Precision Medications for Irritable Bowel Syndrome with Predominant Constipation (IBS-C)

Written by

Dr Robert Varley, Department of Gastroenterology, Connolly Hospital, Dublin, Ireland

Professor Richard J Farrell , Department of Gastroenterology, Connolly Hospital, Dublin, Ireland

Irritable Bowel Syndrome (IBS) is one of the most common gastrointestinal disorders seen in clinical practice. In recent years, significant advances have been made in understanding its complex pathophysiology, with considerable new evidence published concerning its diagnosis, investigation and management. This led to the British Society of Gastroenterology (BSG) publishing updated IBS clinical practice guidelines in 2021.1 In this review, we will outline the approach to diagnosing and managing IBS with Predominant Constipation (IBS-C).

How is IBS diagnosed?

IBS is a clinical diagnosis of exclusion. All patients presenting with symptoms of IBS for the first time must be investigated with:

1. Full blood count (FBC)

2. C reactive protein (CRP) or erythrocyte sedimentation rate (ESR)

3. Coeliac serology: Anti-tissue transglutaminase (Anti-TTG) and IgA levels

4. Thyroid function tests, Calcium and Magnesium levels

5. Faecal calprotectin in under 45 year olds, to exclude inflammatory bowel disease

Local and national guidelines for colorectal and ovarian cancer screening should be followed. In Ireland, all patients aged 6070 should participate in Bowel Screen, the national colorectal cancer screening programme and a home FIT test can be arranged by contacting 1 800 454555.

Colonoscopy is not indicated in IBS without alarm symptoms or signs (summarised in Box 1).1 However, it should be considered in those patients with symptoms suggestive of IBS with diarrhoea who have atypical features and/or relevant risk factors for macroscopic or microscopic colitis (female sex, age ≥50 years, family history of inflammatory bowel disease, coexistent autoimmune disease or inflammatory arthropathy/skin rashes, nocturnal or severe, watery diarrhoea, duration of diarrhoea <12 months, weight loss or use of potential precipitating drugs for microscopic colitis including nonsteroidal anti-inflammatory drugs, aminosalicylates, proton pump inhibitors, statins and SSRIs, etc)

A diagnosis of IBS should be made based on symptoms, the absence of alarm symptoms or signs, and no abnormalities on the above simple blood and stool tests. Referral to gastroenterology is warranted where there is diagnostic doubt, in patients with symptoms that are severe, or refractory to first-line treatments, or on individual patient request.

IBS is diagnosed using the Rome Criteria, last updated as Rome IV in 2016.2 Criteria must be fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis:

Recurrent abdominal pain on average at least 1 day/week in the last 3 months, associated with two or more of the following criteria:

1. Related to defaecation

2. Associated with a change in frequency of stool

3. Associated with a change in form (appearance) of stool

IBS is further subdivided by predominant symptom, summarised in Figures 1 + 2.2 As shown, IBS with Predominant Constipation (IBS-C) requires over 25% of abnormal bowel movements to be very solid (Bristol stool type 1 and 2) with less than 25% being very loose (Bristol stool type 6 and 7).

How is IBS-C Managed?

 The treatment algorithm for IBS is shown in Figure 3, with overall diet and lifestyle advice followed by treatments directed towards predominant symptoms1

 New patients should be given a clear explanation of the diagnosis, pathophysiology, natural history and the most common symptom triggers

 IBS should be explained as a disorder of gut-brain interaction, with the impact of diet, stress, cognitive, behavioural and emotional responses to symptoms, as well as postinfective changes

 To manage expectations, there should be a realistic discussion regarding the limitations of treatments - while there is no cure, significant improvements in symptoms and quality of life are very achievable

 In IBS-C, the treatment target is the normalisation of bowel movement pattern, defined as at least three completed spontaneous bowel movements per week

 It is important to exclude excessive use or dependence on opiates as well as iron tablets, calcium containing antacids and some anti-depressants all of which can contribute to chronic constipation.

 Treatment should commence with either dietary therapies or first-line drugs, as per patient preference

 Second-line drugs are reserved for those not improving with these measures, with many second-line drugs only available in secondary care

 The efficacy of a treatment should be evaluated after 3 months, and discontinued if no response with escalation to the next available treatment

1. Fibre and Dietary Therapy:

 First line dietary advice should be offered to all patients with IBS. This includes eating regular meals, maintaining adequate nutrition, limiting alcohol and adjusting caffeine and fiber intake (increase if constipation, reduce if diarrhoea), and reducing intake of spicy and fatty foods

 Adjusting fruit intake is often critical to managing constipation (reducing bland fruit intake such as bananas, applesauce while increasing more colourful fruit intake such as kiwis, prunes, plums, pears, apples, oranges)

 For IBS-C and IBS-M, diet and lifestyle measures including drinking plenty of water, regular exercise and a high-fibre diet (up to 30g/day) are recommended

 Soluble fibre, such as isphagula (Fybogel), is a bulk-forming laxative and an effective treatment for IBS global symptoms while FybogelMebeverine may be helpful for IBS with constipation or altered bowel habit presents in conjunction with abdominal pain or cramps. This should be commenced at a low dose (3-4g/day) and built up gradually (to 20-30g/day) to avoid bloating

 Insoluble fibre (e.g. wheat, bran) should be avoided as it may exacerbate symptoms

 A diet low in fermentable oligosaccharides, disaccharides, monosaccharides and polyols (i.e. the low FODMAPs diet) is an effective second-line dietary therapy for IBS global symptoms and abdominal pain. It is not effective for managing constipation. Its implementation should be supervised by a dietician, with foods reintroduced according to tolerance.

 Food elimination diets based on IgG antibodies and a gluten-free diet are not recommended and should never be implemented in advance of checking TTG/IgA coeliac serology tests.

2. Probiotics:

 Probiotics significantly improve IBS global symptoms and in particular distention and abdominal pain

 These is currently insufficient evidence to recommend a particular species or strain

 Patients wishing to try probiotics are advised to take them for up to 12 weeks, and discontinue if no improvement in symptoms

 Commonly prescribed probiotics include Alforex, Udos Super 8 and Symprove

3. Laxatives - First-line Drugs for IBS-C:

 Laxative doses should be titrated according to symptoms

 Both osmotic and stimulant and osmotic laxatives are effective in the treatment of chronic idiopathic constipation but long term use of osmotic laxatives are favoured over stimulant laxatives to minimise laxative abuse or a lazy or laxative bowel.

 Osmotic laxatives: lactulose (Duphalac), macrogol (Movicol), polyethylene glycol

 Stimulant laxatives: bisacodyl (Dulcolax), senna (Senokot), sodium picosulfate

 Only osmotic laxatives have been formally evaluated for IBS-C, with limited efficacy seen - across two RCTs, polyethylene glycol significantly increased bowel movements in one trial with no significant effect on abdominal pain in either trial

4. Second-line Drugs for IBS-C and severe constipation: In patients with severe IBS-C and constipation not improving with laxatives (i.e patients who go 4-5 days or over a week between bowel motions despite taking 3-4 Movicol sachets daily, escalation to second-line treatments should be considered. These include two medication classes 5HT4 agonists and Secretagogues:

5HT4 Agonists: These are prokinetic agents, stimulating propulsive gut motility. Examples include:

1) Prucalopride (Resolor): Shown to improve abdominal pain, bloating and frequency of bowel movements in large multiple randomised controlled trials in patients with idiopathic chronic constipation. The safety profile has been encouraging, especially the absence of arrhythmogenic potential. The standard dose is 2mg OD with or without food at any time of the day with some patients reporting increased efficacy up to 4mg daily. To date, there have been no trials specifically for IBS-C

2) Tegaserod: Licenced in the USA for IBS-C in females under 65 years of age with no prior cardiovascular disease history. It is not currently licenced by the EMA

B.Secretagogues: These activate ion channels on the intraluminal surface of enterocytes, causing efflux of ions and water into the lumen, softening stool and accelerating transit. Examples include:

1) Linaclotide (Constella): A guanylate-cyclase c agonist that improves abdominal pain, bloating and frequency of bowel movements. The standard dose is 290µg OD. Across all trials, It is the most efficacious secondline IBS-C treatment but has the highest rate of side-effects, most commonly diarrhoea (over 10%)

2) Lubiprostone (Amitiza): A chloride channel activator that improves abdominal pain, bloating and frequency of bowel movements. The standard dose is 24μg BD. It is efficacious with lower rates of diarrhoea than linaclotide but nausea is common (30%)

3) Other secretagogues: Plecanatide and tenapanor have similar efficacy and safety profiles to linaclotide and lubiprostone. They are licenced for IBS-C in the USA but not currently by the European Medical Agency (EMA)

5. Psychological Therapies:

 IBS-specific Cognitive Behavioural Therapy (CBT) and Gut-directed Hypnotherapy are two areas of ongoing research that may be efficacious in global IBS symptoms

 These should be considered when symptoms have not improved after 12 months of drug treatment, or earlier if locally available or patient preference

 Their role specifically in IBS-C needs further evaluation

As you can see, there are many novel therapeutic options in IBS-C, offering patients many and varied treatments that can significantly improve symptoms as well as quality of life. Furthermore, this remains an area with considerable ongoing research, hopefully providing patients with even more treatment options in the coming years.