Management Of Functional Gastrointestinal DisordersⅢ
Nov 09, 2023
Pharmacotherapy
Biological management of FGID involves either treating the underlying pathophysiology (ie neuromodulators to treat visceral hypersensitivity) or treating the symptoms (eg antiemetics to treat nausea or laxatives to treat constipation). Various algorithms exist to help guide this for functional dyspepsia and IBS (Fig 2).10,41 For this review, a symptom-based approach is presented.
Pain
Opiates should be avoided as they are associated with dependence, tolerance, and addiction, and can lead to narcotic bowel syndrome which causes bloating, constipation, nausea, and a paradoxical increase in pain with increasing doses of opiates.42 Instead, first-line management of pain involves antispasmodics for colicky pain. In more resistant cases, often characterized by chronic burning/neuropathic pain, neuromodulators are used as second-line treatment.
First line: antispasmodic
Antispasmodics are useful for colicky abdominal pain in IBS. There is good evidence for hyoscine (10–20 mg three times a day (TDS); NNT 3) and dicycloverine (10–20 mg tds; NNT 4), though these can cause anticholinergic side effects of dry eyes and a dry mouth, and can worsen constipation. There is also evidence for peppermint oil (eg Coppermine 2 capsules tds; NNT 4). It can cause heartburn, so it may be best avoided for patients with coexisting GORD.30 The evidence for mebeverine (135 mg TDS) is not as good, however, it is well tolerated and can be very effective in a group of patients who do not respond to other antispasmodics.30 Our practice is to trial a second antispasmodic if the first fails to control colicky abdominal pain.
Second line: neuromodulators
Antidepressants.
The most commonly used antidepressants are tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). As a rule, antidepressants improve symptoms, particularly abdominal pain, as well as psychological distress in FGID, and the effect is increased in secondary compared with primary care, which probably reflects the greater psychological and pain comorbidity in the former.31 For every four patients treated with an antidepressant, one will get better.
Most antidepressants will have GI side effects and can cause either constipation or diarrhea (supplementary material S1), so choosing your antidepressant wisely can also help treat the altered bowel habit in IBS. TCAs (eg amitriptyline) are useful for patients with diarrhea by slowing GI transit, whereas SSRIs (eg sertraline, citalopram, fluoxetine) are useful for those with constipation by accelerating transit.
There are no RCTs of serotonin noradrenergic reuptake inhibitors (eg duloxetine) in FGID, however, open-label studies for patients with IBS and comorbid anxiety and depression show that it is well tolerated at a total dose of 60 mg per day and improved IBS symptoms as well as depression and anxiety.43,44
Treatment with antidepressants is for an average of 18 months and stops once patients are symptom-free for at least 6 months. To improve compliance, it is important to clarify to the patients that antidepressants are used primarily to target the IBS symptoms, notably pain, rather than mood. It is important to pre-warn patients about the side effects and, if necessary, start at a very low (subtherapeutic) dose and work up slowly, to reduce adverse effects and therefore improve compliance. We would caution against using more than one antidepressant at a time unless there is expertise in doing this.
Gabapentinoids. Pregabalin and gabapentin are commonly used in chronic pain conditions and have a role in treating visceral hypersensitivity in FGID. Pregabalin is associated with an improvement in IBS symptoms (bloating, diarrhea, and abdominal pain) compared with a placebo, so is a good choice for IBS-D.45 This should be started at a low dose of 50 mg twice a day (bd) and increased gradually in line with the symptomatic response, to a maximum of 300 mg bd, although it is not typically necessary to increase beyond 225 mg bd (3 × 75 mg tablets bd).45 It causes weight gain, so may not be the best choice for obese individuals. Clinicians should be aware that it is addictive and is now considered a drug of abuse, so should be chosen with caution in certain patients. Gabapentin is an alternative but tends to have a worse side effect profile. Although there are no RCTs evaluating the efficacy of gabapentin on IBS symptoms nor the optimal dose for symptom improvement, one study demonstrated that, for patients using 300 mg gabapentin daily, there was a reduction in rectal sensitivity to distension and an increase in the thresholds for abdominal pain, bloating, and discomfort.46
Diarrhea
First line: loperamide Loperamide (Imodium) reduces stool frequency and improves stool consistency in IBS-D, however, it is not effective at reducing abdominal pain or bloating, so it is poorly tolerated in IBS patients.30 Loperamide–simethicone chewable product (Imodium plus) is much better tolerated and results in quicker relief from diarrhoea and greater relief from abdominal discomfort compared with loperamide alone or a placebo and, therefore, this should be preferentially recommended to patients who have IBS-D.47 Patients can be asked to take two tablets to start with and then one tablet after each unformed stool until the diarrhea stops (up to a maximum of eight tablets per day).
Second line: ondansetron Ondansetron, a 5HT3 antagonist, improves stool consistency, frequency, urgency, and bloating but not abdominal pain compared with a placebo or to mebeverine for patients with IBS-D, so it is especially useful for patients who are more troubled with the altered bowel habit than the pain.48 As it is an antiemetic, it can also improve nausea for patients who have overlapping dyspepsia. Alosetron was the precursor to ondansetron for IBS-D, however, it was associated with ischaemic colitis and therefore withdrawn. In a meta-analysis of patients with IBS-D and IBS-M, patients on 5HT3 antagonists did better than those on eluxadoline and rifaximin (see later), so it is worth considering the use of ondansetron early for patients with IBS-D.49
Third line: rifaximin and eluxadoline Rifaximin is a non-absorbable antibiotic used in the treatment of GI disorders. A meta-analysis demonstrated that rifaximin is superior to placebo for reducing symptoms of diarrhea and bloating in non-constipated patients with IBS, however, it did not affect pain.30,50 Recent unpublished evidence suggests that with 550 mg bd for 2 weeks, this effect may be sustained for at least 12 weeks after taking the antibiotic. However, rifaximin remains unlicensed for use in IBS in the UK and the long-term effects on the microbiota are unknown, so it is difficult to make evidence-based recommendations about this antibiotic at the current stage. Eluxadoline is an opioid receptor antagonist which reduces stool frequency and improves global IBS symptoms, however, because of the association with pancreatitis, it is avoided for patients with a risk factor for acute pancreatitis (eg a prior history of pancreatitis, previous cholecystectomy, gallstones or alcohol).30 The RELIEF RCT demonstrated that, in non-responders to Imodium who have an intact gallbladder, eluxadoline can help reduce stool frequency and improve pain over 12 weeks compared with placebo. A typical dose is 100 mg bd but this can be reduced to 75 mg bd in the case of side effects (eg nausea, abdominal pain, constipation, and vomiting).51
Constipation
First line: osmotic laxatives Polyethylene glycol (PEG)-based laxatives (such as Movicol and Laxido) as well as lactulose help to draw water into the bowel to soften the stool. Although they are associated with an increase in the frequency of bowel movements, they do not alleviate pain in IBS. Lactulose can make bloating worse. In practice, it is useful to use osmotic laxatives to improve stool frequency for patients with constipation/IBS-C but this would need to be coupled with other agents to help with other symptoms such as pain.
Second line: prucalopride Prucalopride is a highly selective 5HT4 agonist that acts as a prokinetic in the gut. An RCT demonstrated its efficacy in all patients with chronic constipation and in women with chronic constipation in whom laxatives have failed to provide adequate relief.52 According to NICE, it is licensed for women in whom treatment with two laxatives has failed. A typical dose is 2 mg daily. A higher dose of 4 mg daily will result in improvement in straining than in stool frequency but will also be associated with greater side effects (such as headache, nausea, and diarrhea).52,53 Patients who do not respond in the first 4 weeks are unlikely to do so with more treatment, so this can then be stopped. Prucalopride also acts as a gastric prokinetic, so it can be useful for patients with dyspepsia/gastroparesis-type symptoms and would be a good choice for patients who have IBS-C and functional dyspepsia overlap.
Third line: secretagogues If the above measures fail, then the third-line option involves the use of secretagogues (linaclotide and lubiprostone) which improve bowel frequency and overall IBS symptoms. Some patients experience unwelcome diarrhoea with this so it may be worth reducing the dose in that case. Linaclotide results in increased chloride and bicarbonate secretion into the gut lumen which leads to increased fluid secretion and intestinal transit. It improves bowel frequency and reduces bloating compared with placebo; this effect is similar even if the dose (290 μg) is reduced to 72 μg, which reduces diarrhea (a common cause for discontinuation) and therefore may improve compliance.54,55 Lubiprostone at a dose of 8 μg bd improves abdominal pain, bloating, and stool frequency in IBS-C more than placebo but can be associated with nausea.56
Functional dyspepsia This is the second most common FGID and can be divided into epigastric pain syndrome (EPS), characterized by epigastric pain and burning unrelated to meals, and postprandial distress syndrome (PDS) which causes early satiety, postprandial fullness, nausea, and epigastric bloating. A proportion of patients with FD will also have mild to moderate delays in their gastric emptying (Fig 2b).
First line: proton pump inhibitors and H pylori eradication therapy A meta-analysis showed that H pylori eradication provides significant symptomatic benefits in the long term (>6 months) rather than short term (<6 months); but patients with functional dyspepsia are more likely to experience side effects including diarrhea. It is therefore important to encourage them to remain compliant and complete the course and to ensure eradication following this if they have ongoing symptoms. Patients who are proton pump inhibitor (PPI) responsive should be continued on the lowest dose needed to manage symptoms, and if this is not effective, it should be stopped.10
Second-line treatment: H2 blockers and prokinetics H2 blockers. In a meta-analysis of treatments for functional dyspepsia, H2 antagonists (such as ranitidine) are comparable to, if not more effective than, PPIs. This is not surprising given the increasingly important role played by mast cells and histamine in the development of functional dyspepsia.10 Translating this to clinical practice, it is worth trialing H2 blockers for patients with FD even when PPIs have failed, although, in the current climate, the supply issues with these medications may make this difficult in practice.
Prokinetics. Prokinetics can be used in PDS, particularly if there is
delayed gastric emptying. They improve symptoms but not quality
of life.57 Many prokinetics represented in RCTs are not available in
the UK (eg itopride, acotiamide, cisapride, and mosapride), however,
these were no more effective than domperidone, which is available
in the UK. Domperidone has been associated with increased QT
intervals which have limited its use, however, for patients with a
normal QT interval, domperidone can be safely trialed, although
it is important to recheck electrocardiography once the patient is
established on domperidone. There are no trials assessing other
prokinetics (such as metoclopramide and erythromycin) in FD,
however, theoretically, these can be used in the short term.
Third line: neuromodulators The evidence for antidepressants in functional dyspepsia is less clear but there seems to be a role for low-dose TCAs such as amitriptyline (10–30 mg nocte) or imipramine (25 mg daily for 2 weeks then 50 mg daily) for patients with epigastric pain (ie epigastric pain syndrome).58,59 Patients need to be warned about anticholinergic side effects, which can reduce compliance. Mirtazapine is increasingly gaining popularity, especially for patients with postprandial symptoms (ie discomfort, fullness, and nausea post-meals). It improves symptoms and nutrient tolerance even in the absence of coexisting depression and anxiety and causes weight gain, so would be ideal for patients with symptoms of postprandial fullness who are underweight.60 It also improves sleep and mood which will have a beneficial effect on global symptoms. Patients should start at 15 mg nocte and increase monthly to a maximum of 45 mg. A meta-analysis has demonstrated that there is no role for SSRIs (eg sertraline, fluoxetine, or citalopram) in FD.58 Buspirone is an anxiolytic that can improve gastric accommodation and can be useful for patients with postprandial fullness and early satiety but is associated with poorly tolerated side effects of dizziness and somnolence so not the first choice of neuromodulator.10
Conclusion
FGIDs are common but complex disorders that are associated with a lot of morbidity and associated psychopathology. As the etiology of these disorders is still incompletely understood there remains no cure for them. Treatment involves a good therapeutic relationship and a holistic approach to treating the patient rather than disease, using a biopsychosocial model.
Natural Herbal Medicine For Relieving Constipation-Cistanche
Cistanche is a genus of parasitic plants that belongs to the family Orobanchaceae. These plants are known for their medicinal properties and have been used in Traditional Chinese Medicine (TCM) for centuries. Cistanche species are predominantly found in arid and desert regions of China, Mongolia, and other parts of Central Asia. Cistanche plants are characterized by their fleshy, yellowish stems and are highly valued for their potential health benefits. In TCM, Cistanche is believed to have tonic properties and is commonly used to nourish the kidney, enhance vitality, and support sexual function. It is also used to address issues related to aging, fatigue, and overall well-being. While Cistanche has a long history of use in traditional medicine, scientific research on its efficacy and safety is ongoing and limited. However, it contains various bioactive compounds such as phenylethanoid glycosides, iridoids, lignans, and polysaccharides, which may contribute to its medicinal effects.
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