Chronic Abdominal Pain and Irritable Bowel Syndrome: Clinical Features and Treatment Approaches

• Chronic abdominal pain is characterized by appearing intermittently or constantly for at least 6 months.
   
• Visceral pain is transmitted to the brain through the vagal, thoracolumbar, and lumbosacral afferent nerves.
   
• Non-referred visceral pain is perceived as diffuse, dull, and midline or epigastric because the afferent nervous system of this region is innervated by bilateral splanchnic nerves.
   
• The referred pain is usually close to the surface of the body, and is accompanied by cutaneous hyperalgesia and increased muscle tone of the abdominal wall. Referred pain presents in a dermatomal distribution, which correlates with the spinal cord level site of the affected visceral organ.

> History

The first step in managing chronic abdominal pain is to obtain a detailed medical history, including key factors such as onset, duration, timing, location, radiation, quality, and severity. It is important to ask about the relationship with meals and bowel movements.

A list of medications and supplements should be reviewed, along with the dosage and frequency of pain medications and nonsteroidal anti-inflammatory medications. The characteristics and location of abdominal pain may offer clues to the diagnosis.

Red flag features include, but are not limited to, onset of symptoms after age 50, severe or progressive symptoms, unexplained weight loss, night pain, recent change in bowel habits, or rectal bleeding. The presence of red flag features should raise suspicion of structural diseases and prompt further investigation. However, many patients with structural disease do not have alarming features.

> Physical examination

A detailed physical examination, including a rectal examination, is necessary to elucidate the cause of chronic abdominal pain. In the event of an acute episode of chronic abdominal pain, it is imperative to quickly rule out the possibility of a surgical abdomen. A detailed rectal examination can provide valuable information, such as active bleeding, mass, signs of constipation, pelvic floor dysfunction, or high anal rest tone.

> Approach to chronic abdominal pain

Laboratory studies including complete blood count with differential, complete metabolic panel, lipase, and urinalysis should be performed . Depending on the suspected diagnosis, abdominal imaging is usually ordered as part of the initial workup; This may include ultrasound, CT scan, or MRI.

Imaging is usually not revealing in cases of undiagnosed abdominal pain and should not be repeated unless the patient’s presentation changes. Repeat CT scans in patients with negative findings and non-traumatic abdominal pain have been shown to have poor diagnostic yield and should be avoided.

Once red flag signs are excluded and the history and physical examination do not support an alternative diagnosis or there is a long history of negative diagnostic studies, no further testing should be performed.

Diffuse abdominal pain represents an obstacle for the physician because there is no place to begin the differential creation process. It is important to review the systemic causes of abdominal pain because it is vital that the underlying disorder is recognized and treated appropriately.

Pain that is not related to eating or bowel movements, but related to movement, should raise suspicion of possible chronic abdominal wall pain. The most common cause of chronic abdominal wall pain is anterior cutaneous nerve entrapment syndrome .

It is believed to arise from entrapment of a cutaneous nerve emanating from T7-T12, caused by direct pressure, fibrosis, or edema. Successful treatment of chronic abdominal wall pain with nonnarcotic analgesics, nonsteroidal anti-inflammatory drugs, heat, or physical therapy is beneficial to the patient and confirms the diagnosis.

Musculoskeletal pain is acute and localized to an area of ​​less than 2 cm, which is in stark contrast to visceral abdominal pain. Carnett’s sign is a physical examination finding that is used with 97% accuracy to detect abdominal wall pain.

Pain on palpation increases when raising the head and contracting the rectus abdominis muscle when the Carnett test is positive. Less than 10% of patients with visceral pain have a positive Carnett test; The contraction of the abdominal wall muscles serves to protect the visceral organs from palpation, so visceral pain usually improves with this maneuver.

Disorders of gut-brain interaction (DGBI), also known as functional gastrointestinal (GI) disorders, are the most frequently encountered diagnoses in gastroenterology. The symptoms of DGBI are caused by one or more of the following: altered motility, visceral hypersensitivity, altered mucosal and immune function, altered gut microbiota, and altered central nervous system processing.

The three most common causes of DGBI include

1. Irritable bowel syndrome (IBS) (15-20%)

2. Functional dyspepsia (10%)

3. Centrally mediated abdominal pain syndrome (CAPS) (0.5-2%).

IBS is thought to be caused by increased sensitivity to visceral pain; These patients experience an exaggerated response to normal events .

IBS is a chronic relapsing-remitting disease composed of abdominal pain related to defecation and changes in bowel habits.

Rome IV defined IBS as a functional disorder of the intestine in which recurrent abdominal pain is associated with defecation or a change in bowel habits. Onset of symptoms must occur at least 6 months before diagnosis and symptoms must be present for the last 3 months.

The central nervous system is directly connected to the body’s organs that affect the body as a unit. Strong emotions, such as anxiety, fear, and anger, can alter motility and the perception of symptoms. Emotional or physical stress can increase colonic contractions, induce defecation, cause diarrhea or, conversely, delay gastric emptying and decrease colonic transit time.

Stress can alter the gut microbiome by affecting secretory and mucosal barrier functions, which can cause transmigration of bacteria leading to pain and diarrhea. However, chronic irritable bowel symptoms, such as increased motility and visceral inflammation, can contribute to depression and anxiety; the brain-gut axis is a reciprocal relationship.

Pain management is an important and largely unmet need in the treatment of IBS. There is a delicate balance between feeling pain and suppressing it, which controls the activation state of visceral afferent nerve endings.

Neurotransmitters involved in visceral sensation include 5-HT and neurokinins, making these chemicals targets for pharmacotherapy. Patients with DGBI do not have the same ability to downregulate incoming neural signals. The consequences of IBS are similar to those of other pain conditions, including difficulty sleeping, fatigue, altered mood, and decreased quality of life.

The foundation of effective management strategies is based on a strong doctor-patient relationship. It has been proposed that physicians feel less capable when treating DGBI than when treating a structural diagnosis.

It is important for the treating physician to understand that these patients are challenging, accept them as positive diagnoses, and reduce expectations of a quick recovery. It is essential to provide support and advise the patient to take personal responsibility for their treatment.

Treatment of IBS focuses on the patient’s predominant symptom and the underlying pathophysiology. There are currently no disease-modifying therapeutic agents to treat IBS; However, there are treatments that target the underlying mechanisms, such as increasing abnormal transit time and increasing bile acid concentration in the colon. Current treatment methods include lifestyle and diet modification, herbal and alternative therapies, probiotics, and pharmacotherapy.

> Exercise

Exercise has been shown to be beneficial for health because it reduces the risk of cardiovascular diseases, endocrine disorders, improves bone and muscle conditioning, and reduces levels of anxiety and depression.

Walking has been shown to improve gastrointestinal symptoms and overall anxiety; Yoga has also been beneficial in reducing the severity of symptoms in IBS. There is some evidence to suggest that reduced physical activity may be related to pain intensity levels in children with chronic pain.

> Dietary modifications

Food causes symptoms in IBS patients. There are some hypotheses for the mechanisms behind this, including

(1) altered intestinal microbiota,

(2) sensitivity to gastrocolic reflex,

(3) insoluble fiber exacerbates symptoms and

(4) Antigens in food disrupt the intestinal epithelial barrier.

It is not possible to cure IBS with a specific dietary approach due to the current knowledge of its multifactorial pathogenesis.

> Diet low in fructose, oligosaccharides, disaccharides, monosaccharides and polyols

Fructose, oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) are found in many of the fruits and legumes we eat, and are concentrated in dairy products and artificial sweeteners.

Because these chemicals are poorly absorbed, they can cause osmotic effects or fermentation, which increases bloating and increases colonic sensitivity. Reducing the intake of foods rich in these chemicals has been shown to reduce the abundance of bacteria.

The low FODMAP diet is the most effective dietary approach of all. Studies around the world have shown benefits over placebo, with between 50% and 87% of adult IBS patients responding.

> Fiber

Fibers are used as first-line therapies due to the absence of serious adverse effects, although the evidence is controversial. Psyllium treatment reduces the severity of symptoms in IBS. Its benefits are possibly due to the decrease in inflammatory effects due to the increase in the production of short-chain fatty acids or the alteration of the intestinal microbiota.

A 2011 Cochrane review that included 12 studies concluded that neither soluble ( psyllium ) nor insoluble fibers had a beneficial effect on improving symptoms compared to placebo. However, this was contradicted by another meta-analysis that used the same trials but had a combined end point for abdominal pain and global IBS symptoms where the relative risk (95% confidence interval) was 0.76.

> Gluten-free diet

There is a subset of IBS patients who do not have markers for celiac disease who benefit from a gluten-free diet. There is indeterminate evidence to recommend a gluten-free diet to all patients with IBS; Studies have small sample sizes and variable conclusions.

> Prebiotics, probiotics and synbiotics

Evidence suggesting that an imbalance in the gut microbiota also contributes to IBS has prompted the use of probiotics in the management of IBS. Prebiotics include food ingredients, such as fructo-oligosaccharides or inulin, that remain undigested in the human gastrointestinal system and can promote the growth or activity of intestinal bacteria used selectively by host microorganisms, conferring a health benefit. .

> Herbal therapies

The use of peppermint extracts has been studied in several clinical trials that evaluated the administration of enteric coated (PO) peppermint oil capsules to patients with IBS for 4 to 8 weeks and was found to be associated with a significant increase in quality of life while patients took the oil.

> Pharmacotherapy for irritable bowel syndrome

IBS treatment is unique for each patient and is directed at the predominant or most problematic symptom. There is no single pathological process or pathophysiological explanation for the symptoms; Therefore, it makes sense to focus on symptoms, such as pain and diarrhea or pain and constipation, when understanding the natural history of the disorder.

IBS subtypes are based on the predominant stool pattern used to dictate treatment options, such as constipation-predominant IBS (IBS-C), IBS-D, or mixed stool pattern.

> Antispasmodic drugs

Antispasmodics are a group of drugs that have been used in the therapy of IBS for decades. A subgroup of patients with IBS is known to have altered GI transit and abnormal smooth muscle contractility that contributes to alterations in bowel habit and pain.

Drugs with various mechanisms of action are included, including anticholinergic agents (i.e., butyl scopolamine, hyoscine, cimetropium, bromide, pirenzepine), direct smooth muscle relaxants (PO, papaverine, mebeverine), and calcium channel blockers (calcium citrate). alverine, otilonium bromide, pinaverium bromide) that contribute to pain relief in IBS.

A systematic review and meta-analysis of 22 RCTs compared various antispasmodics with placebo in 1778 patients and found that antispasmodic agents were more effective than placebo in the treatment of IBS; however, these studies detected statistically significant heterogeneity.

However, this meta-analysis studied many drugs not available in the United States, including otilonium bromide and pinaverium, which had the strongest data. Subgroup analyzes for different types of antispasmodics found that the use of cimetropium/dicyclomine, PO, pinaverio, and trimebutine presented statistically significant benefits.

> Antidepressants and psychological treatment

Physiological factors seem to be related to one of the pathophysiological aspects of the manifestation of IBS. There has been some evidence of an association between IBS and psychiatric disorders.

Tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (duloxetine, venlafaxine) are useful in the treatment of chronic pain syndromes due to their noradrenergic and serotonergic effects.

These drugs are also useful in patients with coexisting psychological disorders, which is not uncommon in IBS. Patients may not want to take these medications initially due to the stigma that they only treat psychiatric conditions; Therefore, it is imperative to explain that they are used to treat pain centrally.

Cognitive behavioral therapy is implemented to improve symptom control by adapting maladaptive perceptions, thoughts, and behaviors. Hypnosis and dynamic psychotherapy have been studied in IBS.

> Drugs that act on opioid receptors

Opioids have pharmacological effects throughout the gastrointestinal tract. In the esophagus, they decrease the tone of the lower esophageal sphincter and cause simultaneous contractions. Opioids affect the gallbladder causing increased contraction leading to biliary pain, spasm of the sphincter of Oddi and decreased emptying of the gallbladder. They can also cause anxiety, nausea, vomiting, and gastroparesis by decreasing gastric motility and increasing pyloric tone.

In the small intestine and colon, transit time, tone, and absorption increase, resulting in postoperative ileus, constipation, bloating, and distension. Patients may also experience decreased rectal sensitivity or exertional constipation due to contraction of internal sphincter tone caused by opioids.

Loperamide , an m-opioid receptor agonist (which does not cross the blood-brain barrier), is an antidiarrheal agent used in the treatment of diarrhea in patients with IBS. Its effectiveness is based on little RCT evidence.

There is no evidence to support the use of loperamide for chronic pain in IBS. One study included 90 patients in a prospective double-blind trial comparing loperamide with placebo for 5 weeks. This study demonstrated better stool consistency, lower defecation frequency, and lower pain intensity.

Eluxadoline is a new mixed myk opioid receptor agonist and d opioid receptor antagonist agent used to treat diarrhea. Lacy et al. reported that eluxadoline effectively and safely treated IBS-D symptoms of abdominal pain and diarrhea in patients who reported adequate or inadequate control of their symptoms with prior treatment with loperamide.

> 5-HT3 receptor antagonists

Ninety percent of the body’s total amount of serotonin (5-HT) is found in the enterochromaffin cells of the intestine. Patients with IBS-D have elevated postprandial levels of serotonin, while patients with IBS-C have decreased postprandial levels.

Alosetron is a selective 5-HT3 receptor antagonist approved by the Food and Drug Administration (FDA) for the treatment of women with IBS-D who have not responded to conventional therapy. One study recruited patients using the Rome III criteria and found that the overall treatment response rate was 44.6%, demonstrating control of the two cardinal symptoms of IBS-D, abdominal pain and diarrhea. evaluated by the composite endpoint. This trial also found that fecal urgency, another major symptom of IBS-D, improved significantly during this study.

Network meta-analysis evaluating the efficacy of licensed drug therapies (alosetron, eluxadoline, ramosetron, and rifaximin) in adults with IBS-D or IBS with mixed stool pattern found that all drugs were superior to placebo, but alosetron and ramosetron seemed be the most effective.

This class of drugs can induce constipation, which is controlled by adjusting the dose. Alosetron has been reported to be associated with ischemic colitis in approximately 1:800 people treated.

> Bile acid sequestrants

Recent studies have documented that more than 25% of IBS-D patients have evidence of bile acid diarrhea and have improvement of symptoms with bile acid sequestrants. Bile acid diarrhea is diagnosed by the fecal bile excretion test or fasting serum C4 (7-a-hydroxy-4-cholesten-3-one).

Intraluminal bile acid binders, such as colesevelam and colestipol, have shown benefits on intestinal symptoms and global symptoms in patients with IBS-D. The use of bile acid sequestrants is limited by their poor palatability.

> Antibiotics

Rifaximin has minimal absorption in the gastrointestinal tract, it is a broad-spectrum antimicrobial with activity against aerobic and anaerobic gram-positive and gram-negative organisms. It works by reducing the amount of gas-producing bacteria and altering the predominant species of bacteria present.

Some IBS patients have an underlying small intestinal bacterial overgrowth detected on the hydrogen breath test; however, there is a risk of false positive tests caused by rapid small bowel transit, which is seen in this population.11

Two phase 3 trials showed that treatment with rifaximin at a dose of 550 mg three times a day for 14 days provided better relief of global IBS symptoms in patients without constipation than placebo up to 10 weeks after completion of treatment. .50 The safety profile of rifaximin was similar to that of placebo.50

Additional research is needed on optimal dosage and duration of treatment. A double-blind, randomized, placebo-controlled trial conducted between 2010 and 2013 at three tertiary care centers found that rifaximin plus neomycin was superior to neomycin alone in improving constipation (p = 0.007), straining (p = 5.017) and swelling. (P 5 .020) .51 Rifaximin is currently approved by the FDA to treat patients with IBS-D and allows up to two cycles of retreatment for symptom relapse.

> Intestinal secretagogues

In the last decade, the FDA approved several new secretagogues for the treatment of IBS-C; these include lubiprostone, linaclotide and plecanatide. They are also approved for chronic idiopathic constipation. Tenapanor is pending approval for IBS-C. These drugs were examined in a systematic review and network meta-analysis, which demonstrated their efficacy in placebo-controlled trials in IBS-C, and were more effective than placebo in reducing global symptoms.

Lubiprostone is a prostaglandin derivative that activates the intestinal chloride channel type 2 in the apical membrane of small intestinal enterocytes. Activation leads to the release of chloride and water into the lumen. Lubiprostone was evaluated at a daily dose of 16 mg (8 mg twice daily) versus placebo (twice daily) for 12 weeks in two phase 3, double-blind, randomized, placebo-controlled trials.

Lubiprostone led to a significantly higher number of overall responders and improved individual symptoms in patients with IBS-C compared to placebo; the overall incidence of adverse events was similar to placebo. Another analysis showed that lubiprostone was significantly more effective than placebo in reducing abdominal pain and bloating according to FDA-recommended criteria.

Linaclotide and plecanatide are minimally absorbable peptides that stimulate the guanylate cyclase-C receptor, leading to transport of electrolytes and fluids into the intestinal lumen . In a large phase 3 clinical trial, patients with IBS-C were treated with oral linaclotide 290 mg once daily over a 12-week treatment period, followed by a 4-week randomized withdrawal period.

Linaclotide achieved a statistically significant improvement in abdominal pain and constipation compared with placebo, and there was no worsening of symptoms compared to baseline after discontinuation of linaclotide during the withdrawal period.

Adults meeting Rome III criteria for IBS-C were randomly assigned to placebo or plecanatide (3 or 6 mg) for 12 weeks in two identical, phase 3, randomized, double-blind, placebo-controlled trials. Plecanatide significantly improved stool frequency/consistency. , straining, and abdominal symptoms compared with placebo, and the drug was highly tolerated with approximately 1.3% of patients discontinuing the drug due to diarrhea.

Tenapanor is a first-in-class small molecule inhibitor of sodium-hydrogen GI exchanger 3, which results in increased intraluminal excretion of sodium and water. In a double-blind, phase 2 study by Chey et al., patients with IBS-C had a significant increase in stool frequency and reduced abdominal symptoms after receiving tenapanor 50 mg twice daily. These benefits were maintained over the 12-week treatment period.

> g-aminobutyric acid analogues

G-aminobutyric acid analogues, such as pregabalin and gabapentin, are being studied for use in IBS. Some preliminary reports show it may play a role in reducing symptoms; however, there is insufficient data to support its use.

The IBS field lacks the presence of validated biomarkers, bile acid metabolism or colonic transit time, that can be objectively measured during treatment. There remains a considerable unmet need for effective and safe visceral analgesics.

More high-quality studies, such as RCTs, are needed that focus on the pathophysiological mechanisms underlying IBS. The most effective current therapies for visceral pain primarily target intestinal dysfunction (eg, 5-HT3 antagonists).

Therapies such as lifestyle modifications, dietary changes, and cognitive behavioral therapy should be used in conjunction with pharmacotherapy rather than pharmacotherapy alone.