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Journal of

Clinical Medicine

Review
Abdominal Pain in Inflammatory Bowel Diseases:
A Clinical Challenge
Pauline Wils 1, * , Bénédicte Caron 2,3 , Ferdinando D’Amico 4,5 , Silvio Danese 4 and Laurent Peyrin-Biroulet 2,3

1 Department of Gastroenterology, Claude Huriez Hospital, University of Lille, F-59000 Lille, France
2 Department of Gastroenterology, University of Lorraine, CHRU-Nancy, F-54000 Nancy, France;
caron.benedicte@hotmail.fr (B.C.); peyrinbiroulet@gmail.com (L.P.-B.)
3 Department of Gastroenterology, University of Lorraine, Inserm, NGERE, F-54000 Nancy, France
4 Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, 20132 Milan, Italy;
damico_ferdinando@libero.it (F.D.); sdanese@hotmail.com (S.D.)
5 Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy
* Correspondence: pauline.wils@chru-lille.fr; Tel.: +33-320-445343

Abstract: Up to 60% of inflammatory bowel disease (IBD) patients experience abdominal pain in
their lifetime regardless of disease activity. Pain negatively affects different areas of daily life and
particularly impacts the quality of life of IBD patients. This review provides a comprehensive
overview of the multifactorial etiology implicated in the chronic abdominal pain of IBD patients
including peripheral sensitization by inflammation, coexistent irritable bowel syndrome, visceral
hypersensitivity, alteration of the brain–gut axis, and the multiple factors contributing to pain
persistence. Despite the optimal management of intestinal inflammation, chronic abdominal pain
can persist, and pharmacological and non-pharmacological approaches are necessary. Integrating
psychological support in care models in IBD could decrease disease burden and health care costs.
Consequently, a multidisciplinary approach similar to that used for other chronic pain conditions
should be recommended.

Citation: Wils, P.; Caron, B.; D’Amico, Keywords: inflammatory bowel disease; abdominal pain; quality of life
F.; Danese, S.; Peyrin-Biroulet, L.
Abdominal Pain in Inflammatory
Bowel Diseases: A Clinical Challenge.
J. Clin. Med. 2022, 11, 4269. https:// 1. Introduction
doi.org/10.3390/jcm11154269
Updated STRIDE recommendations (STRIDE II) confirm abdominal pain as a relevant
Academic Editor: Marilena Durazzo target in patients with Crohn’s disease (CD) [1,2]. Despite the current treat-to-target
strategies to improve patient-reported outcomes (PRO), abdominal pain is still a frequent
Received: 10 June 2022
symptom in patients with inflammatory bowel disease (IBD) [3]. Up to 60% of patients
Accepted: 15 July 2022
with CD or ulcerative colitis (UC) experience chronic abdominal pain leading to impacts
Published: 22 July 2022
on daily life and increased psychosocial burdens [4].
Publisher’s Note: MDPI stays neutral Abdominal pain pathogenesis and its perception have multifactorial etiology and
with regard to jurisdictional claims in can be modulated by many factors in patients with IBD. Pain can result from ongoing
published maps and institutional affil- inflammation or coexistent functional disorders like irritable bowel syndrome (IBS) [5].
iations. Literature data demonstrated that in IBD, inflammation sensitizes primary afferent neurons
leading to chronic abdominal pain [6,7]. Moreover, alterations of the brain–gut interactions
can modulate the perception of pain, contributing to its occurrence [8].
Unfortunately, pain is still under treated (24% of IBD patients received no treatment
Copyright: © 2022 by the authors.
for pain in a recent study) [3], and specific treatments for pain management in IBD are
Licensee MDPI, Basel, Switzerland.
poor. Pain control has been identified as one of the top 10 research treatment priorities
This article is an open access article
distributed under the terms and
by clinicians and IBD patients [9]. Opioids and cannabis are frequently used for pain
conditions of the Creative Commons
control by IBD patients (14.7% and 17%) [10,11]. However, the chronic use of opioids
Attribution (CC BY) license (https:// exposes subjects to addiction and relevant side effects, particularly constipation (15% to
creativecommons.org/licenses/by/ 40%), confusion (at high doses), nausea and vomiting (10% to 40%), sedation (20% to
4.0/). 60% of patients receiving oral morphine for cancer pain), and, more rarely, respiratory

J. Clin. Med. 2022, 11, 4269. https://doi.org/10.3390/jcm11154269 https://www.mdpi.com/journal/jcm


J. Clin. Med. 2022, 11, 4269 2 of 15

depression [12]. The regular use of opioids is an independent predictor of mortality in


IBD patients [13]. Therefore, increasing the knowledge on pain pathophysiology in IBD is
crucial for a better therapeutic management of chronic abdominal pain. This article will
review the etiological factors and consequences of abdominal pain in IBD patients, focusing
on currently available pharmacological and non-pharmacological treatments.

2. Assessment and Consequences of Abdominal Pain in IBD


Abdominal pain can be categorized as acute or chronic based on duration. Chronic pain
is defined as pain that occurs consistently for 3 months or intermittently for 6 months [14].
Abdominal pain in IBD patients can result from ongoing inflammation. Several indices
developed to evaluate disease activity (Crohn’s disease activity index (CDAI) for CD or
Lichtiger index for UC) include abdominal pain.
Pain is also a subjective experience, and a patient’s self-report of pain scale must
be encouraged. There are a number of validated pain scales that measure pain intensity:
the Visual Analog Scale (VAS) or Numeric Rating Scale (NRS) are the most numerical
rating scales for pain measurement used in studies (ranging from 0 “no pain” to 10 for
NRS or to 100 mm for VAS corresponding to “worst pain imaginable”), but they are not
specific to abdominal pain in IBD [15]. The irritable bowel syndrome–Symptom Severity
Scale (IBS–SSS) integrates abdominal pain; however, it is not validated for IBD patients.
In addition to these numerical scores based only on intensity measurement, there exist
more detailed scales. The McGill pain questionnaire solicits qualitative descriptions of
pain (15 descriptors in the short form) [16]. The Brief Pain Inventory assesses the intensity
(severity scale) and location of pain as well as its impact on patients’ daily functioning
(interference scale) [17]. In practice, asking patients to use a scale of 0–10 concerning pain
severity and the impacts of pain on their lives can be sufficient.
Pain in IBD can interfere with different areas of daily life. IBD has a substantial impact
on quality of life (QOL) during periods of both active and inactive disease, including
considerable personal, emotional, and social burdens and work-related difficulties [18,19].
In IBD, IBS-like symptoms (such as abdominal pain) are associated with poor QOL [20]. An
association between pain and health-related QOL is well-known in chronic diseases that
also exists in IBD [21,22]. Symptoms of active disease have been reported in multinational
questionnaire-based studies to have substantial impacts on health-related QOL [23]. A
longitudinal study examining the impacts of persistent gastrointestinal symptoms (such as
abdominal pain) in IBD patients revealed higher anxiety and depression and lower QOL
compared with those without symptoms [24]. In a large pan-European survey study in-
cluding 4670 IBD patients, 87% of the respondents had experienced abdominal pain at least
one day a week during their last flare-up, 34% daily, and 62% between flares. In this study,
abdominal pain and fatigue were the most common reason given for work absenteeism
(46% and 51%, respectively) [25]. A recent national Swiss cohort study enrolling 2152 IBD
patients showed that pain was a longstanding problem (>5 years) for a relevant proportion
of patients (49% of UC and 55% of CD patients). In this study, the abdomen was the most
frequent location of pain (59.5%), with a significant reduction of QOL compared with
subjects without pain (38 vs. 77; (−100 very bad; 100 very good) p < 0.0001) [3]. Moreover,
an another study on 334 IBD patients reported that 87.9% of them had pain and showed
significantly reduced QOL compared with healthy controls (p = 0.0001) [21].
Abdominal pain has direct and indirect health care costs including reduced employ-
ment and productivity. There is growing support that opioid use was among the top factors
associated with high health care utilization and costs for patients with IBD [26].

3. Mechanisms of Chronic Abdominal Pain


The heterogeneity in the perceptions of chronic abdominal pain by IBD patients can be
explained by different mechanisms with multiple contributing factors that are summarized
in Figure 1.
J. Clin. Med. 2022, 11, 4269 3 of 15

Figure 1. Proposed representation of mechanisms and multiple contributing factors implicated in


abdominal pain in IBD: psychological and social factors, genetic factors, direct effect of inflammation,
visceral hypersensitivity, co-existent IBS or central pain dysregulation. Abbreviations: IBS: irritable
bowel syndrome; SIBO: Small intestinal bacterial overgrowth.

3.1. Direct Effect of Inflammation


A majority of IBD patients experience abdominal pain during acute flares [27]. Acute
pain may reveal complications: partial or complete gut obstruction, fistulas, or abscesses. It
is commonly assumed that abdominal pain results directly from inflammation and may be
correlated with the degree of disease activity [28]. However, in many IBD patients, there is
a discrepancy between the absence of objective inflammation on endoscopic investigations
or biomarkers and the intensity of pain perception. Around 20% of patients in complete
endoscopic remission experienced pain [27]. The mechanism of the persistence of pain
despite a lack of objective inflammation is unclear and can be controversially explained as
irritable bowel syndrome [29]. Other complications may arise during IBD management
and should be investigated in the absence of inflammation: adherences, small intestinal
bacterial overgrowth, and colorectal cancer [7].

3.2. Peripheral and Central Pain Dysregulation


The mechanisms of chronic abdominal pain in IBD are complex and involve the
enteric nervous system (ENS), the central nervous system (CNS), the gastro-intestinal
immune system, and the intestinal barrier, leading to the dysregulation of brain–gut
interactions [30,31]. The ENS is the intrinsic innervation of the bowel, which controls
gastro-intestinal functions independent of the CNS (like motility, secretion). The ENS,
located in the wall of the gastrointestinal tract, has a pivotal role, receiving input from
the CNS and the autonomic nervous system and interacting with the immune system of
the gut [32].
In IBD, chronic visceral pain can result from peripheral sensitization by inflam-
mation. During inflammation, a multitude of proinflammatory cytokines (interleukin
(IL)-1β, IL-6, tumor necrosis factor (TNF)-alpha), mediators (for example, substance P,
5-hydroxytryptamine), and neuropeptides (including substance P, nerve grow factor, cal-
J. Clin. Med. 2022, 11, 4269 4 of 15

citonin gene-related peptide) are release by tissue damage [32,33] or immune cells (mast
cells or leukocytes). These molecules activate the visceral afferent neurons and sensitize
nociceptive receptors [27,34]. Pain is also driven by the activation of visceral nociceptors
in response to potentially damaging stimuli on the gut (for example distension); these
depolarize the nerve terminal and transmit pain information to the CNS.
In IBD, inflammation can generate nociceptive messages to the CNS, which prolongs
or amplifies the sensitization of visceral afferents, contributing to chronic abdominal pain
(central sensitization) [35]. Moreover, the descending pathway from the CNS modulates
pain transmission by increasing input (facilitation) or decreasing input (inhibition). An
imbalance in the descending pain modulation to facilitation can lead to chronic pain. These
mechanisms are implicated in visceral hypersensitivity.
Abnormalities of the CNS and more particularly in the prefrontal and limbic regions
are also implicated in the amplification of perceptive pain and in humans’ incapacity
to manage pain [36]. Moreover, brain regions associated with emotional regulation and
their dysfunction contribute to increasing the risks of depression and anxiety in IBD
patients [37,38].

3.3. Overlap between IBD and IBS


IBS is a functional gastrointestinal disorder that shares common symptoms with IBD:
recurrent abdominal pain and changes in stool frequency [29]. IBS affects 11% of the general
population [39] and approximately 40% of patients with active or quiescent IBD [40]. In a
recent meta-analysis, symptoms compatible with IBS concerning IBD patients in endoscopic
or histologic remission are reported in approximately 25% of cases and significantly more in
CD than UC patients (34.9% vs. 29.1%; OR 1.58; 95% CI 1.27–1.98) [29]. In clinical practice,
it is difficult to differentiate functional symptoms from ongoing active CD or UC due to
their frequent prevalence.
The pathophysiology of pain in IBS is multifactorial, including a dysregulation of
brain-gut interactions and an increased activation of the brain regions involved in emo-
tional and pain control [41]. Moreover, psychological disorders associated with pain, like
depression and anxiety, are reported both in IBD and IBS patients. In a recent meta-analysis,
IBS patients had higher rates of depression and anxiety than general populations (mean
difference respectively: 9.87 CI95 (6.3–13.4) and 8.10 CI95 (3.7–12.5), p < 0.01) [42].
An abnormal microbiome may be implicated in the development of IBS-type symp-
toms and abdominal pain. Dysbiosis is associated with IBD pathogenesis [43], suggesting—
in comparison with IBS—a role of gut microbiota in visceral hypersensitivity, but data
remain scarce. A previous study on the fecal microbiome in IBD patients with IBS-like
symptoms did not find any difference in the bacterial abundance or diversity between
patients who reported symptoms and those who did not [44]. Then, Pérez-Berezo et al.
reported that an analgesic lipopeptide related to GABA was produced by the probiotic Es-
cherichia coli strain Nissle 1917 [45]. Related to this, probiotics are a presumed therapeutic
option in IBD–IBS patients for improving pain.
Small bowel intestinal overgrowth, frequently revealed by chronic abdominal pain
and other gastrointestinal symptoms, may be associated with gut microbial dysbiosis and
influenced by many factors in patients with IBD: resection of the ileocecal valve, intestinal
motility disorders, or complications such as fistulas or stenoses. Overlap between small
bowel intestinal overgrowth and IBD was not uncommon and was reported in more than
20% of IBD patients in a recent meta-analysis [46].

3.4. Impact of Psychological and Social Factors on Pain


CD and UC are associated with significant psychological comorbidity in both adult
and pediatric patients [47]. Anxiety and depression are the most frequent mood disorders
affecting IBD patients [48]. A recent systematic review and meta-analysis of mood disorders
in IBD patients reported a prevalence of anxiety in 32.1% of patients and a prevalence of
depression symptoms in 25.2% in pooled studies [49]. A bi-directional interaction was also
J. Clin. Med. 2022, 11, 4269 5 of 15

suggested between IBD activity and psychological disorders (anxiety or depression con-
tributing to the progression of IBD and IBD affecting psychological health) in a prospective
longitudinal 2-year study. In this study of 405 patients, IBD activity and anxiety/depression
scores were reported at baseline and after 2 years of follow-up: IBD activity at baseline was
associated with a higher anxiety score at the end of follow-up (HR: 5.77; 95% CI, 1.89–17.7),
and an abnormal anxiety score in quiescent IBD patients at baseline was associated with
later IBD flare-up [50]. Chronic gut inflammation may impact psychological health. Of note,
the administration of cytokines like TNF-alpha, IL-1β, and IL-6 in healthy volunteers can
modify central neurotransmitter release and behavior leading to depressed mood [51,52].
Mood disorders have been shown to amplify symptom severity, particularly abdominal
pain perception [53]. In pediatric and adolescent patients with IBD, depression and child
pain catastrophizing may increase the sensitivity to abdominal pain and pain impact [54].
Moreover, in IBD, stress can lead to abdominal pain, affecting thresholds for pain percep-
tion and visceral hypersensitivity [55]. In accordance with this hypothesis, Schirbel et al.
reported that mental stress intensified pain by 38% in IBD patients [21].
Several psychological and social components contribute to pain in IBD patients. De-
pression and anxiety followed by perceived stress and pain catastrophizing were positively
associated with increased pain [56]. As a vicious circle, increased abdominal pain was
associated with mood disorder (OR = 5.76, CI 95%:1.39–23.89) [56]. On the other hand,
perceived social support and internal locus of control were considered protective psy-
chosocial factors and associated with less pain. A recent study including 297 IBD patients
confirmed these data. Female gender, smoking, surgery, and steroids were associated with
greater pain severity. Interestingly, psychosocial factors such as depression, catastrophizing,
fear avoidance, lower self-efficacy, and worse mental well-being were associated with
pain-related interference [57].

3.5. Genetic Factors


Individual variation in pain perception is influenced by environmental but also genetic
factors [58]. Genetic predisposition is implicated in IBD pathogenesis, and more than
240 single-nucleotide polymorphisms (SNPs) are associated with the risk for IBD [59]. A
genetic link between IBD and IBS has been postulated after the identification of increased
transient receptor vanilloid type 1 (TRPV1) nerve fibers. These are implicated in visceral
hypersensitivity and in quiescent IBD–IBS patients with a correlation to pain severity [60].
Recently, genome-wide association studies have identified other SNPs associated with
IBS [61]. Similarly, another study showed that two IBS-associated SNPs were associated
with maximal abdominal pain in UC patients [62], suggesting the involvement of genetic
factors in these patients.

4. Pain Management
Many IBD therapies (anti-TNF, anti-integrin, anti-interleukin, small molecules) demon-
strated their efficacy in multiple randomized controlled trials (RCTs). Nevertheless, pain
improvement was not considered a key endpoint in the majority of studies even though it
is an essential outcome for patients. More recently, endpoints have evolved, and abdominal
pain improvement is considered a secondary endpoint in RCTs evaluating jak inhibitors
(tofacitinib and upadacitinib) versus placebo in UC [63,64]. Control of disease activity
in IBD is the first step in the management of abdominal pain, but despite an optimal
management of intestinal inflammation, chronic abdominal pain can persist, and pharma-
cological and non-pharmacological approaches can be necessary [6,30,65,66]. Recently, the
American Gastroenterological Association consensus has described the key principles in
the management of functional gastrointestinal symptoms in IBD patients [5].
Figure 2 summarizes in an algorithm a sequential approach for abdominal pain man-
agement. The treatment of acute pain depends on pain intensity (assessing by VAS or
NRS). Simple analgesics are often proposed in the first step, and in the case of severe
pain (VAS > 55 mm or NRS > 7), opioids can be temporarily prescribed. An evaluation of
J. Clin. Med. 2022, 11, 4269 6 of 15

IBD activity is recommended, and IBD therapies were modified accordingly. In quiescent
diseases, a low FODMAPs diet may be an interesting option in IBD–IBS patients, psycho-
logical interventions may be proposed in patients with associated mood disorders, and
adjuvant drugs with antidepressant and analgesic effects can be useful in most patients
with chronic pain. Integrating psychological support in care models in IBD could decrease
disease burden and health care costs. Consequently, a multidisciplinary approach with
a mental health professional for assessing the degree of anxiety and/or depression and
evaluating the probability of responding to specific medications or psychological therapies
is recommended for IBD patients.

Figure 2. Proposed algorithm for pain management with pharmacological agents and non-
pharmacological interventions available for improve chronic abdominal pain.

4.1. Current Pharmacological Options


No therapies have yet proven to be effective in managing IBD-related pain.
Nonsteroidal anti-inflammatory drugs are not recommended for long-term use be-
cause of the risk of relapse or mucosal injury. Although there is no definite evidence in IBD
patients, antispasmodics are commonly used in mild pain [67]. However, antispasmodics
and simple antalgics are often not sufficient, leading to the prescription of opioids. Despite
their potential side effects, a high proportion of IBD patients received opioids for chronic
abdominal pain [10]. Notably, in a large epidemiological study, approximately 5% of IBD
patients were heavy users of opioids within 10 years of diagnosis [13]. However, the
chronic use of opioids should be avoided in IBD patients due to the risks of dependence,
hyperalgesia, narcotic bowel syndrome [68], and premature mortality in heavy users [5,69].
Alternative drugs to opioids should be encouraged [6,7,65,66]. Antidepressant and
anxiolytic medications may be an interesting option for abdominal pain especially if there
are coexisting mood disorders. In particular, a retrospective cohort study involving 81 pa-
J. Clin. Med. 2022, 11, 4269 7 of 15

tients with IBD revealed that tricyclic antidepressants (amitriptyline, nortriptyline, or


desipramine) improved gastrointestinal symptoms (not abdominal pain specifically) [70].
An open-label preliminary study on selective serotonin reuptake inhibitors (citalopram,
paroxetine, fluoxetine, and escitalopram) in psychiatric disorders suggested the efficacy
of paroxetine on abdominal pain in eight IBD patients [71]. Serotonin–norepinephrine
reuptake inhibitors (SNRIs) were effective for the control of chronic pain syndromes in IBS
patients. Interestingly, a large Canadian cohort study of 403,665 patients with new-onset
depression investigated the impacts of depression and antidepressant therapies on the
development of IBD. Selective serotonin reuptake inhibitors and tricyclic antidepressants
were associated with a reduced risk of developing both CD and UC, and SNRIs were protec-
tive against UC [72]. Nevertheless, these treatments are not devoid of side effects, (nausea,
dry mouth, muscle spasms, constipation), bringing an additional burden to patients. Other
studies suggest a potential abdominal pain-relieving effect of gabapentin and pregabalin
(usually prescribed for neuropathic pain), but these have not been investigated in IBD pa-
tients [6]. Other interventions have been associated with a reduction of abdominal pain [66].
In a randomized controlled trial evaluating the efficacy of antibiotics on 29 CD patients
with small intestinal bacterial overgrowth, the antibiotics metronidazole and ciprofloxacin
improved abdominal pain in 50% and 43% of cases, respectively [73]. Rifaximin, a non-
absorbed antibiotic, was an effective treatment of small intestinal bacterial overgrowth,
improving symptoms in 67% of patients in a recent meta-analysis [74]; it could be an option
for IBD patients with small intestinal bacterial overgrowth. Furthermore, restoring the
microbial flora seems to be an interesting option in the management of IBS. Some probiotics
have demonstrated their effectiveness in improving symptoms, including abdominal pain
for patients with IBS (for example L. Plantarum 299v, B. Bifidum MIMBb75) [75,76]. The use
of probiotics in IBD could be a therapeutic option to improve dysbiosis but requires further
studies. Another randomized study demonstrated the efficacy of transdermal nicotine
patches in 72 active UC patients versus placebo: 49% in the nicotine group had complete
remission compared with 24% in the placebo group (p = 0.03), with less abdominal pain in
the nicotine group (p = 0.05) [77]. A small trial evaluating loperamide oxide in CD patients
with chronic diarrhea indicated an improvement in abdominal pain after one week of
treatment [78]. Previous studies reported that around 10% of IBD patients use cannabis
and derivatives to improve symptoms [79]. Patients developed a growing interest in the
potential therapeutic effect of cannabis on IBD-related symptoms and IBD course. Data re-
garding the inflammatory effects of cannabis and derivatives are still limited: small studies
reported an improvement of several IBD-related symptoms, including abdominal pain, but
without any significant improvement of inflammation markers or disease course [11,80,81].
A phase 2a trial evaluating the efficacy and tolerability of cannabidiol in steroid-dependent
CD patients is still ongoing [82]. Table 1 details pharmacological options in IBD patients
with chronic abdominal pain.

Table 1. Data supporting the efficacy of pharmacological and non-pharmacological interventions in


IBD patients with chronic abdominal pain.

Age
Treatment Study Design Study Intervention (Year) Number of Abdominal Pain
Sex F Patients Outcome

Pharmacological treatment
TCA improved
tricyclic gastrointestinal symptoms
IBD patients with inactive
antidepressants or mildly active disease in 59.3% of IBD patients
(TCA) [70] Retrospective and persistent 41.3 (Likert score ≥ 2)
(nortriptyline, 58 CD/23 UC Response was better in
cohort study gastrointestinal symptoms 69%
amitriptyline, UC than in CD patients
(median TCA dose: 25 mg
desipramine, (1.86 ± 0.13 vs.
doxepin) (10–150 mg)) 1.26 ± 0.11, respectively,
p = 0.003)
J. Clin. Med. 2022, 11, 4269 8 of 15

Table 1. Cont.

Age
Treatment (Year) Number of Abdominal Pain
Study Design Study Intervention Patients Outcome
Sex F
Pharmacological treatment
CD patients with small
intestinal bacterial
overgrowth (confirmed by
hydrogen/methane breath Improvement of
Antibiotics: 39 abdominal pain in 50%
metronidazole or RCT and glucose tests) 29 CD
41% (group A) and 43%
ciprofloxacin [73] receiving metronidazole
250 mg t.d.s (group A) or (group B) of cases
ciprofloxacin 500 mg b.d
(group B) for 10 days
Transdermal nicotine (5 or Abdominal pain rate on
15 mg) versus placebo in
Transdermal Randomized active UC patients; 0–2 scale at 6 weeks was at
nicotine patch 44 72 UC 0.3 inthe nicotine group
double-bind improvement of 43%
[77] study and at 0.6 in the placebo
abdominal pain was a
secondary outcome. group (p = 0.05)

At one week, the


investigator’s assessment
Loperamide 1 mg or of the change in
Loperamide Double-blind placebo after passage of 35
53% 34 CD abdominal pain was
oxide [78] investigation each unformed stool for
one week significant for loperamide
oxide (p = 0.020) but not
for placebo.
17.6% of patients used
cannabis to relieve
symptoms associated with
Consecutive patients with their IBD.
IBD who had used Cannabis improved
Monocentric cannabis specifically for 36.6 abdominal pain (83.9%),
Cannabis [11] 303
cohort the treatment of IBD or its 50% (users)
symptoms were compared abdominal cramping
with those who had not (76.8%), joint pain (48.2%),
and diarrhea (28.6%),
although side effects
were frequent.
Dietary measures
IBD patients in remission Approximately 70% of
Improvement of 5 points patients were adherent to
Low-FODMAPs Retrospective or more for 48 the low-FODMAPs diet
diet [83] gastrointestinal symptoms 39% 52 CD/20 UC
telephone survey After 3 months, 56% had
after dietary information clinical improvement of
on low-FODMAPs diet abdominal pain (p < 0.02)
Psychological approaches
Evaluation of IBD activity Compared with
(PCDAI and PUCAI) and supportive non-directive
Cognitive RCT (CBT versus depression in young therapy, CBT showed a
supportive 14.3
patients (after 3-month 46% and 161 CD and 56 greater reduction in IBD
behavioral UC
therapy [84] nondirective 52%
therapy) course of CBT or activity (p = 0.04); both
supportive nondirective psychotherapies decreased
therapy rate of depression scale
Patients received seven
sessions of HPN or
RCT nondirective discussion.
Evaluation of proportion 68% versus 40% of
Gut-directed hypnotherapy patients maintaining
hypnotherapy of participants in each 38 54 quiescent
(HPN) versus 54% UC remission for 1 year
[85] nondirective condition that had
discussion remained clinically (p = 0.04)
asymptomatic through 52
weeks post treatment
J. Clin. Med. 2022, 11, 4269 9 of 15

Table 1. Cont.

Age
Treatment (Year) Number of Abdominal Pain
Study Design Study Intervention Patients Outcome
Sex F
Psychological approaches
RCT
stress
management, CD patients considered in Significant decrease in
Stress self-directed non-active stage of disease abdominal pain in both
management 31.7
stress under sulfasalazine 64% 45 CD stress management arms
program [86] management, or Evaluation of symptoms (14.2% and 6.6% versus
conventional post-treatment 48%)
medical
treatment
Abbreviations: TCA: tricyclic antidepressants; CD, Crohn’s disease; UC, ulcerative colitis; FODMAP: fermentable
oligosaccharides, disaccharides, monosaccharides, and polyols; RCT: randomized controlled trial; CBT: cognitive
behavioral therapy; PCDAI: Pediatric Crohn’s Disease Activity Index; PUCAI: Pediatric Ulcerative Colitis Activity
Index; HPN: hypnotherapy.

4.2. Non-Pharmacological Interventions


4.2.1. Dietary Measures
The presence of indigestible carbohydrates or osmotic molecules in the luminal gut
may result in high fermentation, the production of gas and short chain fatty acids, and
distention and could participate in IBS-like symptoms such as abdominal pain in IBD
patients [87]. Lactose and fructose malabsorption are frequent in CD patients, an estimated
42% and 61% of patients, respectively, in a previous study [88] and could be associated with
abdominal pain. Several dietary measures including lactose-reduced or low fermentable
oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) diets may
improve functional gastrointestinal symptoms [87]. Despite the low grade of evidence, the
low-FODMAP diet proved to be effective for the IBS-like symptoms of IBD patients in remis-
sion [83]. In addition, a randomized controlled cross-over trial reported an exacerbation of
functional gastrointestinal symptoms in quiescent IBD patients exposed to FODMAPs [89].
However, considering the risk of compromised nutritional status, the use of restrictive diets
in IBD patients in remission should be carefully supervised by a dietician.

4.2.2. Psychological Approaches


Psychosocial factors impact the quality of life of IBD patients and often can benefit
from non-pharmacological approaches. Notably, the consequent association between pain
and depression, stress, or anxiety suggests that the optimal management of these mood
disorders may improve pain levels and QOL. In the IBD field, psychological interventions,
particularly cognitive behavioral therapy (CBT), have been found as valid approaches
for functional gastrointestinal symptoms and pain [7,66]. Coping skill training, another
psychological and educational intervention, developed to increase individuals’ ability to
manage uncomfortable or anxiety-provoking situations, improved somatic symptoms in
IBD adolescents but did not significantly affect pain [84]. Notably, psychological interven-
tions were associated with clinical improvement in pediatric and adult IBD patients with
anxiety or depression [85,90,91]. However, another randomized controlled trial evaluating
the impact of a 10-week cognitive behavioral therapy in adult IBD patients did not find an
influence of CBT in the course of IBD over 24 months [92]. Another proposed option is hyp-
notherapy, a technique used to create a state of focused attention and help to gain control
over undesired behaviors or treat stress with suggestions for relaxation. Hypnotherapy has
been associated with positive outcomes for different chronic-pain conditions (e.g., cancer,
low-back pain, arthritis pain). For IBD, a prospective study demonstrated a significant
effect of gut-directed hypnotherapy on prolonging clinical remission in 54 patients with
quiescent UC [85]. There is also consistent evidence for a contribution of stress in the IBD
disease course [93]. For this reason, a stress management program including 45 CD patients
was proposed. A significant reduction in abdominal pain was detected in subjects who
J. Clin. Med. 2022, 11, 4269 10 of 15

received training in self-directed and therapist-led stress management [86]. Acupuncture,


derived from traditional Chinese medicine, is a practice designed to rebalance a patient’s
Qi. In IBD patients, acupuncture can be a complementary approach that helps reduce
chronic abdominal pain [94].

5. Future Directions
Further therapeutic options are necessary. Among therapeutic options with prelim-
inary data, selective blockade of transient receptor potential Vanilloid 4 (TRPV4) [65,95],
and NOP (nociceptin/orphanin peptide receptor) agonists [96–99] could be new potential
therapeutic options with possible anti-inflammatory and antinociceptive actions. A pre-
vious study indicates that TRPV4 localized in the gastrointestinal tract may play a role in
mechanisms of defense in intestinal inflammation and that selective blockade of TRPV4 in
animal model alleviates colitis and pain associated with the intestinal inflammation [100].
Preliminary data suggest a protective role of the nociceptin/orphanin FQ–NOP receptor
system (N/OFQ ligand and its receptor nociceptin/orphanin peptide) in the pathogenesis
of IBS–D and as a potential target for intestinal disorders [96]. NOP receptors share similar-
ities with opioid receptors but with very low affinity to opioid ligands. NOP receptors are
distributed in the central and peripheral nervous systems and also in the gastrointestinal
tract, where they may interact with gastrointestinal functions like motility, secretion, or
pain perception [97]. A NOP agonist was developed in a mouse model of IBD with possible
anti-inflammatory and antinociceptive action [99].
Among new approaches to pain management, transcranial direct current stimulation
acting on the central mechanisms of pain is currently being explored in IBD patients.
It proved to be a relevant strategy for chronic abdominal pain in 20 IBD patients in a
randomized controlled double-blind study [101].
However, progress is limited by insufficient understanding of the causes of chronic
abdominal pain in IBD. To try to respond to this need, the Crohn’s & Colitis Founda-
tion launched in 2021 the chronic pain in translational IBD research initiative focused
both on the understanding of chronic abdominal pain and its clinical management in
IBD [102]. Finally, educating gastroenterologists on the management of chronic pain in-
cluding non-pharmacological treatments should improve access for patients with IBD to all
available treatments.

6. Conclusions
Abdominal pain remains a common symptom in IBD patients with a negative im-
pact on daily life. Currently, there are several options for treating visceral pain but not
specifically for IBD. This review highlights first a new attention to pain recognized as a
burden for patients and second the lack of consensus on managing long-term pain in IBD.
The resolution of abdominal pain should be incorporated as an independent endpoint into
clinical trials for optimizing IBD management. As chronic pain is complex and associated
with emotional and social factors, a multidisciplinary approach involving psychologists,
dieticians, pain therapists, and psychiatrists is recommended.

Author Contributions: P.W. wrote the article. B.C., F.D., S.D. and L.P.-B. critically revised the
manuscript. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
J. Clin. Med. 2022, 11, 4269 11 of 15

Conflicts of Interest: P.W. declares no conflict of interest. B.C. declares no conflict of interest. F.D.
declares no conflict of interest. S.D. has served as a speaker, consultant, and advisory board member
for Schering-Plough, AbbVie, Actelion, Alphawasserman, AstraZeneca, Cellerix, Cosmo Pharmaceuti-
cals, Ferring, Genentech, Grunenthal, Johnson and Johnson, Millenium Takeda, MSD, Nikkiso Europe
GmbH, Novo Nordisk, Nycomed, Pfizer, Pharmacosmos, UCB Pharma, and Vifor. L.P.-B. declares
personal fees from Galapagos, AbbVie, Janssen, Genentech, Ferring, Tillots, Celltrion, Takeda, Pfizer,
Index Pharmaceuticals, Sandoz, Celgene, Biogen, Samsung Bioepis, Inotrem, Allergan, MSD, Roche,
Arena, Gilead, Amgen, BMS, Vifor, Norgine, Mylan, Lilly, Fresenius Kabi, OSE Immunotherapeutics,
Enthera, Theravance, Pandion Therapeutics, Gossamer Bio, Viatris, Thermo Fisher; grants from
Abbvie, MSD, Takeda, and Fresenius Kabi; stock options: CTMA.

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