Jurnal 5 Fatma
Jurnal 5 Fatma
Jurnal 5 Fatma
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
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].
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].
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.
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)
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.
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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