Pain in Irritable Bowel Syndrome: Does Anything Really Help?

Abstract

Pain relief remains a significant challenge in the management of irritable bowel syndrome (IBS): “Does anything really help relieve the pain in patients with IBS?”. Interventions aimed at pain relief in patients with IBS include diet, probiotics or antibiotics, antidepressants, antispasmodics, and drugs targeting specific gastrointestinal receptors such as opioid or histamine receptors. In the systematic review and meta-analysis published in this journal, Lambarth et al. examined the literature on the role of oral and parenteral anti-neuropathic agents in the management of pain in patients with IBS. This review article appraises their assessment of the efficacy of the anti-neuropathic agents amitriptyline, pregabalin, gabapentin, and duloxetine in the relief of abdominal pain or discomfort, and impact on overall IBS severity and quality of life. This commentary provides an update of current evidence on the efficacy of the dietary and pharmacological treatments that are available or in development, as well psychological and cognitive behavioral therapy for pain in IBS. Advances in recent years augur well for efficacious treatments that may expand the therapeutic arsenal for pain in IBS.

Introduction

In the systematic review and meta-analysis published in this issue of the journal,¹ Lambarth et al. examined the literature on the role of oral and parenteral anti-neuropathic agents in the management of pain in patients with irritable bowel syndrome (IBS)². The primary outcome of interest was abdominal pain or discomfort, and secondary outcomes were overall IBS severity and quality of life (QOL). Out of the 1225 articles identified in their literature search, thirteen studies with a total of 629 participants fulfilled their inclusion criteria. Six of the included studies investigated amitriptyline, four α2δ-ligands (pregabalin and gabapentin), and three investigated the selective serotonin and norepinephrine reuptake inhibitor, duloxetine.

The vast majority (84%) of participants in amitriptyline studies had diarrhea predominant IBS (IBS-D). While all amitriptyline studies reported improvement in overall IBS severity, the effect on pain seemed to be influenced by the nature of the study.

Among the α2δ-ligands studies, 47% of participants had IBS-D and 21% had constipation-predominant IBS (IBS-C). α2δ-ligands did not consistently result in improved pain outcomes with only one of the 4 studies reporting improvement of pain in the therapeutic group whereas 2 studies reported improvement of some but not all measures of pain and another study reported no difference in pain between therapy and placebo. Outcomes related to overall IBS severity and quality of life were only reported in one of the 4 studies of α2δ-ligands, with improvement of some but not all the endpoints.

Of the participants in the duloxetine studies, 35% had IBS-C. While all three duloxetine studies reported improvement in overall IBS severity in patients taking duloxetine, and two studies reported improvement in quality of life, only some (not all) outcomes related to pain were improved with duloxetine.

For the meta-analysis of controlled trials pooled for assessment of dichotomous outcomes, three studies with a total of 278 patients were included. Although these three trials actually used different outcomes to identify relief of pain, the relative risk (RR) of not improving while on the medication was significant with an RR estimate of 0.50 (95%CI 0.38 to 0.66, p<0.00001). While the meta-analysis results favor the use of anti-neuropathic agents for pain in IBS, it is important to note that the analysis only included three out of the twelve studies mentioned in the systematic review with one study having assessed pregabalin and two studies amitriptyline. Some of the limitations of the presented data include the small sample size of some of the included studies, the lack of subgroup analysis, and the low number of studies included in the meta-analysis. Overall, through their analysis, Lambarth et al.¹ have provided valuable insight into the role of anti-neuropathic, analgesic agents in the management of pain in IBS.

Given the multifactorial etiology of IBS and the diversity of clinical presentations, recent guidelines have suggested the need to individualize the management of IBS patients based on the predominant symptom notably pain, constipation, or diarrhea, or targeting an actionable biomarker that is consistent with the mechanism of the IBS subtype or bowel dysfunction.³ However, pain remains the significant challenge in the management of IBS, and this leads to the rhetorical question: “Does anything really help relieve the pain in patients with IBS”? Interventions aimed at pain relief in patients with IBS include diet, probiotics or antibiotics, antidepressants, antispasmodics, and drugs targeting specific gastrointestinal (GI) receptors such as opioid or histamine receptors.⁴ This commentary provides an update of current evidence on the efficacy of these treatments as well psychological and cognitive behavioral therapy for pain in IBS.

Diet, probiotics, and antibiotics

Whereas a diet high in fiber appears to reduce constipation,⁵ in a systematic review, fiber treatment did not seem to be superior to control in improving abdominal pain [RR 0.87 (95% CI: 0.76 to 1.0)].⁶ Multiple studies have examined the effect of a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) on IBS symptoms with conflicting results. While a systematic review and meta-analysis supported the efficacy of a low FODMAP diet in the treatment of abdominal pain in IBS,⁷ other studies have suggested that traditional dietary advice might be as efficient as a low FODMAP diet in reducing IBS symptoms while avoiding the high level of dietary restriction associated with the latter.⁸

A systematic review of 15 trials of probiotics showed favorable results in the treatment of abdominal pain; ⁹ another, more recent systematic review suggested that improvement in pain with probiotics might be strain dependent.¹⁰ The non-absorbed antibiotic rifaximin also seems to be beneficial for treating pain in patients with IBS, and in a systematic review, rifaximin was more effective than placebo for global symptoms and bloating in patients with IBS, ¹¹ and in reduction of pain in patients with IBS-D or mixed IBS (IBS-M).¹²

Medications approved for pain in IBS

The medications (currently approved in the United States) that are used as off-label treatment of pain in IBS belong to three categories based on their mechanism of action: antidepressants (more recently termed central neuromodulators in the IBS literature), antispasmodics, and peppermint oil (see table reproduced from a recent publication). ³

Table. Summary of Current Medications Approved for Treatment of IBS-Related Symptoms.

(Adapted from Camilleri M. Diagnosis and Treatment of Irritable Bowel Syndrome: A Review. JAMA. 2021;325: 865-877)³

Therapy class, examples	Mechanism of action	Efficacy on SRMA [OR or RR (95%CI)]/ RCTs/ NNT	Quality of data	Adverse events	Limitations of data; other comments
Antispasmodic drugs: 6,54 Hyoscine, otilonium, pinaverium, cimetropium	Inhibition of muscarinic Ach receptors, or block Ca++ channels, GI smooth muscle	May be effective OR 0.68 (0.57 to 0,71) Overall NNT 5 NNT for: hyoscine 3.5, otilonium 4.5, cimetropium 3, pinaverium 3	Low	More likely with antispasmodics in a meta-analysis of 22 RCTs in 2008, particularly dry mouth, dizziness, and blurred vision	No high-quality trials, heterogeneity between studies, possible publication bias, and only a small number of RCTs assessing each individual antispasmodic
Peppermint Oil 2,6,23	Block L-type Ca++ channels on muscle, activate TRPM8 receptors on nociceptive afferents	Effective OR: 0.43 (0.32 to 0.59); Global: RR 2.23 (1.78 to 2.81) Overall NNT 2.5; RCT of sustained release formulation: ↓ pain, bloat, urgency but not total IBS scores	Moderate	No increase in adverse events in a meta-analysis of 4 RCTs	Heterogeneity between studies. Ranked first for global IBS symptoms in network meta-analysis
Antidepressants 2,13	Psychological, anti-nociceptive, slow (TCA) or fast (SSRI) transit effects	Effective OR: 0.67 (0.58 to 0.77) for global; 0.62 (0.43 to 0.88) for abdominal Pain, NNT 4	Moderate	More likely with antidepressants in a meta-analysis of 17 RCTs, particularly dry mouth and drowsiness	Only 3 high quality trials, heterogeneity, possible publication bias, and some atypical trials included. NNT overestimates efficacy. Ranked first for abdominal pain in network meta-analysis

Ach: Acetylcholine; CI: confidence interval GI: gastrointestinal; IBS: irritable bowel syndrome; NNT: number needed to treat; OR: odds ratio; RCT: randomized controlled trial; RR: risk ratio; SRMA: systematic review and metaanalysis, SSRI: serotonin reuptake inhibitor; TCA: tricyclic antidepressant.

1-. Antidepressants

While the recent systematic review by Lambarth et al.¹ studied anti-neuropathic agents notably amitriptyline and duloxetine, other systematic reviews have also investigated the effectiveness of antidepressants in the treatment of pain in IBS. In one systematic review, the beneficial effect of tricyclic antidepressants (TCA) on abdominal pain [RR of not improving of 0.59 (95% CI: 0.42 to 0.83)] was observed, but such benefit was not demonstrated with selective serotonin re-uptake inhibitors (SSRIs) [RR of not improving of 0.64 (95% CI: 0.32 to 1.27)]. Moreover, patients on antidepressants were more likely to experience adverse events [RR of any adverse event of1.56 (95% CI: 1.23 to1.98)], especially drowsiness and dry mouth in patients receiving TCAs.¹³

A more recent network meta-analysis included 18 studies on gut-brain neuromodulators notably TCAs and SSRIs. In this analysis, TCAs ranked first in achieving improvement of abdominal pain [RR of failure to achieve improvement in pain of 0.53 (95% CI 0.34–0.83)] while SSRIs did not perform better than placebo [RR of failure to achieve improvement in abdominal pain of 0.82 (95% CI: 0.58 to 1.16)]. Interestingly, in the network meta-analysis which provides indirect comparison of each drug by relative efficacy compared to placebo, no significant difference in relief of abdominal pain was found between TCAs, SSRIs, peppermint oil, antispasmodics, and ispaghula husk. It was noteworthy that TCAs were more likely than placebo to lead to adverse events [RR of1.59 (95% CI: 1.26 to 2.06)]. ²

2-. Antispasmodics

Antispasmodics are often used as first-line treatments in IBS. However, most clinical trials are old and are constrained by their suboptimal methodology, considerable heterogeneity, and incomplete reporting of IBS subtypes in the clinical trials.¹⁴ Moreover, efficacy endpoints of these studies do not meet standards of either the Food and Drug administration or the European Medicines Agency. Among 26 clinical trials of antispasmodics identified by the American College of Gastroenterology Monograph of 2018, only two had low risk of bias,¹⁵ the evidence was weak, and any recommendations were of low strength. Network meta-analysis comparing soluble fiber, antispasmodics, peppermint oil, and central neuromodulators ranked antispasmodics second after TCAs in terms of abdominal pain improvement at 4-12 weeks. Sensitivity analysis according to type of antispasmodics revealed that non-antimuscarinic antispasmodics (alverine, drotaverine, mebeverine, otilonium, pinaverium, and pargeverine) ranked first in terms of efficacy [RR of not improving pain of 0.48 (95% CI: 0.35 to 0.64)] followed by TCA. In contrast, antimuscarinic type antispasmodics (cimetropium, hyoscine, pirenzipine, rociverine, and trimebutine) ranked last of all the treatments tested and were (as a class) not better than placebo.²

A meta-analysis of 22 randomized clinical trials of antispasmodics in IBS found them to be superior to placebo in relieving IBS symptoms (61% vs 44%; P<0.001) with significant heterogeneity between studies.⁶ Of the antispasmodics studied, the best evidence (based on the strongest available data) supports efficacy of both hyoscine and otilonium bromide (OB). One trial of OB showed significant improvement of abdominal pain and bloating compared to placebo,¹⁶ and another showed reduction in the frequency of pain episodes and in the severity of abdominal distension.¹⁷ A systematic analysis by Ruepert et al. found that 58% of patients on antispasmodics had improvement in abdominal pain compared to 46% of patients on placebo [relative risk of 1.32 (95% CI: 1.12 to 1.55); P<0.001].¹⁸ In general, antispasmodics are well tolerated, except for their anticholinergic side-effects.⁶

3-. Peppermint oil

Peppermint oil and its active ingredient, menthol, are naturally occurring agents that inhibit calcium channels and relax smooth muscles in the GI tract.¹⁹ Menthol also has analgesic²⁰ and anti-inflammatory effects,²¹ inducing a sensation of cooling by activating TRPM8, a temperature-sensing ion channel, which is the principal mediator of analgesia in acute and inflammatory pain.²² These properties suggest that peppermint oil, with analgesic and antispasmodic effects, would relieve pain better than standard antispasmodics. In a systematic review and meta-analysis of five randomized clinical trials, peppermint oil was significantly better than placebo for global improvement of IBS symptoms [RR of 2.23 (95% CI: 1.78 to 2.81)].²³ Pooled analysis for relief of abdominal pain showed active treatment to be significantly better than placebo, 57% vs. 15% respectively [RR of 2.14 (95% CI: 1.64 to 2.79)]. There was no statistically significant heterogeneity for both comparisons. However, most of the included trials had small sample sizes and used older formulations of peppermint oil. Adverse events in patients receiving peppermint oil were more frequent, but transient and mild in nature, and included heartburn, dry mouth, and peppermint taste and smell.

A new formulation of peppermint oil was tested in a small trial and showed no superiority compared to placebo, but pain, bloating, and urgency were significantly reduced.²⁴ Network meta-analysis examining soluble fiber, antispasmodics, peppermint oil, and neuromodulators showed peppermint oil to be third in efficacy through it was reported to be the best treatment of the group in relieving abdominal pain when randomized clinical trials performed in non-western countries were excluded.²

Other medications

1-. Opioids

The first systematic review and meta-analysis on the efficacy of three opioid receptor modulators in patients with IBS²⁵ appraised loperamide (a peripheral μ-opioid receptor agonist), asimadoline (a κ- opioid receptor agonist²⁶) and eluxadoline, a peripherally acting μ- and κ-opioid receptor agonist, and δ-opioid receptor antagonist with minimal oral bioavailability).²⁷ The meta-analysis involved 9 studies with 2834 patients who received opioid receptor modulators, and 1322 patients on placebo. The RR of persistent global IBS symptoms or abdominal pain was 0.85 (95% CI: 0.79 to 0.92; P<0.01)]. The three studies of loperamide (total n=48) compared to34 patients on placebo showed no difference [RR of persistent symptoms of 0.43 (95% CI: 0.18 to 1.07; P>0.05)]. Similarly, the two studies that assessed 404 patients on asimadoline and 147 patients on placebo showed no difference [RR of persistent symptoms of 0.84 (95% CI: 0.63 to 1.10; P>0.05)] with relatively high heterogeneity (I²= 67%; P=0.08).

Eluxadoline was assessed in three studies (with two studies using different doses of eluxadoline) that included 2382 patients in the eluxadoline group and 1141 patients in the placebo group. There was significant benefit with eluxadoline [RR of persistent symptoms of 0.88 (95% CI: 0.85 to 0.91; P<0.01)] with no heterogeneity identified.

2-. GABAergic agents

Pregabalin is a derivative of gamma-aminobutyric acid (GABA). Pregabalin binds the α2δ subunit of voltage-gated calcium channels within the central nervous system thereby inhibiting excitatory neurotransmitter release.²⁸ It has analgesic and anxiolytic effects. Pregabalin reduces visceral hypersensitivity in IBS patients²⁹ and a single 200 mg dose of pregabalin in healthy volunteers resulted in a 25% decrease in gas and pain sensation ratings.³⁰ Saito et al. conducted the first randomized, placebo-controlled, 12-week clinical trial of 225 mg of pregabalin in 85 IBS patients (86% female) with at least 3 pain attacks per month.³¹ The subtypes of IBS and fibromyalgia status in both treatment arms were balanced. Pregabalin treatment resulted in lower mean bowel symptom scale (BSS) pain scores over the last 4 weeks of the study compared to placebo as well as significantly lower overall IBS, diarrhea, and bloating BSS scores compared to placebo. There were no differences in mean BSS scores for IBS-C group or in in IBS QOL scores between treatment groups. Adverse events were common in both groups with neurological adverse events being more common with pregabalin.

3-. Linaclotide and new formulations

Linaclotide is a guanylate cyclase-C (GC-C) agonist approved for treatment of IBS-C and chronic idiopathic constipation. One study found patients with IBS-C to have more frequent and bothersome abdominal pain compared to other IBS subtypes.³² Linaclotide relieves constipation by stimulating increased chloride and fluid secretion and accelerating of colonic transit.^33–36 However, linaclotide also leads to extracellular secretion cGMP into intestinal submucosa leading to inhibition of colonic nociceptors and analgesia in animal models.³⁷

Linaclotide was efficacious in treatment of abdominal score (AS) in 614 patients with IBS-C and abdominal pain ≥3 (0-10 scale) in a 12-week phase 3B trial of linaclotide 290 μg or placebo.³⁸ The primary end point was weekly AS, that is a composite of abdominal bloating, discomfort, and pain, each rated on a 0-10 scale (0=none and 10=worst possible). The overall AS mean change from baseline was significantly greater for linaclotide compared with placebo (−1.9 vs −1.2; P<0.0001). Diarrhea was the most common treatment-emergent adverse event.

Two experimental delayed-release formulations of linaclotide (DR1 and MD-7246) were investigated in a phase 2b clinical trial.³⁹ All linaclotide DR1 and MD-7246 groups had a greater improvement in abdominal pain from baseline compared to placebo. MD-7246 had an incidence of diarrhea comparable to that of placebo. This dissociation of the secretory and analgesic effects of linaclotide opens the door for treatment of abdominal pain in IBS with such formulations, regardless of the IBS subtype.

Experimental Treatments

A-. Histamine antagonists

Ebastine is a second-generation nonsedating histamine H1 receptor antagonist that is indicated for allergic rhinitis and urticaria but not yet licensed in the United States.⁴⁰ Wouters et al. conducted a proof-of-concept 12-week randomized, placebo-controlled clinical trial of ebastine in patients with IBS.⁴¹ Abdominal pain was assessed weekly and clinical IBS symptoms were assessed at baseline and at the end of the12-week treatment period. A responder for abdominal pain relief was defined as a patient having at least a 30% reduction of abdominal pain scored on a 100-mm visual analogue scale (VAS) during 6 or more of the 12 study weeks. Fifty-five patients (34 females) were randomized to 20 mg ebastine or placebo. During the 12-week treatment, ebastine resulted in a steady increase in the proportion of responders in comparison to placebo. Ebastine had a significantly higher proportion of responders compared to placebo (46% vs 13%; P=0.024) with significant decrease in abdominal pain scores over the 12 weeks relative to baseline in the ebastine compared to placebo However, using the Food and Drug Administration’s definition of a responder for relief of abdominal pain, ebastine resulted in a non-significant increase of percentage of responders compared to placebo (41% vs 20%; P=0.19). Further studies in larger samples are required.

B-. Neurokinin-2 receptor antagonists

Substance P, a neurokinin (NK), and NK-2 receptors are abundant in the gastrointestinal tract and are known to mediate long-lasting contractions of smooth muscle.⁴ NK-2 receptor activation is involved in stimulation of sensory neurons and mediation of visceral reflexes. These properties provide the rationale for investigating NK-2 receptor antagonists as a potential treatment for IBS. Ibodutant, is a highly selective NK-2 receptor antagonist with high oral bioavailability and tolerability.⁴² Tack et al. conducted a phase 2 8-week, multinational double-blind, placebo-controlled trial that showed dose-dependent improvement of overall symptoms, abdominal pain, and stool pattern in females but not in males, and female patients also showed statistically significant improvement using the FDA-endorsed endpoints with the 10mg dose for example.⁴³. Van Kessel et al. postulated differences in the pathophysiology of pain in IBS between men and women to account for the efficacy only in female patients.⁴⁴

Psychotherapy and Behavioral Modification

According to a Rome working team report, Brain-Gut behavior therapy (BGBT) is defined as non-pharmacological short-term interventions administered by a clinician with the aim to decrease gastrointestinal symptoms. BGBT encompasses several techniques including disease self-management, cognitive behavior therapy (CBT), gut-directed hypnotherapy, mindfulness-based stress reduction and psychodynamic interpersonal psychotherapy.⁴⁵

1-. Disease self-management

In disease self-management, patients are empowered to become active participants in their care. A 2015 systematic review and meta-analysis included 10 randomized controlled trials with a total of 886 participants, and concluded that psychological-based guided self-help had a medium effect size on the decrease of IBS symptom severity [standardized mean difference of 0.72 (95% CI: 0.34 to 1.08); p<0.0001] and a large effect size on the increase of patients’ QOL [standardized mean difference= 0.84 (95% CI: 0.46 to 1.22); p<0.0001].⁴⁶

2-. Cognitive behavioral therapy

CBT involves unlearning maladaptive behaviors and is one of the most studied types of psychotherapy. A 2019 systematic review and meta-analysis compared the efficacy of antidepressants and psychological therapy in patients with IBS based on 9 randomized clinical trials with 610 patients. This analysis suggested that CBT was superior to control in improving IBS symptoms [RR of not improving of 0.60 (95% CI: 0.44 to0.83)]. However, there were methodological concerns including lack of blinding in some studies, funnel plot asymmetry and significant heterogeneity between studies (I²= 70%, p<0.001).¹³

A more recent systematic review and network meta-analysis concluded that CBT-based interventions and gut-directed hypnotherapy were the most efficacious long term, though high risk of bias may overestimate the efficacy of psychological therapies.⁴⁷ A multisite trial evaluating the cost-effectiveness of a minimal contact version of CBT (MC-CBT) relative to standard clinic-based CBT and a non-specific comparator of education/support revealed that MC-CBT was cost-effective and provided better symptom improvement immediately and at 6 months compared to standard CBT.⁴⁸

3-. Gut-directed Hypnotherapy

Gut-directed hypnotherapy is a form of medical hypnosis whereby patients are placed into a state of heightened awareness. In five trials that included 278 patients comparing hypnotherapy to control therapy such as supportive therapy or symptom monitoring wait-list control¹³, hypnotherapy reduced IBS symptoms including abdominal pain [RR of not improving of 0.74 (95% CI: 0.63 to 0.87)] with no significant heterogeneity detected between studies. Gut directed hypnotherapy, along with CBT-based interventions, were efficacious long term [RR of not improving of 0.67 (95% CI: 0.49 to 0.91)].⁴⁷

4-. Mindfulness

Mindfulness is defined as an intentional present-focused awareness that is clinically useful for the self-regulation of chronic pain.⁴⁹ In a randomized controlled trial with 75 IBS patients, there was a greater reduction in symptom severity in the mindfulness group compared to the control both immediately after training (26.4% vs. 6.2% reduction, P=0.006) and at 3 months follow up (38.2% vs. 11.8%, p=0.001).⁵⁰ Mindfulness-based stress reduction (MBSR) is an intensive 8-week workshop focused on the cultivation of mindfulness. In one study with 68 patients with IBS, MBSR led to a significant reduction in GI symptoms post-treatment and at 3 months follow up, with 71.6% and 76.3% responder rates respectively. Specifically, the strongest predictor was the “act with awareness” facet of mindfulness, that is defined as focusing attention on one’s current activity.⁵¹

5-. Psychodynamic -interpersonal therapy

Psychodynamic-interpersonal therapy is a BGBT based on a strong trusting collaboration between the patient and the psychotherapist. It is effective in functional somatic syndromes⁵² as well as in IBS.⁵³

In summary, diverse types of BGBT show promising results in the treatment of pain in IBS, but there is evidence of significant heterogeneity between studies and bias in most studies, notably the lack of blinding. Moreover, these interventions are rarely offered as a stand-alone therapy, should be considered in conjunction with medical therapy, and appropriate patient selection is critical such as the recognition by the patient of the relevance of a brain-gut interaction contributing to their symptoms.

Conclusion

In conclusion, the multifaceted management of pain in IBS reflects its multifactorial etiology and includes dietary modifications, medical therapy notably central neuromodulators, antispasmodics, and peppermint oil, as well as psychotherapy. While it may be that no single approach is universally successful, it is fair to conclude that advances in recent years augur well for efficacious treatments that may expand the therapeutic arsenal for pain in IBS, which is still currently an incompletely resolved clinical need.