REVIEW ARTICLE 1

Edson Guzman

Firmado digitalmente por Edson Guzman

Nombre de reconocimiento (DN): cn=Edson Guzman, o, ou, email=edson_guzman@hotmail.com, c=PE
Fecha: 2019.04.12 20:37:33 -05'00'

An Approach to the Patient With Chronic Undiagnosed

REVIEW ARTICLE
Abdominal Pain
Nipaporn Pichetshote, MD1 and Mark Pimentel, MD, FRCP(C)1

Abdominal pain is a common reason for referral to a gastroenterologist. The workup of patients with chronic abdominal
pain can be extremely challenging as clinicians are responsible for determining whether the patient can be observed
or treated symptomatically or this abdominal pain heralds a more systemic disease. The differential is typically wide and
given the innervation of the abdomen, localization of abdominal pain does not always provide clear insight into the
etiology. This review attempts to help the gastroenterologist narrow down that broad differential and focus on key
elements of the patient visit. We emphasize the importance of a detailed history from the patient, along with review-
specific details of their history and physical examination that can clue one in about the etiology of the abdominal pain. We
review the causes of diffuse abdominal pain that may not first be considered along with uncommon causes of localized
abdominal pain. We also review the functional causes of abdominal pain and the importance of identifying these
disorders, to avoid unnecessary testing that commonly occurs with these patients.
Am J Gastroenterol 2019;00:1–7. https://doi.org/10.14309/ajg.0000000000000130

INTRODUCTION distension of the small intestine is usually perceived in the peri-

Evaluation of any patient with abdominal pain can be a daunting
task. The differential diagnosis is typically broad and over-
whelming. Evaluating the etiology of undiagnosed abdominal
pain can lead to the proverbial “rabbit hole” the majority of
physicians/gastroenterologists fear to go down, as it is often
fraught with multiple and repeat imaging, expensive and slow-to-
report laboratory tests, all the while watching the patient suffer
with little means other than pain medication to provide relief.
Before attempting to determine the etiology of a patient’s
abdominal pain, it is important to understand its pathogenesis.
There are pain receptors that lie in the abdomen and that respond
to both mechanical and chemical stimuli. The principal me-
chanical stimulus is stretched and is involved in visceral noci-
ception, although distension, contraction, traction, and
compression are also perceived (1). Visceral receptors responsible
for these sensations are located on the serosal surfaces, within the
mesentery, and within the walls of hollow viscera. Visceral mu-
cosal receptors respond primarily to chemical stimuli, while other
visceral nociceptors respond to chemical or mechanical stimuli.
Sensory inputs from the underlying abdominal viscera are
collected by visceral afferent fibers that travel through 1 of 3 main
thoracic splanchnic nerves and terminate in the dorsal horn of the
spinal cord (Figure 1). Spinal visceral afferents are the main
source of visceral nociception and are spread across a broad range
of dorsal root ganglions. As a result, there is a generalized and
overlapping distribution of the afferent (2). Nonreferred visceral
pain is characterized as dull, poorly localizable and usually mid-
line (being that splanchnic innervation is generally bilateral), in
either the epigastrium, the periumbilical region or the lower ab-
domen. For example, afferent nerves mediating pain arising from
the small intestine enter the spinal cord between T8 and L1. Thus,
1
Division of Gastroenterology and the Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, Los Angeles, CA. Correspondence: Mark
Pimentel, MD, FRCP(C). E-mail: pimentelm@cshs.org
Received April 18, 2018; accepted December 14, 2018; published online January 23, 2019
umbilical region. The reason pain is poorly localized is that in-
nervation of the abdominal viscera is multisegmental (Figure 2).
In tandem with that, viscera contain fewer nerve endings than the
skin of the abdominal wall (3).
Pain that is clearly lateralized most likely arises from the ip-
silateral kidney, ureter, ovary, or somatically innervated struc-
tures, which have predominantly unilateral innervation.
Exceptions to this rule include the gallbladder and ascending and
descending colons, which, although bilaterally innervated, have
predominant innervation located on their ipsilateral sides (4). In
contrast, referred pain is aching and perceived to be near the
surface of the body. In addition to pain, 2 other correlates of
referred pain can be detected: skin hyperalgesia and increased
muscle tone of the abdominal wall (which accounts for the ab-
dominal wall rigidity sometimes observed in patients with an
acute abdomen). Referred pain is ordinarily located in the cuta-
neous dermatomes that share the same spinal cord level as the
affected visceral inputs (5).
HISTORY
The initial step in evaluating a patient with chronic abdominal
pain is to elicit a detailed history from the patient. The mnemonic
SOCRATES (Site, Onset, Character, Radiation, Associations,
Time Course, Exacerbating/relieving factors, and Severity) can be
helpful in obtaining the important details of each patient’s pain.
Further details of the time course of the pain, including its abruptness
of onset, duration, and frequency should also be elicited.
Other factors to elicit from the patient’s history are the site of
the pain and possible radiation, severity, character of pain, and
pattern. The location of abdominal pain helps narrow the dif-
ferential as different pain syndromes typically have characteristic

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Copyright © 2019 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
 2 Pichetshote and Pimentel
REVIEW ARTICLE
Figure 1. Sensory inputs from the gut to the brain.
locations. When asking the patient about the pattern of their pain,
it is important to determine its relationship to meals or bowel
movements, together with aggravating and alleviating factors.
Asking the patient about associated symptoms will also help
narrow down the differential. For example, given distension is
a mechanical stimulus involved in nocioception, a history of
bloating and abdominal distension can also help focus the phy-
sician to the etiology (Table 1).
One should also not forget to ask about medications, CAM,
and supplements that can also be a cause of abdominal pain. It is
important to ask patients about their opiate use considering that
information of how much they take may not be forthcoming.
When taking a history, it is also important to recognize that
several biopsychosocial factors (environmental exposures, ge-
netics, early trauma, healthcare seeking behaviors, abuse) can
interact with potential triggers (infections, major loss, unresolved
abuse, somatic illness, unresolved interpersonal difficulties,
drug use) to express pain. This is important to identify as an
effective patient–physician relationship might reverse this
interaction (6). Alarm features should never be overlooked
when obtaining the history of the patient with abdominal pain.
Figure 2. Diagram of abdominal innervation.
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Copyright © 2019 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
Alarm features include, but are not limited to, symptom onset
after the age of 50 years, severe or progressive symptoms,
unexplained weight loss, nocturnal pain, recent change in
bowel habits, or rectal bleeding. The presence of alarm features
should raise the suspicion for structural diseases. However,
many patients with structural disease do not have alarm
features (7).
PHYSICAL EXAMINATION
The overall sensitivity and specificity of the history and physical
examination in diagnosing the different causes of abdominal pain
is poor, particularly for benign conditions (8). Unfortunately, in
the setting of conditions such as dyspepsia, physicians can fare
pretty poorly (9,10). Despite this, a complete physical examina-
tion (including a rectal examination) is indicated as it can provide
evidence of a systemic disease along as an aid to help determine
the etiology of a patient’s pain. Rectal examination should be
performed to evaluate fecal impaction leading to obstruction, as
this may not clearly be obtained from the history, especially in
older adults. A detailed description of how to perform and in-
terpret a rectal examination was given in an article by NJ Talley in
2008 in the American Journal of Gastroenterology (11). Localized
pain in a specific quadrant of the abdomen can help further guide
one’s workup (Table 2) regarding disease entities that typically
present with pain in a specific location.
The pain of functional gastrointestinal (GI) disorders relates
primarily to visceral or central hypersensitivity, and when the
predominant feature is pain, these functional GI disorders are
subcategorized based on their bodily location: irritable bowel
syndrome (IBS) in the mid- to lower abdomen; the epigastric pain
syndrome of functional dyspepsia in the epigastrium; the func-
tional gallbladder and sphincter of Oddi disorders in the right
upper quadrant and epigastrium; functional anorectal pain in the
anorectal area; and functional abdominal pain syndrome, which
is diffusely located in the abdomen (12).
SYSTEMIC DISEASES LEADING TO DIFFUSE
ABDOMINAL PAIN
Diffuse abdominal pain can be the most challenging obstacle that
faces a gastroenterologist. Being unable to localize the abdominal
pain poses a real conundrum to the physician, as it may feel like
there is no clear starting point to work from. Diffuse abdominal
pain should prompt the gastroenterologist to delve deeper into
VOLUME 00 | MONTH 2019 www.amjgastro.com

Table 1. Abdominal pain characteristics
Pain qualifiers Examples
Location Pain of pancreatitis classically bores to the
back
Renal colic radiates to the groin
Onset Pain of pancreatitis may be gradual and steady
Perforation and peritonitis are sudden and
maximal at onset
Quality Burning/gnawing pain is typical of GERD and
PUD
Colicky/cramping pain is typical of
gastroenteritis or intestinal obstruction
Pattern of pain Pain shortly after meals can be seen with
dyspepsia
Chronic pain within 1 hr of eating can be seen
with chronic mesenteric ischemia usually starts
within 1 hr of eating, pain relieved with meals
and recur several hours after a meal is seen
with duodenal ulcers
Associated symptoms Bloating/abdominal distension should indicate
small intestinal bacterial overgrowth, chronic
intestinal pseudoobstruction, or small bowel
obstruction
Radiation Pain of pancreatitis bores to the back
Renal colic radiates to the groin
the search for a systemic disease. Examples of some diseases that
can present with diffuse abdominal pain are as follows.
In the appropriate population, abdominal pain from familial
Mediterranean fever (FMF) should be considered. FMF is most
prevalent in individuals of Turkish, Armenian, North African,
Jewish, and Arab descent (13). FMF is a hereditary auto-
inflammatory disorder characterized by recurrent bouts of fever
and serosal inflammation. Patients are typically asymptomatic
between attacks. Fever is one of the most constant features of FMF
and is present in almost all cases during attacks. Ninety-five
percentage of patients with FMF have episodic abdominal pain.
Abdominal pain and tenderness may initially be localized and
then progress to become more generalized. Since the cause of the
abdominal pain is inflammation of the peritoneum, signs of
peritonitis such as guarding, rebound tenderness, rigidity, and an
adynamic ileus are often present.
In patients who have had previous abdominal surgery or
trauma, immune-mediated disorders, or malignancy, one should
consider sclerosing mesenteritis (14,15). Sclerosing mesenteritis
is a rare, non-neoplastic inflammatory and fibrotic disease that
affects the mesentery. Pain associated with sclerosing mesenteritis
can sometimes be diffuse or localized with an associated mass.
Sclerosing mesenteritis can affect the integrity of the GI lumen
and mesenteric vessels by a mass effect. It is hypothesized that
sclerosing mesenteritis occurs in genetically predisposed indi-
viduals who have abnormal responses to healing and repair of
connective tissue in response to trauma. The most common
presenting features are abdominal pain (30%–70%), systemic
symptoms including fever, malaise and weight loss (20%–23%),
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Patients With Chronic Undiagnosed Abdominal Pain 3
Table 2. Abdominal pain by location
REVIEW ARTICLE
Location Possible disease etiologies
Right upper quadrant Diseases of the liver or biliary tree; sphincter of
Oddi; functional gallbladder
Epigastrium Pancreatitis, gastric etiologies such as PUD;
functional dyspepsia
Left upper quadrant Splenic etiologies
Lower abdomen Distal intestinal tract; irritable bowel syndrome
and altered bowel habits with either constipation or diarrhea
(20%) (16,17).
Patients with chronic mesenteric ischemia also present with
chronic abdominal pain caused by episodic or constant hypo-
perfusion of the small intestine, commonly in the setting of ath-
erosclerotic stenosis. Approximately half have peripheral
vascular disease or coronary artery disease (18). However, in
contrast to most other atherosclerotic diseases, chronic mesen-
teric ischemia is more frequently seen in women (19). This is
likely secondary to the differences in the orientation of the mes-
enteric vessels to the aorta, with a more acute angle to the aorta in
women compared to men (20). Patients typically present with
abdominal pain and weight loss from sitophobia. The abdominal
pain in these patients are typically postprandial, and therefore,
important to ascertain the timing of abdominal pain in relation to
meals, due to the insufficient splanchnic blood flow during
periods of heightened demand. Postprandial pain is typically
crampy and dull in nature, beginning shortly after eating and
lasting 1–2 hours. Other nonspecific symptoms are also associ-
ated with chronic mesenteric ischemia, such as nausea, vomiting,
and diarrhea.
Hereditary angioedema is a disease characterized by recurrent
episodes of angioedema, without urticaria or pruritus, which
most often affect the skin or mucosal tissues of the upper re-
spiratory and GI tracts. GI attacks present as varying degrees of GI
colic, nausea, vomiting, and/or diarrhea (21). These symptoms
result from bowel wall edema. GI attacks are experienced by
a majority of patients with hereditary angioedema and can be the
principal presentation in one quarter of patients (22).
Acute intermittent porphyria has always been on the differ-
ential with undiagnosed abdominal pain. It is an autosomal
dominant disorder with low penetrance caused by mutation of
the gene which is responsible for regulating heme synthesis. The
most common symptoms are GI and neurologic and include pain
in the abdomen, chest, back, and extremities. Abdominal pain is
the most common and often the earliest symptom in acute in-
termittent porphyria, occurring in 85%–95% of patients with
acute attacks. These symptoms are due to the overproduction of
heme pathway intermediates that affect the peripheral, auto-
nomic, enteric, and central nervous systems. It is usually severe,
steady, and poorly localized, and sometimes there is associated
cramping. Also common are constipation, bloating, nausea,
vomiting, and signs of ileus such as abdominal distension and
decreased bowel sounds. Diarrhea and increased bowel sounds
are sometimes seen. As pain and other symptoms are neuropathic
rather than infectious or inflammatory, abdominal tenderness,
rebound tenderness, fever, and leukocytosis are usually minimal
or absent during an acute attack (23).
The American Journal of GASTROENTEROLOGY
 4 Pichetshote and Pimentel
Mast cell activation syndrome can be difficult to diagnose, but
considered especially in patients who have associated flushing. In
addition to abdominal pain and cramping, mast cell activation
REVIEW ARTICLE
syndrome can cause heartburn, nausea, vomiting, and diarrhea.
Heartburn and nausea may be partially caused by gastric acid
hypersecretion from parietal cells, which can be stimulated by
histamine in patients with increased mast cell burden. Histamine
and lipid-derived mast cell mediators (such as leukotrienes)
contribute to abdominal pain and diarrhea (24).
Ehlers Danlos syndrome (EDS) is a diverse group of heritable
disorders of connective tissue that are characterized by varying
degrees of skin hyperextensibility, joint hypermobility, general-
ized skin fragility (25). Abdominal pain is a common complaint
(reported in 56.1% of patients with EDS) followed by nausea,
constipation, and heartburn (26). While the pathophysiology of
abdominal pain in these patients is largely unknown (these
patients have been associated with dysautonomia, (27) dys-synergic
defecation, (28) nausea, vomiting, constipation, diarrhea, and reflux
disease (29)), these patients are prone to torsion and ischemia, per
case reports and these entities should not be missed when evaluating
abdominal pain in the EDS patient.
Endometriosis is identified in up to 80% of women presenting
with chronic pelvic pain (defined as noncyclic lower abdomi-
nal pain lasting for 6 months) and affects up to 10% of all
reproductive-age women. It typically presents with perimenstrual
lower abdominal pain and dyspareunia; dysuria, urgency, and
hematuria are other symptoms. The diagnosis is confirmed by
laparoscopy-guided biopsy (7).
The most common sites of extragenital endometriosis are the
GI and urinary tracts. GI endometriosis is found in 3.8%–37% of
women with a known diagnosis of endometriosis (30). Such
significant differences in the estimated incidence may be due to
differences in opinion regarding the definition of bowel endo-
metriosis, or a reflection of missed diagnosis (31). GI endome-
triosis is most commonly found on the rectosigmoid colon (90%
of cases of intestinal endometriosis), followed by the rectum, ileum
(12%), appendix (8%), and cecum (6%) (32,33). There have also been
case reports of endometriosis found on the transverse colon and
stomach (34,35). Although isolated bowel involvement can be seen,
the majority of patients with bowel endometriosis have evidence of
disease elsewhere (31). GI endometriosis should be suspected in
patients who report deep dyspareunia, dyschezia, catamenial di-
arrhea, hematochezia, constipation, pain with sitting, and pain ra-
diating to the perineum. Lesions of the enteric nervous system may
cause nausea, vomiting, and bloating if they involve Aurbach’s
plexus, Meisner’s plexus, or the interstitial cells of Cajal (36).
Whether adhesions cause pain is debatable (37). Although
adhesions and chronic pain often coexist after abdominal surgery,
the relationship between adhesions and pain is complex and has
been the subject of much controversy. In a randomized trial,
patients undergoing either laparoscopic adhesiolysis or no
treatment beyond pneumoperitoneum for chronic pain related to
adhesions both experienced long-term pain relief, further fueling
the debate (38). Addressing this ongoing controversy with a series
of pain mapping experiments, Demco (39) found that touching
and moving adhesions elicited a clear pain sensation that was
most prominent for filmy adhesions connected to mobile organs.
Disruption of painful filmy adhesions by pneumoperitoneum
may explain the long-term pain relief of control patients in the
randomized trial described above. Adding further complexity to
this topic are reports of nonsurgical treatment of abdominal or
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Copyright © 2019 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
pelvic pain in patients with adhesions using either pregabalin or
wearable, therapeutic ultrasound devices (40,41).
CAUSES OF LOCALIZED ABDOMINAL PAIN
The abdominal wall should be suspected as the cause of symp-
toms when there is a complaint of chronic and unremitting ab-
dominal pain that is unrelated to eating or bowel function but
clearly related to movement. Approximately 10%–30% of
patients presenting to gastroenterologists with chronic abdomi-
nal pain are eventually diagnosed with chronic abdominal wall
pain (CAWP); yet awareness of this disorder is frequently lacking
(42). Patients with CAWP often undergo expensive diagnostic
testing and imaging to rule out visceral sources, and if no clear
source of the patient’s pain is found, the physician may errone-
ously default to a diagnosis of functional abdominal pain or
conversion disorder.
The most common cause of CAWP is anterior cutaneous
nerve entrapment syndrome. It is a condition in which the pain is
believed to occur when there is entrapment of a cutaneous branch
of a sensory nerve that is derived from a neurovascular bundle
emanating from spinal levels T7–T12. The nerve entrapment may
be related to pressure from an intra- or extra-abdominal lesion or
to another localized process, such as fibrosis or edema (43). Other
causes of CAWP include myofascial pain, pain from nerve en-
trapment in a surgical scar, spigelian hernia, rectus sheath he-
matoma, diabetic radiculopathy, compression of thoracic spinal
nerves by tumor and slipped rib syndrome.
Estimates on the prevalence of CAWP vary significantly be-
tween studies. In a study of 2,709 patients referred to a gastro-
enterology clinic at Kaiser Permanente Health Center in San
Diego, California, over a 5-year period, 133 patients (4.9%) had
a sustained diagnosis of CAWP after workup (44). The prevalence
was 3.6% for patients presenting to a Dutch primary care practice
with a previous diagnosis of functional abdominal pain (45).
However, in another study, 30% of patients referred to a gastro-
enterology clinic with undifferentiated abdominal pain were di-
agnosed with CAWP (32). To date, there are no studies
examining the prevalence of CAWP in the general population.
The right upper quadrant is the most common area for focal pain,
but a large proportion of patients also report pain in the epigas-
trium or in multiple locations.
Musculoskeletal abdominal pain, in contrast to visceral ab-
dominal pain, is sharp and localized to an area of the abdominal
wall usually smaller than 2 cm. The backbone for the diagnosis of
CAWP centers around the Carnett’s test. A positive Carnett’s sign
has a diagnostic accuracy of 97% for abdominal wall pain. Con-
versely, less than 10% of patients with visceral pain have been
reported to have a positive Carnett’s sign (7). A positive Carnett’s
sign indicates stable or worsening pain at the point of maximal
tenderness during contraction of the abdominal wall muscula-
ture. Moreover, a positive sign suggests pain from a somatic
rather than a visceral source; in contrast to somatic pain, visceral
pain usually is improved by contraction of the abdominal wall
because the musculature serves to protect the abdominal viscera
from palpation (3). Figure 3 illustrates how to perform a Carnett’s
sign test.
FUNCTIONAL CAUSES OF ABDOMINAL PAIN
There are 3 most common functional disorders associated with
abdominal pain: functional dyspepsia (FD), irritable bowel
VOLUME 00 | MONTH 2019 www.amjgastro.com
 Patients With Chronic Undiagnosed Abdominal Pain 5

Table 3. Workup of patients with undiagnosed abdominal pain

For localized pain

Positive Carnett’s sign
Negative Carnett’s sign
For diffuse/nonspecific abdominal
pain
And appropriate ethnic group
And h/o abdominal surgery,
autoimmunity, cancer, abnormal laparoscopy
imaging with mass/LAD
And h/o peripheral vascular
Figure 3. Performance of Carnett’s sign test. First determine the site of disease or coronary artery
maximum tenderness on the abdomen. The patient is then asked to con- disease
tract the abdominal muscles by raising his/her head from the examination
table while the examiner continues to apply pressure to the tender site or And h/o angioedema
zipping his legs together and raising both legs. The test is positive if tenderness
becomes more severe or is unchanged. A positive test suggests that the ab- And concomitant neurovisceral
dominal wall is the source of pain. The test is negative, when tenderness is symptoms (muscle weakness,
reduced, which suggests that the pain has an intra-abdominal source. psychiatric symptoms, pain in
limbs, head, neck chest)
REVIEW ARTICLE
Consider CAWP
Consider FD or IBS
Consider FMF with empiric trial of
colchicine
Consider sclerosing mesenteritis with
Consider chronic mesenteric
ischemia and obtain CT angiography
Consider HAE and check C4, C1
inhibitor
Consider AIP and check urine PBG (at
time of attack)

syndrome (IBS), and centrally mediated abdominal pain syn- And symptoms of mast cell Consider MCAS and check tryptase
drome (CAPS). activation (flushing, tachycardia, (at baseline and time of attack)
In North America, approximately 20% of adults have symp- MSK pain, hypotension)
toms of FD and 10%–15% have symptoms of IBS (46,47). FD is And physical examination Consider EDS (with Brighton criteria)
characterized by unexplained chronic early satiety (inability to consistent with skin and evaluate for visceroptosis with
finish a normal-sized meal), postprandial fullness (often de- hyperextensibility, joint UGI with SBFT with upright films
scribed by patients as bloating), and epigastric pain or burning. hypermobility, or tissue fragility
IBS is a chronic, potentially disabling disorder of the GI tract with And associate symptoms of Consider endometriosis with
a relapsing/remitting course in which abdominal pain is associ- dyspareunia, dyschezia, laparoscopy
ated with defecation or changes in stool form or frequency (48). catamenial diarrhea
Pain in FD and IBS is thought to be secondary to increased
No associated symptoms Consider CAPS
visceral sensitivity, which has been documented with increased
perception of GI balloon distension (gastric and rectal). In- And use of opiates with increased Consider NBS
creased sensitivity refers to an exaggerated awareness of normal dosages causing worsening pain
events. This may be due to sensitization of peripheral afferent AIP, acute intermittent porphyria; CAPS, centrally mediated abdominal pain
receptors or spinal dorsal horn neurons, alterations in descending syndrome; CAWP, chronic abdominal wall pain; EDS, Ehlers Danlos syndrome;
modulation, or central amplification (49). FD, functional dyspepsia; FMF, familial Mediterranean fever; h/o, history of;
In comparison to FD and IBS, the prevalence of CAPS is much HAE, hereditary angioedema; IBS, irritable bowel syndrome; LAD,
lymphadenopathy; MCAS, mast cell activation syndrome; NBS, narcotic bowel
lower, around 0.5%–2.1% (50). CAPS is characterized by con-
syndrome; SBFT, small bowel follow through; and UGI, upper GI series.
tinuous, nearly continuous, or frequently recurrent abdominal
pain that is often severe and only rarely related to gut function.
CAPS has a strong central component and is relatively in- pain, which is poorly localized. No particular time frame or
dependent from motility disturbance or evidence for visceral dosage of opioids is required for diagnosis because NBS can occur
hypersensitivity (51). Pain associated with CAPS may be colicky within a few weeks and with varying dosages (52). Although
in nature, as in IBS, although it tends to be more prolonged and narcotic bowel is rarely diagnosed, given the current epidemic of
widespread. Another description that is quite common, especially opioid use, it is likely to be under-recognized. The underlying
after a previous surgery, is that the pain is burning in character; pathophysiological mechanisms of NBS are incompletely un-
this form is particularly challenging to treat. It is thought to result derstood; however, opioid-induced hyperalgesia is likely a central
from central sensitization with disinhibition of pain signals, facet (53).
rather than increased peripheral afferent excitability (52).
Narcotic bowel syndrome (NBS) can also present with chronic THE WORKUP OF ABDOMINAL PAIN
abdominal pain. It is characterized by the paradoxical de- The workup of undiagnosed abdominal pain should first start
velopment of or increase in abdominal pain associated with with a detailed history and physical examination. Initial labora-
continuous or increasing dosages of opioids. Patients with NBS tory tests should include a CBC with a differential count, uri-
will have relief or meaningful improvements of their pain when nalysis, complete metabolic panel, and serum lipase. Metabolic
the opioids are withdrawn. Pain typically reported in patients acidosis should not be missed, as this is associated with tissue
with NBS is moderate to severe colicky or constant abdominal hypoperfusion.

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Copyright © 2019 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
 6 Pichetshote and Pimentel
Patients with abdominal pain often have imaging as part of
their evaluation. The imaging modality chosen will depend on
suspected etiologies. Imaging modalities that may be used to
REVIEW ARTICLE
evaluate abdominal pain include ultrasound, computed tomog-
raphy (CT) scan, magnetic resonance imaging (including mag-
netic resonance cholangiopancreatography).
While these images are often ordered, in a patient with un-
diagnosed abdominal pain, they are typically unrevealing. Repeat
imaging, unless the patient’s presentation has changed, is discour-
aged. A study by Nojkov et al. (54) showed that repeat abdominal CT
after initially negative CT(s) performed for non-traumatic abdom-
inal pain has a low diagnostic yield. In patients with diffuse ab-
dominal pain, additional testing should be based on the physician’s
suspicion (Table 3 for further details).
Diagnostic testing should be limited and tailored to the clinical
features, alarm symptoms, symptom severity, and response to
prior therapy. Absent alarm features, symptoms generally suffice
to diagnose functional GI disorders. A complete blood cell count
should be checked in all patients. Some guidelines recommend
consideration of a blood test (e.g., tissue transglutaminase anti-
bodies) or duodenal mucosal biopsies to diagnose celiac disease,
given the potential long-term consequences of missing this di-
agnosis (55). A C-reactive protein may be indicated if the patient
has abdominal pain and diarrhea, especially if rectal bleeding is
present.
CONCLUSIONS
Pain itself (including abdominal pain) is a challenging symptom
as pain thresholds and descriptions of pain vary among indi-
viduals. In this era of narcotic overuse, a thorough assessment of
pain and its causes are more important than ever before. Al-
though abdominal pain as described in this article can be due to
a variety of etiologies, what will always help lead us as gastro-
enterologists down a productive pathway is taking a very detailed
history. The most important aspect of that history taking is to
identify any alarm features that point away from a functional GI
disorder that may and can take more time to diagnose.
CONFLICTS OF INTEREST
Guarantor of the article: Mark Pimentel, MD, FRCP(C).
Specific author contributions: N.P. drafted and revised the
manuscript. M.P. reviewed and revised the manuscript. Both N.P.
and M.P. approved the final draft submitted.
Financial support: None.
Potential competing interests: Cedars-Sinai has licensing agree-
ments with Valeant Pharmaceuticals International Inc., Common-
wealth Laboratories Inc., and Synthetic Biologics Inc. Dr Pimentel is
a consultant for Valeant Pharmaceuticals, Commonwealth Labora-
tories Inc., Synthetic Biologics Inc., Micropharma Inc., and Naia
Pharmaceuticals and is on the advisory boards for Valeant Phar-
maceuticals and Commonwealth Laboratories. Dr. Pichetshote has
no conflicts to disclose.
REFERENCES
1. Ray BS, Neill CL. Abdominal visceral sensation in man. Ann Surg 1947;
126:709–23.
2. Knowles CH, Aziz Q. Basic and clinical aspects of gastrointestinal pain.
Pain 2009;141:191–209.
3. Glissen Brown JR, Bernstein GR, Friedenberg FK, et al. Chronic
abdominal wall pain: An under-recognized diagnosis leading to
unnecessary testing. J Clin Gastroenterol 2016;50:828–35.
The American Journal of GASTROENTEROLOGY
Copyright © 2019 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
4. Chapman WP, Herrera R, Jones CM. A comparison of pain produced
experimentally in lower esophagus, common bile duct, and upper small
intestine with pain experienced by patients with diseases of biliary tract
and pancreas. Surg Gynecol Obstet 1949;89:573–82.
5. Yarze JC, Friedmen LS. Chronic abdominal pain. In: Feldman M,
Friedman LS, Brandt LJ, (eds). Gastrointestinal and Liver Disease.
Philadelphia, PA: Elsevier Health Sciences; 2015.
6. Tornblom H, Drossman DA. Centrally targeted pharmacotherapy
for chronic abdominal pain. Neurogastroenterol Motil 2015;27:
455–67.
7. Bharucha AE, Chakraborty S, Sletten CD. Common functional
gastroenterological disorders associated with abdominal pain. Mayo Clin
Proc 2016;91:1118–32.
8. Yamamoto W, Kono H, Maekawa M, et al. The relationship between
abdominal pain regions and specific diseases: An epidemiologic approach
to clinical practice. J Epidemiol 1997;7:27–32.
9. Heikkinen M, Pikkarainen P, Eskelinen M, et al. GPs’ ability to diagnose
dyspepsia based only on physical examination and patient history. Scand J
Prim Health Care 2000;18:99–104.
10. Thomson AB, Barkun AN, Armstrong D, et al. The prevalence of
clinically significant endoscopic findings in primary care patients with
uninvestigated dyspepsia: The Canadian adult dyspepsia empiric
treatment—prompt endoscopy (CADET-PE) study. Aliment Pharmacol
Ther 2003;17:1481–91.
11. Talley NJ. How to do and interpret a rectal examination in gastroenterology.
Am J Gastroenterol 2008;103:820–2.
12. Tornblom H, Drossman DA. Centrally targeted pharmacotherapy for
chronic abdominal pain: Understanding and management. Handb Exp
Pharmacol 2017;239:417–40.
13. Sarkisian T, Ajrapetian H, Beglarian A, et al. Familial mediterranean fever
in Armenian population. Georgian Med News 2008:105–11.
14. Kelly JK, Hwang WS. Idiopathic retractile (sclerosing) mesenteritis and its
differential diagnosis. Am J Surg Pathol 1989;13:513–21.
15. Emory TS, Monihan JM, Carr NJ, et al. Sclerosing mesenteritis,
mesenteric panniculitis and mesenteric lipodystrophy: A single entity?
Am J Surg Pathol 1997;21:392–8.
16. Durst AL, Freund H, Rosenmann E, et al. Mesenteric panniculitis:
Review of the leterature and presentation of cases. Surgery 1977;81:
203–11.
17. Akram S, Pardi DS, Schaffner JA, et al. Sclerosing mesenteritis: Clinical
features, treatment, and outcome in ninety-two patients. Clin
Gastroenterol Hepatol 2007;5:589–96; quiz 523-4.
18. Moawad J, Gewertz BL. Chronic mesenteric ischemia. Clinical
presentation and diagnosis. Surg Clin North Am 1997;77:357–69.
19. White CJ. Chronic mesenteric ischemia: Diagnosis and management.
Prog Cardiovasc Dis 2011;54:36–40.
20. Oderich GS, Bower TC, Sullivan TM, et al. Open versus endovascular
revascularization for chronic mesenteric ischemia: Risk-stratified
outcomes. J Vasc Surg 2009;49:1472–9 e3.
21. Nzeako UC, Longhurst HJ. Many faces of angioedema: Focus on
the diagnosis and management of abdominal manifestations of
hereditary angioedema. Eur J Gastroenterol Hepatol 2012;24:
353–61.
22. Bork K, Meng G, Staubach P, et al. Hereditary angioedema: New findings
concerning symptoms, affected organs, and course. Am J Med 2006;119:
267–74.
23. Anderson KE, Bloomer JR, Bonkovsky HL, et al. Recommendations for
the diagnosis and treatment of the acute porphyrias. Ann Intern Med
2005;142:439–50.
24. Jensen RT. Gastrointestinal abnormalities and involvement in systemic
mastocytosis. Hematol Oncol Clin North Am 2000;14:579–623.
25. Callewaert B, Malfait F, Loeys B, et al. Ehlers-Danlos syndromes and
Marfan syndrome. Best Pract Res Clin Rheumatol 2008;22:165–89.
26. Nelson AD, Mouchli MA, Valentin N, et al. Ehlers Danlos syndrome and
gastrointestinal manifestations: A 20-year experience at mayo clinic.
Neurogastroenterol Motil 2015;27:1657–66.
27. Gazit Y, Nahir AM, Grahame R, et al. Dysautonomia in the joint
hypermobility syndrome. Am J Med 2003;115:33–40.
28. Mohammed SD, Lunniss PJ, Zarate N, et al. Joint hypermobility and rectal
evacuatory dysfunction: An etiological link in abnormal connective
tissue? Neurogastroenterol Motil 2010;22:1085-e283.
29. Zarate N, Farmer AD, Grahame R, et al. Unexplained gastrointestinal
symptoms and joint hypermobility: Is connective tissue the missing link?
Neurogastroenterol Motil 2010;22:252-e78.
VOLUME 00 | MONTH 2019 www.amjgastro.com

30. Young S, Burns MK, DiFrancesco L, et al. Diagnostic and treatment
guidelines for gastrointestinal and genitourinary endometriosis. J Turk
Ger Gynecol Assoc 2017;18:200–9.
31. Nezhat C, Li A, Falik R, et al. Bowel endometriosis: Diagnosis and
management. Am J Obstetrics Gynecol 2018;218:549–62.
32. Veeraswamy A, Lewis M, Mann A, et al. Extragenital endometriosis. Clin
Obstetrics Gynecol 2010;53:449–66.
33. Redwine DB. Intestinal endometriosis. In: Redwine DB (eds). Surgical
Management of Endometriosis. New York, NY: Taylor & Francis Group; 2004.
34. Hartmann D, Schilling D, Roth SU, et al. Endometriose des Colon
transversum. Dtsch Med Wochenschr 2002;127:2317–20.
35. Iaroshenko VI, Salokhina MB. [Endometriosis of the stomach]. Vestn
Khir Im I I Grek 1979;123:82–3. Russian.
36. Remorgida V, Ragni N, Ferrero S, et al. The involvement of the interstitial
Cajal cells and the enteric nervous system in bowel endometriosis. Hum
Reprod 2005;20:264–71.
37. ten Broek RPG, Bakkum EA, Laarhoven CJHM, et al. Epidemiology
and prevention of postsurgical adhesions revisited. Ann Surg 2016;
263:12–9.
38. Swank DJ, Jeekel H. Laparoscopic adhesiolysis in patients with chronic
abdominal pain. Curr Opin Obstet Gynecol 2004;16:313–8.
39. Demco L. Pain mapping of adhesions. J Am Assoc Gynecol Laparosc
2004;11:181–3.
40. Silverman A, Samuels Q, Gikas H, et al. Pregabalin for the treatment of
abdominal adhesion pain: A randomized, double-blind, placebo-
controlled trial. Am J Ther 2012;19:419–28.
41. Wiseman DM, Petree T. Reduction of chronic abdominal, pelvic,
urological and GI pain using wearable therapeutic ultrasound up to 17
months. J Minimally Invasive Gynecol 2013;20:S76.
42. Srinivasan R, Greenbaum DS. Chronic abdominal wall pain: A frequently
overlooked problem. Practical approach to diagnosis and management.
Am J Gastroenterol 2002;97:824–30.
© 2019 by The American College of Gastroenterology
Copyright © 2019 by The American College of Gastroenterology. Unauthorized reproduction of this article is prohibited.
Patients With Chronic Undiagnosed Abdominal Pain 7
43. Oor JE, Unlu C, Hazebroek EJ. A systematic review of the treatment for
abdominal cutaneous nerve entrapment syndrome. Am J Surg 2016;212:
165–74.
REVIEW ARTICLE
44. Costanza CD, Longstreth GF, Liu AL. Chronic abdominal wall pain:
Clinical features, health care costs, and long-term outcome. Clin
Gastroenterol Hepatol 2004;2:395–9.
45. van Assen T, de Jager-Kievit JW, Scheltinga MR, et al. Chronic abdominal
wall pain misdiagnosed as functional abdominal pain. J Am Board Fam
Med 2013;26:738–44.
46. Talley NJ, Ford AC. Functional dyspepsia. N Engl J Med 2016;374:
896.
47. Saito YA, Schoenfeld P, Locke GR, III. The epidemiology of irritable
bowel syndrome in North America: A systematic review. Am J
Gastroenterol 2002;97:1910–5.
48. Mearin F, Lacy BE, Chang L, et al. Bowel disorders. Gastroenterology
2016;150:1393–407.
49. Farmer AD, Aziz Q. Mechanisms and management of functional
abdominal pain. J R Soc Med 2014;107:347–54.
50. Clouse RE, Mayer EA, Aziz Q, et al. Functional abdominal pain
syndrome. Gastroenterology 2006;130:1492–7.
51. Schmulson MJ, Drossman DA. What is new in rome IV.
J Neurogastroenterol Motil 2017;23:151–63.
52. Keefer L, Drossman DA, Guthrie E, et al. Centrally mediated disorders of
gastrointestinal pain. Gastroenterology 2016. [Epub ahead of print
February 19, 2016.]
53. Szigethy E, Schwartz M, Drossman D. Narcotic bowel syndrome and
opioid-induced constipation. Curr Gastroenterol Rep 2014;16:410.
54. Nojkov B, Duffy MC, Cappell MS. Utility of repeated abdominal CT scans
after prior negative CT scans in patients presenting to ER with
nontraumatic abdominal pain. Dig Dis Sci 2013;58:1074–83.
55. Chey WD, Kurlander J, Eswaran S. Irritable bowel syndrome: A clinical
review. JAMA 2015;313:949–58.
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