain the drug function chloride ion channels (84). There have been promising and the need for its consumption for 1 to 4 weeks (94, 95). results in the use of lubiprostone for the management of It is recommended that TCAs be used for 6 to 12 months the IBS-C (85-87).
and then tapered (93, 96).
3.14. Inhibitors 3.17. Selective Serotonin Re-Uptake Inhibitors The K channels and the 3Na/2K pump develop an elec- trochemical driving force for the release ofchloride, The effect of SSRIs on the GI tract motility is more pro- which is followed by the secretion of sodium and water. nounced than that on decreasing visceral pain. Parox- The CFTR regulates the chloride ion channels. CFTR is etine accelerates gastric accommodation in healthy in- an inhibitory enterocytes membrane component and dividuals and does not affect fasting gastric compliance blocks GI secretion. (45, 97). SSRIs are widely used and have no serious untow- Crofelemer interacts with the CFTR inhibitory function. ard effects in the management of psychiatric disorders It also possesses advantages in the management of the (98, 99). In four studies, the therapeutic standard dose IBS-D and enhances secretion (88).
regimen of SSRIs was applied in the IBS and improvement in lifestyle and global good advantages were observed. In addition, there was no considerable effect on noxious vis- ceral perception (90, 97, 98). In another clinical study, 84% The application of antidepressants in a considerable of the subjects who received SSRIs (vs. 37% on placebo) part of gastrointestinal disorders is accepted. The anal- wanted to continue with the drug. SSRIs have convenient gesic effect of some of these drugs is responsible for the advantages in patients with somatization (100, 101). relief of pain in these patients. The concurrent existence of anxiety and depression with the IBS is remarkable. An- 3.18. Fiber and Laxatives tidepressants are effective in relieving the visceral pain in the IBS through modulating the interactions between Constipation is a frequent complaint in the IBS-D. Many the central and enteric nervous systems (46, 84, 89-91). different drugs with naturally herbal-derived ingredi- Antidepressants are categorized as selective serotonin ents and/or chemical origins are applied to relieve this re-uptake inhibitors (SSRIs), tricyclics and related antide- symptom. Fiber such as bran and methylcellulose helps pressants, and monoamine oxidase inhibitors (MAOIs). form bulky feces and improve large intestinal motility.
The drugs include duloxetine, flupentixol, mirtazapine, The most important laxatives are divided into four reboxetine, tryptophan, and venlafaxine (84, 91, 92).
groups: fecal softeners (e.g. liquid paraffin); stimulant It should also be considered that, in addition to antide- laxatives (e.g. bisacodyl); osmotic laxatives (e.g. meth- pressants therapy, psychological management has a cru- ylcellulose); and bulk-forming laxatives (e.g. lactulose). cial role in the IBS treatment.
There is no sign of intestinal damage in the long-term prescription of laxatives, but the side effect of laxatives is 3.16. Tricyclic Antidepressants hypokalemia. The untoward effects of stimulant laxatives are dependency and tachyphylaxis (102-104).
Functional gastrointestinal disorders (FGIDs) and the IBS are the therapeutic targets of tricyclic antidepres- sants (TCAs). In a comprehensive study, one third of the 3.19. Antidiarrheal Drugs subjects used an antidepressant, although the purpose of The analogues of the opioid receptors in the GI tract taking the drug was not obvious (92). TCAs are drugs with such as diphenoxylate and loperamide inhibit intesti- J Arch Mil Med. 2015;3(3):e30057 Abtahi SR et al. nal motility and secretion. The anti-diarrheal effect of emerging therapies in the IBS based upon the evolving loperamide is higher than its anti-spasmodic effect (105, understanding of the pathophysiology of this disorder. 106). Loperamide has negligible side effects. A combina- The chief complaint of the IBS patients is abdominal tion of diphenoxylate and atropine (co-phenotrope) is pain. A percentage of these patients present with aggra- available, but loperamide is preferred. Another agent is vated pain sensitivity to gut distention (visceral hyper- codeine phosphate, which is not convenient due to its risk of dependency (107). Both co-phenotrope and lop- Various pharmacological agents have been used in the eramide may be prescribed for the management of this management of the IBS, but with limited efficacy for the syndrome (107, 108). symptom-based approach. Consensus-based pharmaco- logical therapy in the IBS advocates the use of traditional 3.20. Antibiotics and/or novel drugs that have an equivalent effect on pain, flatulence, diarrhea, and constipation. The prescribed Sometimes bacterial gastroenteritis results in the devel- medications consist of TCAs, SSRIs, antispasmodics, cen- opment of the IBS, as has been demonstrated in a large trally acting agents, κ-opioid receptor agonists, 5-HT3 number of studies (109). The lactulose hydrogen breath receptor agonists and antagonists, aminobutyric acid test is useful and is positive in 70% of the IBS patients analog, and agents acting on the chloride channels in (110). In the absence of bacteria in the small intestine, the GI tract. In addition, antimotility drugs may subside lactulose fermentation does not occur and it reaches the diarrhea and laxatives may alleviate constipation. Finally, large intestine without any chemical conversion (111). The not only do probiotics offer considerable potential in the presence of small intestinal bacterial overgrowth is sug- treatment of FGIDs, but also there is now new evidence to gestive for starting chemotherapy (109).
support their efficacy in the management of the IBS.
It is recommended to prescribe wide-spectrum antibi- otics such as clarithromycin, ciprofloxacin, amoxicillin, metronidazole, and doxycycline for 10 days. Thirty-three of these patients became asymptomatic (112). Rifaximin The authors would like to thank the IT Service of AJA uni- has also been demonstrated to be efficacious (113, 114).
versity of medical sciences for supporting and providing data acquisition facilities.
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