1. Introduction
Visceral pain, i.e., pain arising from the viscera is the cardinal symptom of patients with irritable bowel syndrome (IBS), a prevalent disease afflicting 10% - 20 % of the world population (1-3). IBS patients generally experience enhanced sensation to normal bowel functions, reduced perception threshold and tenderness in somatic referral, which are manifestations of peripheral and central hyperalgesia of the nervous system (4). Unlike other hyperalgesia that is often accompanied by tissue injury and inflammation, apparent structural damage in IBS colon is lacking. Thus, diagnosis of IBS generally resorts to symptomatic classification following the “Rome III” or the most recent “Rome IV” criteria established from epidemiological analysis and clinical experience (5, 6). Symptomatically, IBS patients can be categorized into constipation predominant (IBS-C), diarrhea predominant (IBS-D), mixed constipation and diarrhea (IBS-M), and unsubtyped (IBS-U) subgroups. The etiology of IBS remains undetermined and has been under constant investigation which suggests contributions from negative life experience (7, 8), psychological disorders (9), genetic predisposition (10) and environmental contributions (11, 12). The post-infectious IBS (PI-IBS), a subset of IBS appears to be caused by an acute infectious gastroenteritis, i.e., a bout of bacterial infection in the stomach and intestines (13). In addition, increased gut permeability has been linked to the development of IBS symptoms (14). Recently, difference in intestinal microbiota has been discovered between IBS patients and healthy population, suggesting abnormality of intestinal microbiota as a causal factor of IBS (15).
Visceral pain associated with IBS has been attributed to the malfunction of the brain-gut axis in the nervous system (16). Central sensitization from abnormal information processing by the central nervous system (CNS) and/or dysregulated CNS modulation clearly play a key role in chronic visceral pain, which is implicated by enhanced perception of normal sensory signal input as pain and descending modulation incapable of suppressing persistent pain (17). However, like in many chronic pain conditions, prolonged visceral pain in IBS is initiated by activities in peripheral sensory (afferent) neurons (4, 18, 19). This is readily supported by simple clinical and preclinical experiments of blocking afferent input into the CNS. Indeed, infusion of local anesthetics into the rectum significantly relieves discomfort and pain in IBS patients and animal models, including relief of referred abdominal hyperalgesia (tenderness) (20-22). In contrast, rectal infusion of glycerol, an intestinal mucosal irritant, enabled healthy volunteers experience IBS-like symptoms, include visceral hyperalgesia and referred tenderness (23). Recent success of several peripherally restricted drugs has further confirmed that targeting the periphery organs and nerves is viably strategy to manage IBS-related pain.
This review will be focused on the current medications available for treating IBS, especially their therapeutic profiles (benefits vs. side effects) in managing visceral pain. Due to space limitations, excluded in this review are nonpharmacological treatments (e.g., acupuncture, hypnotherapy and psychotherapy) and drugs/mixtures that lack well-defined pharmacological targets, (e.g., antispasmodics, dietary fibers, bulking agents, probiotics, prebiotics and herbal medicines). We will first summarize categories of conventional pain managing drugs that were historically adopted to treat visceral pain in IBS. Then, particular focus will be given to drugs available to IBS patients that target the gastrointestinal (GI) tract and peripheral nerves, which generally have minimum off-target side effects on the CNS. Last, we will survey the most recent advances in candidate pharmacological targets and investigational drugs for treating IBS.
2. Conventional Pain Managing Drugs Adopted For The Viscera
Visceral pain is less defined and often poorly and unreliably localized clinically. This is likely caused by the complexity of the neuroanatomic innervation of the visceral organs consisting of web-like neural plexus throughout the thoracic and abdominal cavities with central projections from each visceral organ to multiple vertebral segments of the spinal cord (24). Accordingly, our understanding about visceral pain lags behind other types of pain. It is thus common practice for clinicians to adopt conventional pain managing drugs to treat visceral pain patients. Summarized below are four categories of drugs generally prescribed to IBS patients in the clinics.
Non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen and aspirin are used to treat bowel pain because of the analgesic and anti-inflammatory effects. However, the efficacy of these drugs in treating IBS pain does not seem to be supported by any systematic studies or formal clinical trials. On the other hand, long-term use of all these drugs are associated with chronic constipation (25). Further, NSAIDs appear to have negative effects on IBS patients as evidenced by a close correlation between frequent use of NSAID and development of IBS symptoms (26) as well as compromised intestinal permeability in IBS patients using NSAIDs (27-29). Other adverse effects of NSAIDS and aspirin include enteropathy, mucosal damage, intestinal strictures, ulcers, colitis and rectitis. Acetaminophen can cause liver necrosis and fatal liver damage when overdosed (30, 31). Based upon the above evidence, NSAIDs may not be recommended for treating IBS pain.
Narcotics consisting of morphine, heroin and derivatives effectively suppress pain mainly by mediating the opioid receptors in the central nervous system. Despite their anti-nociceptive benefits, narcotics come with several significant side effects from non-specific targeting of the CNS, including habituation, dependence, addiction, and opioid-induced hyperalgesia. In addition, narcotics negatively affect the gastrointestinal tract by causing nausea and vomiting, constipation, delay in GI transit, and more importantly the development of narcotic bowel syndrome (NBS) that actually enhances abdominal pain (32, 33). Narcotics appear to be effective in alleviating acute visceral pain, but their long-term efficacy on IBS pain has not been supported by any large-scaled clinical studies. In light of the severe side effects and moderate benefits, narcotics should not be prescribed to IBS patients with chronic visceral pain.
Benzodiazepines that are effective in treating psychiatric disorders are also commonly used for IBS patients as both type of disorders often co-exist. Benzodiazepines (BZD) function as a GABAA receptor enhancer to inhibit neural activities mainly at the central nervous system (34). It is safe to treat psychiatric disorders using benzodiazepines for short-term use, whereas long-term use of BZD leads to cognitive impairment and other adverse mental and physical effects (35). Various forms of benzodiazepines have been extensively investigated for managing IBS symptoms (36), among which dextofisopam even reached Phase IIb clinical trial but failed to demonstrate any significant anti-nociceptive benefits (37). Thus, the BZD should be considered mainly for treating some IBS patients comorbid with anxiety.
Tricyclic antidepressants (TCAs) are commonly selected for treating IBS symptoms. Most TCAs act as serotonin-norepinephrine reuptake inhibitors but also have antagonistic/agonistic effect at several serotonin receptor subtypes, NMDA receptors and sigma receptors. Compared to the treatment of depression, a lower dose of TCAs is used in treating IBS, which is supported by several studies to improve the global symptoms of IBS and reduce pain perception and discomfort especially for IBS-D patients (38, 39). However, due to severe adverse effects including hypotension, drowsiness and constipation, TCAs are not among the first choices for the treatment of IBS, and should be carefully used (38, 39).
Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have more confined pharmacological targets than TCAs and have undergone extensive investigation for efficacy in managing IBS symptoms, among which fluoxetine, citalopram, and paroxetine all went to clinical trials. Fluoxetine significantly mitigate pain perception, improve bloating symptom and stool consistency in a 12-week clinical study (40), which nevertheless conflicts with the outcome of another 6-week trial (41). Outcomes from clinical trials of citalopram are also controversy with some showing improved IBS symptom (42) and others insignificant effects (43, 44). Paroxetine could improve overall well-being in a 12-week trial, but, symptoms of IBS are not significantly improved (45). Besides unclear efficacy in the treatment of IBS, adverse effects of taking SSRIs and SNRIs include agitation, insomnia and nausea. Thus, SSRIs and SNRIs appears only have moderate effect in alleviating IBS symptoms and should be prescribed to IBS patients comorbid with depression.
Clonidine, an alpha-2 adrenergic agonist, has proved to relieve certain IBS symptoms, including attenuating fast colonic tone, reducing postprandial gastric volume, alleviating abdominal pain sensation and enhancing colonic compliance (46, 47). All these effects collectively benefit patients to mitigate the discomfort of IBS. Commonly seen adverse effects of clonidine includes drowsiness, dry mouth and sleep problems, which limit the wide use of clonidine in the treatment of IBS (46, 47).
Gabapentin and pregabalin have been recently recommended for treating IBS pain which are widely used for managing neuropathic pain in diabetic neuropathy, fibromyalgia and post-herpetic neuralgia etc (48, 49). Gabapentin and pregabalin were originally designed as analogs of GABA but were found to have no binding affinity with GABA receptors. Studies have indicated that the pain relieving effect of gabapentin and pregabalin is through binding with α2δ-1, an auxiliary subunit of voltage gated calcium channels. The use of gabapentin and pregabalin to treat IBS symptom is supported by two clinical studies of small scale, in which symptoms of abdominal pain, urgency, and bloating were significantly improved (50, 51). Adverse effects include dizziness and drowsiness. The therapeutic benefits of gabapentin and pregabalin in treating IBS pain requires further confirmation by large-scaled clinical studies.
3. Peripherally Restricted Drugs For Managing Visceral Pain
The aforementioned generic pain-managing drugs are either ineffective or moderate in managing IBS-related pain. In addition to suppressing pain perception, they often affect other CNS regions to cause various adverse effects that out-weight the therapeutic benefits. Alternatively, drugs that target the peripheral organs and nerves can potentially enhance the therapeutic profile by minimizing off-target side effects. Thus, primary afferent neurons, especially nociceptors have become the target for pharmacological modulation in treating visceral pain and other types of chronic pain (52). Nociceptor sensitization necessary for prolonged visceral pain is orchestrated by an array of membrane ion channels, intracellular molecules and messengers (see an elaborated review (52) for details), which in theory are all valid pharmacological targets for IBS pain (53). However, only a short list of drugs targeting the periphery have emerged and all are reviewed below.
4. Serotonergic Agonist/Antagonist
Serotonin, despite being an important neurotransmitter in the CNS, is mostly (> 90%) present in enterochromaffin cells (ECs) in the GI tract (54). Release of serotonin in the intestine results in smooth muscle contraction or relaxation, GI transit time alternation and luminal secretion. Recent works have revealed that 5-HT3 and 5-HT4 receptors are located in the mucosa of the small and large intestines and on epithelial and ECs of distal colon (55). Stimulation of the 5-HT4 receptors results in smooth muscle relaxation, whereas stimulation of 5-HT3 causes smooth muscle contraction. In addition, neural activities of visceral afferent neurons were reportedly suppressed by blockage of 5-HT3 receptors in animal studies (56). So far, three drugs of this category are available for IBS patients, which are all 5-HT3 receptor antagonists.
Alosetron is one of the 5-HT3 receptor antagonists for treating IBS-D patients. Studies, based on clinical trials, have demonstrated the efficacy of alosetron in the symptomatic treatment of IBS-D resulting in improved fecal discharge pattern, reduced urgency, and relief from abdominal pain (57). Alosetron’s 5-HT3 antagonism decelerates the process of fecal discharge through the large intestine, increase water absorption in the gut wall and control the moisture content and volume of the remaining waste particles. The duration of action is longer in male than in female patients. Alosetron was initially approved by the FDA in 2000 for the treatment of female patients with IBS-D, withdrawn from the market for two years due to case reports of ischemic colitis and complicated constipation, and reintroduced for more than a decade under a risk managing program. The usage of this drug has been kept very limited, such as, for patients who have experienced IBS symptoms for at least six months, and have not responded adequately to conventional therapy (58).
Granisetron and ondansetron are two other 5-HT3 receptor antagonists that are less potent than alosetron, and they are widely used to alleviate nausea and vomiting derived from cancer chemotherapy. Efficiency of both drugs in IBS were supported by the outcomes of several clinical studies. Granisetron significantly reduces rectal sensitivity to balloon distension in 12 IBS patients in a dose-dependent manner. Postprandial motility is also reduced by granisetron (59). In a separate study, ondansetron relieved pain perception by significantly increasing rectal sensory threshold to electrical stimulation, and patients suffered fewer times of daily pain after taking ondansetron (60). From another large scaled clinical trial on 120 IBS-D patients, ondansetron significantly improved stool consistency, increased GI transit time and relieved urgency and intestinal bloating in many IBS-D patients. However, the pain-relieving effect of ondansetron was not systematically explored in the study (61). From the above evidence, granisetron and ondansetron are deemed to possess potential efficacy in treating IBS-D patients. The most common adverse effect is constipation.
5. Peripherally Restricted Opioids
Opioids can affect both the central and peripheral nervous systems. In addition to profound modulatory effect to the CNS, opioids can modify GI function by binding with opioid receptors on the enteric circuitry and primary afferent nerve endings (62). Opioid receptors in the GI tract play major roles in regulating GI motility, secretion, and visceral sensation (63). Opioid receptors are divided into three major categories: the μ-opioid, κ-opioid, and δ-opioid receptors, all of which are G-protein coupled receptors. Although each class of receptors differs in their responsiveness to different agonists, in general they all work via inhibition of adenylyl cyclase and cyclic adenosine monophosphate formation, inhibition of N-type calcium channels, and neuronal hyperpolarization via inwardly rectifying potassium channels (63). Usually, μ-opioid receptor agonists inhibit smooth muscle contractile activity resulting in constipation. Delta-opioid agonists are more likely to exhibit their inhibitory effects on GI circular muscle. And κ-opioid receptors play roles in GI propulsion and visceral sensation. Among this category of drugs, loperamide and eluxadoline are available for treating IBS-D patients (63).
Loperamide, a synthetic peripheral μ-opioid receptor agonist, is nonabsorbable with low bioavailability and incapable of diffusing through the blood-brain-barrier. Thus, loperamide lacks the array of central opioid-like adverse effect and restricts its effects within the GI tract. It is originally used with strictly precise dosage for acute diarrhea treatment. Use of loperamide to treat IBS patients have been supported by several clinical studies (64-66). Apparent efficacy was observed after 3 - 5 weeks of treatment demonstrating global symptom improvements, reduced abdominal pain, and increased stool consistency. Common side effects of loperamide include nausea, cramping and constipation. In particular, the aggravated constipation symptom has limited its usage on IBS-C patients.
Eluxadoline, a newly FDA-approved drug for the treatment of IBS-D, is an orally active μ-opioid receptor agonist and δ-opioid receptor antagonist, with both the antidiarrheal and analgesic effects (67). The action of eluxadoline is restricted only in the GI tract, and scarcely has any hazardous effect in the CNS (68). Different studies have demonstrated that eluxadoline can attenuate visceral hypersensitivity without complete inhibition of GI motility (63). In the first place, as a μ-opioid receptor, eluxadoline slows down GI motility, decreases visceral sensation, and inhibits secretion. In the second place, as a δ-opioid receptor antagonist, eluxadoline counteracts with some of the μ-opioid effects, usually identified as adverse effects, such as excessive slowing of motility and reinforcement of μ- and κ-opioid receptor-mediated effects on visceral sensation (68). Hence, this drug possesses almost all of the advantages of its counterparts while discards a few of the adverse effects. Thus, eluxadoline appears to be one of the most suitable opioids for alleviating abdominal pain and improving GI transit state in IBS-D patients without inducing severe constipation (62). However, common side effects of eluxadoline include constipation (69) especially in elderly patients with a higher rate of comorbid hepatic/biliary tract disease (62).
6. Chloride Channel Activator
Lubiprostone is a chloride channel activator approved by the FDA for treating female IBS-C patients (70, 71), which acts locally on the apical membrane of epithelial cells in the gastrointestinal lumen (72, 73). As a derivative of prostaglandin E1, lubiprostone selectively combines with prostaglandin receptor to activate chloride channel 2 leading to chloride-rich fluid secretion (1, 74). Increasing fluid secretion softens stools and improves intestinal motility, which finally contributes to alleviate constipation symptoms of IBS-C. The effect of lubiprostone is restricted to the GI tract as evidenced by its rapid metabolism within the lumen and low concentration of its metabolite M3 in the blood stream (75). Outcomes from two 12-week phase III clinical trials supported the efficacy of lubiprostone in mitigating global symptoms of IBS-C. An additional extension trial for 9 - 13 months confirmed the long-term safety and tolerability of lubiprostone in IBS-C patients. Adverse effects include nausea, diarrhea, flatulence, abdominal pain and vomiting (76). Lupiprostone cannot be used on pregnant women due to evidence of increased risk of fetal loss (70). However, no reported evidence has indicated that lubiprostone can significantly alleviate IBS pain. Thus, lubiprostone appears suitable for IBS patients with overt constipation while suffering from minor or moderate visceral pain.
7. Guanylate Clyclase-C (GC-C) Agonist
Linaclotide, a pH-independent 14-amino acid guanylate cyclase-C (GC-C) agonist, is an oral-intake drug for treating IBS-C approved by U.S. FDA and European medicines agency (1). It selectively binds to GC-C receptors in the GI tract to release intracellular cyclic guanosine-3, 5- monophosphate (cGMP), which activates the cystic fibrosis transmembrane conductance regulator (70, 75). Consequently, chloride and bicarbonate ions are secreted and sodium absorption is inhibited, leading to improved GI transit (2, 72). In addition, linaclotide was proven to act as an analgesic to alleviate visceral pain perception by inhibiting mechano-sensitivity of colorectal afferent neurons via synthesis of cGMP (72, 77, 78). Action of linaclotide is restricted to the GI tract due to its low bioavailability, rapid metabolism, and more importantly the restricted expression of its target, GC-C receptors within the intestinal mucosal layer (77). Hence, systemic exposure is minimal at normal doses (71, 74). The efficacy of linaclotide is supported by the outcomes of two phase III clinical trials on IBS-C patients from which alleviated abdominal pain and increased complete spontaneous bowel movement were reported (79, 80). The most common adverse effect is diarrhea which is well-tolerated. Linaclotide should not be used for human under age 18, and is in pregnancy category C (71, 72). Overall, linaclotide appears to be an ideal drug for IBS-C patients in the absence of any apparent side effects.
8. Promising Novel Targets and Drugs For Ibs Pain
Since IBS-related visceral pain is a severe healthcare burden and unmet clinical need, persistent efforts have been devoted to the quest for better medications for IBS with an emphasis on drugs targeting the periphery. Candidate molecules in the GI tract and visceral afferent neurons were thoroughly reviewed by Holzer (53). Additional molecular targets have been suggested by recent neuroscience and gastrointestinal research for next-generation drugs to treat IBS. We recently showed that voltage-gated sodium channel NaV1.6 plays necessary roles in repetitive spiking of mechanosensitive visceral afferents to colon stretch (81), the activation of which reliably evokes painful sensation in the viscera (82). Osteen et al. reported the presence of NaV1.1 in high-threshold mechanoreceptors innervating the colon and rectum and NaV1.1 was shown to regulate the excitability of sensory nerve fibers that medicate mechanical pain (83). Most recently, Castro et al. reported that activation of GABAB channels in colorectal afferent neurons reduced their excitability to mechanical colon stimuli via downstream effectors of two voltage gated calcium channels CaV2.2 and CaV2.3 (84).
In addition, a number of drugs for treating IBS have completed small scaled clinical trials with positive outcomes documented in the literature and will be reviewed below, including asimadoline, rifaximin, mesalamine, ketotifen and cromoglycate.
Asimadoline is a selective peripheral κ-opioid receptor agonist with significantly higher selectivity of κ- over either δ- or μ-opioid receptors. Unlike a previous κ-opioid agonist fedotozine which failed to show significant efficacy in clinical trials (85), asimadoline has shown promising effects in treating IBS-D patients in a phase II clinical trial (86). Asimadoline have restricted effects within the GI tract due to its poor permeability through the blood brain barrier. The analgesic effect is presumably mediated by opioid receptors which reduces the excitability of nociceptors on peripheral nerve endings (87). Currently, phase III clinical trial of asimadoline in treating IBS-D patients has just been completed and the outcomes are yet to be released.
Rifaximin is a nonabsorbable antibiotic with restricted effect in the GI tract due to poor oral bioavailability. Rifaximin has been approved by the FDA for travelers’ diarrhea and hepatic encephalopathy. Efficacy of rifaximin in treating IBS patients without constipation has been supported by five well-designed clinical trials (88). All five studies showed global improvement of IBS symptom by rifaximin and two studies reported alleviation of abdominal pain. After only a short treatment period (10 - 14 days), the efficacy of rifaximin was observed to persist up to 12 weeks (88). Adverse effects with rifaximin were minimum in clinical trials, including extremely low incidence of peripheral edema, dizziness, fatigue, and nausea (88). Current limitations of rifaximin includes its high cost and lack of clinical data from long-term studies on IBS patients.
Mesalamine, a 5-aminosalicylic acid is an anti-inflammatory drug and extensively used for treating inflammatory bowel disease. The presence of low-grade inflammation and mucosal immune activation in IBS provides the rationale for using mesalamine in IBS patients. Mesalamine reportedly improved the global symptoms in a small trial of 20 patients with IBS (89) and reduced fecal bacterial counts in a separate trial on 12 IBS-D patients (90). Conflicting outcomes were received regarding the pain relieving effect of mesalamine from two other independent clinical trials (91, 92). Large scaled clinical studies are required to further determine the therapeutic efficacy of mesalamine in treating IBS pain.
Ketotifen as a mast cell stabilizer features a new type of treatment scheme for IBS aiming at the immune system in the GI tract. Ketotifen has been shown to prevent the activation of mucosal mast cells by cholecystokinin (CCK) (93). The efficacy of ketotifen for treating IBS is supported by a clinical trial on 60 IBS patients (94). Ketotifen significantly decreased abdominal pain in IBS patients as indicated by increased discomfort threshold to rectal balloon distension. In addition, the number of mast cells in rectal biopsies and spontaneous release of tryptase were lower in IBS patients receiving Ketotifen. Adverse effects including sedation and drowsiness were mild and well tolerated. However, the exact mechanism of the above clinical benefits is unclear as ketotifen did not alter histamine and tryptase release. Further studies are needed to define the role of ketotifen for the treatment of IBS.
Cromoglycate is another investigational drug that target intestinal mast cells, inhibiting their release of mediators including histamine, leukotrienes and a slow reacting substance of anaphylaxis. Effect of cromoglycate in treating IBS-D patients with food intolerance was supported by a clinical study on 66 IBS-D patients selected from 120 IBS-D population showing concomitant symptoms of food intolerance (95). The cohort that received both cromoglycate and strict exclusion diet treatment showed significant improvement of global IBS symptoms whereas the other cohort receiving diet treatment alone only had moderate improvement. However, no specific assay to assess the pain-relieving effect was designed in that study. A recent clinical study on 18 general IBS patients reported beneficial effects of cromoglycate, which include reduced release of tryptase from intestinal biopsies, attenuated expression of TLR2 and TLR4, and clinical improvement of bowel function in the IBS-D subgroup (96, 97). Effect of cromoglycate in treating abdominal pain and other symptoms in different subgroups of IBS needs to be studied in a larger number of patients.
9. Conclusions
Visceral pain associated with IBS differs greatly from other types of pain and requires special pharmacological managements. Certain conventional drugs for relieving pain do not significantly improve IBS symptoms based upon negative or lack of clinical and research data, including NSAIDs, acetaminophen, aspirin, and various narcotics. IBS patients with comorbidities of anxiety and/or depression may benefit from anxiolytic (benzodiazepine) and antidepressant drugs (TCAs, SSRI and SNRI). Drugs that effectively manage neuropathic pain disorders (gabapentin and pregabalin) reportedly improved global IBS symptoms and alleviated visceral pain, which requires further confirmation. Clonidine appears to be the only conventional pain-managing drug that benefits the general IBS population.
Medications that target the GI tract and peripheral nerves have better therapeutic profiles by limiting adverse CNS effects. The optimal drugs for managing pain in IBS-D and IBS-C patients appear to be eluxadoline and linaclotide, respectively. Lubiprostone effectively relieves constipation symptoms in IBS-C but has no apparent pain-relieving effect. Loperamide is efficacious in managing diarrhea symptoms but tends to tip the balance towards constipation, which limits its usage at a higher dose to relieve pain. The 5HT3 antagonists alosetron, granisetron and ondansetron can benefit IBS-D patients, among which alosetron needs to be used with caution due to potential cardiovascular toxicity. Promising investigational drugs for treating IBS pain include asimadoline, rifaximin, mesalamine, ketotifen and cromoglycate.
