Autonomic Neuroscience: Basic and Clinical 215 (2018) 70–77

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Autonomic Neuroscience: Basic and Clinical

journal homepage: www.elsevier.com/locate/autneu

Review

The gastrointestinal symptoms present in patients with postural tachycardia T

syndrome: A review of the literature and overview of treatment☆
⁎
Gisela Chelimskya, , Thomas Chelimskyb
a
Department of Pediatrics, Division of Pediatric Gastroenterology, Medical College of Wisconsin, United States of America
b
Department of Neurology; Medical College of Wisconsin, United States of America

A B S T R A C T

Orthostatic intolerance, including postural tachycardia syndrome, is often associated with gastrointestinal symptoms. In the vast majority of the cases, the gas-
trointestinal symptoms are not secondary to the orthostatic disorder, but rather just a comorbid condition. This concept is critical, since treatment aimed at the
orthostatic condition will not improve the gastrointestinal symptoms. Only when the gastrointestinal symptoms develop in the upright position and improve or
resolve in the supine position, they may be related to the orthostatic stress.
The most common symptoms associated with orthostatic intolerance include nausea, dyspepsia, bloating and constipation. The majority of subjects do not have
gastroparesis. The chapter discusses available treatments of these conditions.

1. Introduction: what comorbidities are part of postural that develop while standing and resolve when supine are part of the
tachycardia syndrome (POTS)? orthostatic disorder per se, while the symptoms that are present irre-
spective of body position are simply comorbid conditions and do not
Postural tachycardia syndrome (POTS) as well as orthostatic intol- constitute an intrinsic manifestation of the POTS syndrome or the or-
erance (OI) is associated with gastrointestinal (GI) symptoms, such as thostatic disorder. Such conditions will typically occur with or without
nausea, epigastric discomfort, sometimes vomiting (Ojha et al., 2011; OI. The importance of this differentiation lies in the choice of treatment
Antiel et al., 2008; Safder et al., 2009). OI is defined as difficulties strategy.
tolerating the upright position due to symptoms, that resolve or im- To investigate this concept, we compared the co-morbid conditions
prove drastically when in the supine position (Stewart et al., 2018). in patients with chronic overlapping pain condition with and without
POTS is defined as having daily symptoms of chronic OI with an ex- POTS. We found that the comorbidities present in subjects with POTS
cessive tachycardia of > 40 bpm in the first 10 min of upright tilt, and those without POTS were not significantly different. These co-
without a significant drop in the blood pressure. In this chapter, we will morbidities included fatigue, sleep complaints, dizziness, syncope, mi-
use the term OI when symptoms worsen or develop in the upright po- graines, chronic nausea, fibromyalgia and joint hypermobility. Given
sition. POTS is one of the disorders included in chronic OI (Stewart that all the comorbidities were similar, we concluded that POTS was
et al., 2018). not the driver of the comorbidities (Chelimsky et al., 2015). Similar
Our understanding of the association of orthostatic disorders with findings were described by Antiel et al., 2008. This concept is critical.
GI issues has recently evolved. On the one hand, POTS is comorbid with Many patients and physicians attribute all the comorbid conditions to
many other syndromes, such migraine headaches, fibromyalgia, chronic POTS or OI leading to disappointment when either the patient has no
fatigue, nausea, sleep disorders, abdominal pain, etc. (Ojha et al., 2011) POTS on autonomic testing (which were ordered in an attempt to ex-
On the other hand, some symptoms develop mainly in the upright po- plain these symptoms) or concerned that the comorbid symptoms did
sition. It is critical to conceptually differentiate these two categories of not improve with treatment aimed at the orthostatic challenge.
associations: co-morbid disorders without an orthostatic mechanism
(e.g. chronic idiopathic nausea) and symptoms secondary to the or-
thostatic changes that primarily occur in the upright position and im-
prove when the person is supine (e.g. upright nausea). The symptoms

☆
This work was supported by an Advancing Healthier Wisconsin 5520298 grant.
⁎
Corresponding author at: Medical College of Wisconsin, Division of Pediatric Gastroenterology, 8701 Watertown Plank Road, Milwaukee, WI 53226, United
States of America.
E-mail address: [email protected] (G. Chelimsky).

https://doi.org/10.1016/j.autneu.2018.09.003
Received 19 February 2018; Received in revised form 6 September 2018; Accepted 6 September 2018
1566-0702/ © 2018 Published by Elsevier B.V.
G. Chelimsky, T. Chelimsky Autonomic Neuroscience: Basic and Clinical 215 (2018) 70–77

2. Upper gastrointestinal symptoms reproduced during an headache, nausea and vomiting. Therefore, it is important to assess for
orthostatic challenge in OI: which symptoms and why other possible causes of nausea replicated in the upright position
(Michali-Stolarska et al., 2017).
Such symptoms are defined by replication during the upright posi-
tion and resolution or significantly improvement once supine. A few 3. POTS and gastroparesis
elegant studies have shown the relationship of the orthostatic challenge
and gastrointestinal symptoms. The gastrointestinal symptoms that Despite the high prevalence of nausea in subjects with POTS, only
often occur during HUT include nausea and abdominal pain (Fortunato 9–18% show delayed gastric emptying; the majority has normal gastric
et al., 2011; Fortunato et al., 2014; Sullivan et al., 2005). Moak et al. emptying (34–64%) or accelerated gastric emptying (27–48%)
performed 24-h antroduodenal manometry studies in pediatric patients (Loavenbruck et al., 2015; Park et al., 2013). Interestingly, the symp-
with OI and GI symptoms and tilted the subjects during the antroduo- toms of delayed gastric emptying and accelerated gastric emptying are
denal motility study. The vast majority of the patients reproduced the very similar. Patients with fast gastric emptying may complain of
GI symptoms during tilt, suggesting that the symptoms were related to nausea, feeling faint, bloating followed by diarrhea, feeling lethargic,
the orthostatic challenge. Furthermore, the head up tilt (HUT) induced usually within the first 3 h after a meal. The symptoms are related to a
abnormalities in antroduodenal motility in 68% of the subjects, with drop in serum glucose due to dumping. This can be evaluated with an
neurogenic intestinal dysmotility, antral hypomotility, visceral hyper- extended glucose tolerance test, which will show an appropriate in-
algesia, and regurgitation or a combination of these findings (Moak crease in glucose followed by a drop in serum glucose between 150 and
et al., 2016). Sullivan et al. (2005) and later Fortunato et al. (2011) 300 min after the glucose load. These subjects will often respond to a
documented that nausea replicated during HUT often improves with change in diet, “grazing” small amounts of food throughout the day
volume expansion with fludrocortisone. Other symptoms and com- (Middleton and Balan, 2012). At least in children, the velocity of gastric
plaints which also improved with this treatment, including dizziness, emptying in teens with and without POTS did not differ (Antiel et al.,
abdominal pain, flushing, and missing school (Fortunato et al., 2014). 2008).
Why the orthostatic challenge induces symptoms in subject with OI The relationship of delayed gastric emptying and POTS is only an
is still unclear. Some studies have shown change in the electrical ac- association. Given that is impossible to perform a gastric emptying
tivity of the stomach while upright. Safder et al. also described that the during a tilt, all the reports just describe the results of a supine scanning
electric activity of the stomach worsens during HUT in subjects with during gastric emptying test with the presence or absence of POTS
POTS, with a decrease in the normal 3 cpm, increase in the bradygas- evaluated at a different time. This could be evaluated by utilizing a
tria, tachygastria and gastric arrythmia but not in those without POTS wireless motility capsule that can assess gastric emptying (see below).
(Safder et al., 2010). Subjects with POTS also have more abnormalities In some cases of delayed gastric emptying in subjects with POTS, an
in the gastric electrical activity while supine. Even within the POTS autonomic neuropathy was present (Loavenbruck et al., 2015). A few
group, the subjects with gastrointestinal symptoms have differences in studies report more gastrointestinal symptoms in patients who have
the electrical activity when compared to those with POTS and no GI neuropathic POTS vs non-neuropathic POTS, suggesting that the neu-
symptoms (Fortunato et al., 2014; Seligman et al., 2013). Whether ropathy present in these patients may involve gastrointestinal in-
gastric dysrhythmias improve with fludrocortisone remains to be seen. nervation (Gibbons et al., 2013; Al-Shekhlee et al., 2005).
Abnormal electrical activity in some patients with POTS could be
explained in part by a more generalized alteration in overall autonomic 4. Symptoms that may be present in patients with POTS and OI,
modulation. Cardiovagal modulation, as measured by heart rate but are not reproduced or exacerbated in the upright position
variability (HRV), particularly the high frequency band (hfHRV), pro-
vides a broader measure of autonomic modulation. hfHRV drops in Some gastrointestinal symptoms are associated with POTS or OI, but
healthy subjects with standing. However, pediatric subjects with func- are NOT produced by the orthostatic challenge. Many subjects with OI
tional gastrointestinal disorders and chronic overlapping pain condi- including POTS complain of constipation, diarrhea, abdominal pain or
tions have much lower cardiovagal modulation than healthy control discomfort with may be suggestive of irritable bowel syndrome, chronic
subjects both supine and upright (unpublished data). Similarly, adults nausea, bloating and swallowing difficulties (Ojha et al., 2011; Deb
with irritable bowel syndrome have also decreased vagal modulation, et al., 2015). These symptoms will probably not improve with treat-
although the reports are only in the supine position (Liu et al., 2013). ment aimed at the orthostatic challenge.
However, the presence or absence of POTS does not seem to influence Given the frequent overlap of OI and GI symptoms, even if not re-
this general finding in chronic overlapping pain conditions with func- lated to the OI, it is important for the practitioners to understand the
tional GI disorders (unpublished data), suggesting that lower vagal basic management of the most common symptoms such as: nausea,
modulation may be associated more with chronic pain disorders rather abdominal pain, constipation, and bloating. All the medications and
than with POTS subjects. Of particular interest, cardiovagal modulation treatments described in this chapter are used off label. It is critical to
improved in adults with gastroparesis after treatment with gastric emphasize that prior to treatment, organic causes need to be ruled out.
electrical stimulation as shown by a decrease in the low-frequency/ This may require endoscopies, laboratory studies or imaging.
high-frequency ratio (baseline 1.4 ± 0.1 vs. follow-up 1.1 ± 0.07,
P = 0.1) (Stocker et al., 2016). To the best of our knowledge, no study 4.1. Nausea
has evaluated HRV simultaneously with electrogastrography to de-
termine the relationship between gastric and cardiovagal modulations. Nausea is typically defined as a subjective, unpleasant sensation
Another possible explanation may be a redistribution of the that often precedes vomiting, but may occur in isolation and on a
splanchnic blood flow in the upright position in patients with POTS. In chronic basis. It is defined as chronic idiopathic nausea when no cause
orthostatic hypotension, which is a different condition from POTS, in is identified. This feeling can be perceived in different locations, like in
the post-prandial state during head-up tilt, the mesenteric artery flow the epigastric area, back of the throat, or in head (Stern et al., 2011).
decreases (Fujimura et al., 1997). Interestingly, subjects with normal- When trying to understand the causes of nausea in patients with OI, it is
flow POTS have mesenteric hyperemia rather than decreased flow when critical to determine when the nausea occurs (Fig. 1). For example, is it
in the upright position, questioning the role of splanchnic perfusion in present in the morning before getting up from bed or during the night?
the pathophysiology of symptoms (Stewart et al., 2011). Does it happen when the person stands up and is associated with diz-
Although not common, intracranial hypotension, which is caused by ziness? Is it only related to migraines or headaches with photo or
low cerebrospinal fluid pressure, can present with an orthostatic phonophobia? Does it happen only after eating or is it related to

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Fig. 1. This figure shows the possible causes of nausea based on time of the day and position when nausea develops, and suggested treatments.

anxiety? In our clinical experience, nausea seldom happens in only one the medication if it stops working. Metoclopramide has also severe
of these circumstances, but rather it is related to 2–3 situations. These potential side effects including depression, tardive dyskinesia which has
symptoms associated with the nausea may give some guidance on how an FDA black box warning. Except if otherwise indicated, metoclopra-
to treat the nausea. For example, in a study in pediatrics, awakening mide should not be used for > 12 weeks (Lacy et al., 2018). Interest-
from sleep with nausea was directly correlated with gastric retention ingly, since the relationship between gastroparesis and vomiting is not
(Wong et al., 2014). clear, a prokinetic may or may not help (Stapleton and Wo, 2009). In
severe cases of gastroparesis refractory to medical medication, a gastric
electrical modulator with or without pyloroplasty may be an option
4.2. Gastroparesis
(Davis et al., 2017; McCallum et al., 2010). In diabetic gastroparesis,
Relamorelin which is a selective prokinetic agonist of ghrelin has shown
Gastroparesis is characterized by delayed emptying of the stomach
to accelerate gastric emptying and improve symptoms, but it is still in
without a mechanical obstruction. Idiopathic gastroparesis is defined as
clinical trials and not yet approved by the FDA (Camilleri et al., 2017;
gastroparesis without a known cause to explain the delayed emptying,
Chedid and Camilleri, 2017).
including medications. It is the most common cause of gastroparesis
(Soykan et al., 1998). Other causes of gastroparesis include diabetes,
post-surgical, Parkinson's disease, multiple sclerosis, amyloidosis and 4.3. Migraine
medications (Zyluk, 1996). The symptoms of idiopathic gastroparesis
include nausea, early satiety, vomiting and upper abdominal dis- Migraine can be associated also with nausea and vomiting. Almost
comfort. Depending on the severity of the symptoms, weight loss and 60% of adults with migraine will report having nausea and vomiting
malnutrition may develop. These symptoms often overlap with func- (Gajria et al., 2017). Given the high overlap of POTS, OI and migraine,
tional dyspepsia. Usually, abdominal pain is more predominant in it is critical to include in the possible causes of nausea an association
functional dyspepsia (Pasricha and Parkman, 2015). There is little with migraines (Chelimsky et al., 2015). In our clinical experience,
correlation between the severity of the gastroparesis and the severity of nausea often responds with the medical management of migraines. The
the symptoms. The symptoms that are better correlated with the gas- nausea in migraine can be a premonitory symptom, and therefore is not
troparesis are the nausea, early satiety, vomiting and postprandial related to trigeminal activation or pain. A PET scan study comparing
fullness (Pathikonda et al., 2012; Cassilly et al., 2008). When trying to subject with migraine with and without nausea, showed that the nausea
understand the cause of nausea, sometimes is important to obtain a 4 h group had activation of the rostral dorsal medulla and periaqueductal
gastric emptying test with solid food to determine if gastroparesis is grey (PAG) which was not present in the subjects without nausea,
playing a role. Other studies available to assess for gastric emptying suggesting involvement of the vagus in the development of migraine
include wireless motility capsule, which is a capsule that gets swal- with nausea (Maniyar et al., 2014).
lowed and measures pH, pressure and temperature, and a breath test As described earlier in the chapter, nausea may also be due to an
which uses a stable isotope (13C-octanoate or 13C-spirulina) which is orthostatic challenge. The possible causes of this were discussed earlier
absorbed in the small intestine, then metabolized to 13CO2 and exhaled in this chapter. As described earlier, nausea replicated during HUT
in breath (Lacy et al., 2018). (therefore secondary to an orthostatic challenge) often improves with
Treatment of gastroparesis depends on the severity. Dietary changes volume expansion with fludrocortisone (Fortunato et al., 2011; Sullivan
like small frequent meals, low fiber and low-fat diet may help. If et al., 2005).
symptoms are more severe, a liquid nutrient or blenderized diet may be When treating nausea in the setting of subject with OI, depending on
indicated. If these measurements are not successful, a naso-jejunal tube the presence of migraine, photo and phonophobia with the nausea,
or gastro-jejunal tube may be needed to improve hydration and nutri- association of the nausea to headaches, etc., different treatment options
tional status. Prokinetics such as metoclopramide, erythromycin or should be considered. If the nausea is not related to orthostatic chal-
azithromicin and antiemetics such as ondansetron, promethazine, pro- lenge and there is no clear delayed gastric emptying, we usually treat
chlorperazine may help. Metoclopramide works both on the D1 and D2 the nausea with cyproheptadine (monitor closely for increase weight), a
dopamine receptors and is the only Food and Drug Administration tricyclic antidepressant or topiramate (Stapleton and Wo, 2009). To-
(FDA) approved medication for gastroparesis. Tricyclic antidepressants piramate is an anticonvulsant. Some of the most common side effects of
may help modulate the symptoms (Lacy et al., 2018). Erythromycin topiramate include weight loss, metabolic acidosis, kidney stones,
should be used with caution, since it prolongs QT interval. Further- cognitive slowing and glaucoma (Marmura, 2014). These medications
more, the response may decrease with time, requiring a “vacation” of have many potential side effects that need to be discussed with the

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Table 1
Medications used in dyspepsia, mechanism of action and side effects.
Medication Mechanism of action Effects produced Side effects

Histamine-type 2 ? reducing gastroesophageal reflux and Some improvement in epigastric pain and post- Very seldom, and include headaches, dizziness,
receptor antagonists microscopic inflammation prandial fullness, but trials are poor (Lacy feeling tired mild gastrointestinal issues such as
et al., 2012; Pinto-Sanchez et al., 2017) diarrhea, constipation and nausea (Vial et al.,
1991)
Proton pump inhibitor Suppress HCl secretion Modest improvement in reflux symptoms and Increased risk of C. difficile infection,
“ulcer-like” symptoms, but not in “dysmotility- pneumonia. Nutritional deficiencies,
like” symptoms (Lacy et al., 2012; Pinto- osteoporosis, headaches (Ksiadzyna et al.,
Sanchez et al., 2017) 2015)
Tricyclic antidepressant Centrally mediated effect on antinociceptive May reduce nausea, but more studies are Prolonged QTc, increased risk of suicide, mood
pathways needed (Lacy et al., 2012) changes, constipation, dry mouth
Acotiamide Muscarinic and cholinesterase inhibitor Improvement in early satiety, abdominal Diarrhea and headaches
In phase III trial for non-ulcer dyspepsia bloating and post-prandial fullness (Lacy et al.,
2012)
STW 5-II Contains extracts of bitter candy tuft, matricaria Improvement of dyspepsia symptoms (Lacy Liver toxicity (Saez-Gonzalez et al., 2016)
flower, peppermint leaves, caraway, licorice root et al., 2012)
and lemon balm.
Works on many levels, decreasing inflammation,
relaxing fundus, increases antral contraction,
modulates acid secretion (Allescher and Abdel-
Aziz, 2017)

Dyspepsia with normal

upper endoscopy and NO
H. pylori infecon

Try CBT, peppermint oil

or STW 5
Try PPI or H2Blocker for 4-
8 weeks

No improvement

Try TCA and SSRI

No improvement

Consider prokinecs, an-

nocicepve medicaons,
other complimentary

Fig. 2. Dyspepsia. In our institution we introduced peppermint oil, STW 5 and cognitive behavioral therapy (CBT) at any point in the managements.

patient (Marmura, 2014; He et al., 2017). Often we use a combination erythromycin, acotiamide (a muscarinic and cholinesterase inhibitor),
of medications. tandospirone (5-HT1A agonist), buspirone (relaxes the gastric fundus),
as well as some herbal products such as STW-5, and rikkunshito
(Table 1). As a second line, tricyclic antidepressants (TCA) and ser-
4.4. Dyspepsia otonin reuptake inhibitors (SSRI) can be used. Low dose TCA are better
tolerated than SSRI's and produce better results (Suzuki, 2017;
Rome IV now includes 2 subgroups in dyspepsia, postprandial distress Monkemuller and Malfertheiner, 2006). A consensus of which medi-
syndrome (PDS) and epigastric pain syndrome (EPS). These 2 sub-types of cation to use and in which order is not available. In general, after upper
dyspepsia can overlap. PDS usually present with fullness after eating endoscopy has been done and an H pylori infection ruled out, most
and early satiety but can also have epigastric pain/burning and nausea. centers would start with antacid therapy with either a proton pump
Bloating and belching can also be present in both types of dyspepsia inhibitor or an H2 blocker. If the patient has delayed gastric emptying,
(Schmulson and Drossman, 2017). a prokinetic could be tried. If these therapies fail, then TCA and SSRI
Treatment of dyspepsia includes acid suppression, prokinetics like

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Fig. 3. Algorithm of proposed treatment of irritable bowel syndrome diarrhea predominant (IBS-D) and constipation predominant (IBS-C). The boxes in light blue
may apply to IBS-C and IBS-D.

should be tried. Complimentary therapy can be tried as well as proki- gas reducers (simethicone), or medications that treat constipation and
netics without gastroparesis when the first 2 lines of therapy have failed increase fluid in the gut like lubiprostone and linaclotide. SSRI and TCA
(Yamawaki et al., 2017; Lacy et al., 2012). Fig. 2 summarizes a possible can be tried too (Seo et al., 2013).
algorithm of treatment of dyspepsia.

4.6. Diarrhea and constipation associated with abdominal pain or

4.5. Bloating and abdominal distention discomfort

These 2 terms, although similar, are different. Bloating is a sensa- Altered bowel pattern has been reported in 70% of POTS patients
tion of abdominal pressure that may or may not be associated with (Wang et al., 2015). In contrast to the upper GI symptoms that often are
visible distention of the abdomen (Malagelada et al., 2017). Many or- replicated during the upright position, to the best of our knowledge
ganic causes can produce bloating and distention. We will only focus there are no reports of diarrhea and constipation triggered by the up-
here on functional bloating and distention. The mechanism of bloating right position, therefore when discussing these symptoms, having POTS
is poorly understood. Several theories have been proposed, from small does not affect the management. In this chapter we will focus on the
intestine bacterial overgrowth (SIBO), altered gas motility and ab- symptom of diarrhea and constipation that are usually part of irritable
normal gas handling, altered abdominal muscle reflexes, visceral hy- bowel syndrome.
persensitivity, carbohydrate malabsorption, and constipation. Based on Irritable bowel syndrome (IBS) is defined in the current Rome IV
these theories, the available treatment include antibiotics, like rifax- criteria.by a constellation of symptoms. IBS is a functional bowel dis-
imin, probiotics (although the results are inconsistent), prokinetics like order associated with recurrent abdominal pain for at least 1 day/week
levosulpiride and acotiamide have been used, again with conflictive in the 3 months preceding diagnosis with and two or more of the fol-
results (Seo et al., 2013). Antispasmodic are also used, like peppermint lowing: a) pain related to defecation, b) pain associated with change in
oil, mebeverine and otilonium bromide among others (Seo et al., 2013). frequency of stool, c) pain associated with a change in form of stool.
Dietary changes like low FODMAP (fermentable oligosaccharides, dis- Rome IV described 4 types of IBS: IBS with predominant constipation
accharides, monosaccharides, and polyols) diet can be tried, as well as (IBS-C), IBS with predominant diarrhea (IBS-D), IBS with mixed bowel

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Table 2
Medications used in irritable bowel syndrome, mechanism of action and side effects (Wall et al., 2014).
Mechanism of action Effect produced Side effects

Loperamide Synthetic opioid inhibits peristalsis Decreases stool frequency, improves Constipation, not suggested in IBC-C(Hovdenak,
stool consistency, does not reduce 1987)
abdominal pain in IBS-C(Jailwala
et al., 2000)
Tricyclic antidepressants Centrally mediated effect on antinociceptive Decreases abdominal pain Prolonged QTc, increased risk of suicide, mood
pathways changes, constipation, dry mouth
Bulking agents: psyllium, Bulking of stool Increase stool frequency, quality and Insoluble fiber like wheat or corn bran increase
calcium polycarbophil, transit time, but improvement in bloating (Brandt et al., 2009)
ispaghula abdominal pain
Osmotic laxatives: PEG 3350 Increasing intraluminal water Helps with constipation, but no Gas (mainly lactulose)
& lactulose effect in reducing abdominal pain
and bloating
Lubiprostone Activates chloride channel in GI tract with increase Decreases abdominal discomfort and Nausea and diarrhea
fluid secretion pain, improves stool consistency, Contraindicated in pregnancy. Women should use
decreases straining and improves contraception while on lubiprostone (Brandt et al.,
constipation 2009)
Linaclotide Agonist of guanylate cyclase, which leads to Improves constipation, decreases Diarrhea (McCormack, 2014)
secretion of guanylin and uroguanylin into the abdominal symptoms (Yang et al.,
lumen where they act as a second message to 2018)
release fluids and electrolytes into the large bowel
Rifaximin Antibiotic with little or no systemic absorption Not FDA approved in the US for IBS. In TARGET 1 and 2 studies, 2 weeks of Rifaximin did
Treats small bowel bacterial not produce any Clostridium difficile infection
overgrowth
Improves abdominal bloating and
decrease IBS symptoms
Peppermint oil Antispasmodic, blocking calcium channels Decrease IBS symptoms Gastroesophageal reflux, but limited data on side
effects (Brandt et al., 2009)
Alosetron 5HT3 receptor antagonist Decreases abdominal pain, urgency, Potential serious side effects including constipation
diarrhea complaints and global IBS and colon ischemia. Indicated only in females with
symptoms (Brandt et al., 2009) severe IBS-D that have failed conventional therapy
(used with restrictions by the FDA in the USA)
(Brandt et al., 2009)

habits (IBS-M), and unclassified IBS (IBS-U) (Lacy et al., 2016). a TCA, which produce constipation due to the anticholinergic effect.
The symptoms of diarrhea and abdominal discomfort although The dose is started low and slowly advanced over a few weeks. EKG
common in IBS, can also be present in other organic disorder. should be followed for the risk of prolonged QTc. Furthermore, these
Therefore, it is important to recognize when more evaluation is in- medications have a black box warning regarding suicidal risk
dicated. Some of these red flags include fever, weight loss, blood in the (Pimentel, 2018). If the patient is being treated with a selective ser-
stool (even occult), low albumin, elevated inflammatory markers, ele- otonin reuptake inhibitor (SSRI) for psychiatric symptoms, consider
vated calprotectin in the stool, family history of colon cancer or in- switching to a serotonin norepinephrine reuptake inhibitor (SNRI)
flammatory bowel disease, history of antibiotic use, onset after age 50, which may improve IBS symptoms, mainly in IBS-D (may produce
failure to thrive (mainly in pediatrics), new onset, worsening of constipation) (Brennan et al., 2009). SNRI like duloxetine can produce
symptoms, etc. (Pimentel, 2018; Hulisz, 2004) A colonoscopy is in- tachycardia. If significant, the heart rate can be lowered by adding
dicated in the following situations: patients > 50 yr and in African propranolol (Stevens, 2008). Alosetron can be tried when everything
Americans > 45 yrs., presence of any red flags, family history of colon else has failed and is only approved in the US with restrictions in the
cancer, and diarrhea that does not respond to initial management treatment of IBS-D in women. It reduces pain, stool frequency and rectal
(Pimentel, 2018). urgency. It is a highly selective 5-HT3 antagonist. The uncommon side
Like in many of the symptoms described in this chapter, hyper- effects include ischemic colitis and constipation (Lacy et al., 2016).
algesia and visceral hypersensitivity are often the key factors in the IBS-C: First line treatment include Psyllium, PEG or if needed, the
pathogenesis of the symptoms of IBS, therefore treatment is aimed at newer chloride channel activators such as Lubiprostone (Lacy et al.,
pain modulation rather than treatment aimed at the end organ. The 2016). Linaclotide is a guanylate cyclase-C agonist that has shown to
treatment should be stepwise depending on the severity of the symp- improve constipation as well as abdominal symptoms (Yang et al.,
toms (Fig. 3; Table 2). In general terms, the treatment should include 2018). If a tricyclic antidepressant is needed, desipramine may be more
increase exercise, stress modulation, and cognitive behavioral therapy. useful, since it produces less constipation (Lin and Chang, 2017).
For IBS-C and IBS-D, if bloating and gas are a predominant or sig-
nificant symptom, low FODMAP (fermentable oligosaccharides, dis-
accharides, monosaccharides, and polyols) diet and treatment with 5. Conclusion
Rifaximin for presumed bacterial overgrowth should be considered
(Pimentel, 2018). POTS and OI are frequently associated with gastrointestinal symp-
For IBS-D, sometimes adding fiber to the diet or using bulking toms. From a therapeutic and diagnostic perspective, it is critical to
agents may increase the stool consistency. Loperamide, a synthetic determine if such symptoms are part of OI itself, because upright po-
opioid, acts on the intestinal muscles prolonging transit time and de- sition replicates these symptoms and recumbence improves them, or are
creases peristalsis. There is little evidence that it helps in reducing the just comorbid conditions unrelated to upright position which could
abdominal pain (Wall et al., 2014). A bile acid binder can also be occur whether or not the patient has OI or POTS. The pathophysiology
added. Sometimes treatment of bacterial overgrowth with rifaximin of the gastrointestinal symptoms produced by the orthostatic challenge
may help the symptoms (Pimentel, 2018). Next step treatment includes is still unclear. Several theories can be postulated, including changes in
perfusion, changes in vagal tone with consequent changes in motility,

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