Gastroenterology 2017;152:430–439
Etiology and Treatment of Pain and Psychosocial Issues
in Patients With Inflammatory Bowel Diseases
Miguel Regueiro1 Julia B. Greer1 Eva Szigethy1,2
1
Division of Gastroenterology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and 2Department of
Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
There is increasing evidence that brainLgut interactions as an “unpleasant sensory and emotional experience,”9
are altered during development of inflammatory bowel becomes chronic, there is growing evidence of functional
diseases (IBDs). Understanding the relationship between reorganization of the brain.10 While acute abdominal pain is
the neurobiology, psychological symptoms, and social ram- an important clinical correlate of IBD activity, chronic
ifications of IBD can guide comprehensive care for the whole abdominal pain is different and involves both central nervous
patient. The most common psychological conditions in pa- system reorganization and dysregulation of the braingut
tients with IBD are chronic abdominal pain, anxiety, and axis.11 This braingut dysregulation predisposes patients
depression. We review the evidence-based data and rates of with chronic IBD pain to anxiety and depression.12,13 When
these conditions and their respective relationship to IBD chronic abdominal pain occurs in the absence of measurable
and the diagnostic approaches to identify patients with objective IBD activity, for example, elevated C-reactive
these conditions. Different treatment options for pain and protein or endoscopic evidence of inflammation, it has been
psychosocial conditions are discussed, and new models of
called comorbid irritable bowel syndrome (IBS-IBD). This
team-based IBD care are introduced. Providing the health
IBS-IBD nomenclature does not necessarily imply, however,
care provider with tools to diagnose and manage psycho-
that IBD and IBS are the same condition.7,14
logical conditions in patients with Crohn’s disease or
ulcerative colitis is necessary for their total care and should The incidence of IBS-IBD has been reported to be as high
be part of quality-improvement initiatives. as 59% in patients with Crohn’s disease (CD) and 38% in
patients with ulcerative colitis (UC).6 In a study of 149
patients with IBD (44 with UC and 105 with CD) who
Keywords: CD; UC; Psychology; Behavioral Therapy. reported inactive IBD during the previous 12 months,
IBS-like symptoms were common; additionally, 27.3% of the
A lterations in braingut interactions are an impor-
tant component of inflammatory bowel diseases
(IBD).1 There is a complex communication system con-
patients with UC and 31.3% of those with CD, with inactive
disease, met the criteria for major depression.15 These
findings were consistent with the larger-scale SONIC trial,
necting the brain with the gastrointestinal (GI) tract. This where 1 of 3 of patients with a diagnosis of moderate to
system involves modulating interactions among the hypo- severe IBD on the Crohn’s Disease Activity Index, did not
thalamicpituitary adrenal axis, autonomic nervous system, have evidence of inflammation on colonoscopy.16 In a meta-
GI immune system, and intestinal barrier and microbiota. analysis examining the prevalence of IBS-IBD, the pooled
Dysregulation of this braingut axis can lead to an exacer- prevalence of IBS-IBD in all patients was 39%; 35%
bation of GI processes, including inflammation and motility, described in remission and 44% with active IBD. IBS-like
particularly under conditions of stress.2–5 In patients with symptoms were higher overall in patients with CD (46%
IBD, the most common psychosocial and modifiable condi- vs 36% for UC).8 The range of rates of IBS-IBD from 27% to
tions are chronic abdominal pain, anxiety, and depression.
We review clinically relevant information related to the
neurobiological etiology, and the rates, diagnosis, and Abbreviations used in this paper: BAS, behavioral activation system; BIS,
treatment of these nervous system correlates of IBD. behavioral inhibition system; CBT, cognitive behavioral therapy; CD,
Crohn’s disease; GI, gastrointestinal; IBD, inflammatory bowel disease;
IBS, irritable bowel syndrome; PROMIS, Patient-Reported Outcomes
Pain, Anxiety, and Depression Measurement Information System; UC, ulcerative colitis.
Most current article
Pain
© 2017 by the AGA Institute
Abdominal pain is common in patients with IBD and can 0016-5085/$36.00
be present with active or inactive IBD.6–8 When pain, defined http://dx.doi.org/10.1053/j.gastro.2016.10.036
, January 2017 BrainGut Interactions and Development of Inflammatory Bowel Disease 431
59% is largely due the different criteria used to define approximately one-quarter of all outpatients with IBD take
remission and abdominal pain and differences in the IBD opioid medications on a chronic basis.34–37 Narcotic use in
type examined. It is important to note that abdominal pain is IBD patients has been associated with female sex, moderate
often a subscore of IBD activity scores used in clinical to severe pain, anxiety, depression, substance abuse, clinical
research trials, as well as an important clinical end point in disease activity, as well as histories of 2 or more surgeries
patient-reported outcomes. In fact, abdominal pain will be or sexual, emotional, and/or physical abuse.34 There is no
required by the US Food and Drug Administration as a evidence that narcotic analgesics are effective treatments
patient-reported outcome for CD in future IBD trials. One for IBD, and they pose numerous health risks, including
way to differentiate more functional chronic pain is to opioid-induced constipation, worsening pain (narcotic
measure pain beliefs and pain interference.17 bowel syndrome), and an increased risk of infection and
In UC patients with IBS-IBD, higher levels of serum death.38,39
cytokines, such as interleukin-6, have been reported and
may be related both to visceral hypersensitivity and the
increased psychopathology reported.12 Cytokines and Anxiety and Depression
immune modulators have been implicated in other models Rates of anxiety and depression are higher among pa-
of inflammatory depression in humans.18 IBS-IBD has also tients with IBD compared with other diseases as well as the
been associated with increased health care use.19,20 Collec- general population.40–42 Pooled incidence values for anxiety
tively, the existing literature shows no definitive causal and depression were reported to be 19% and 21%,
relationship between the degree of IBD activity and respectively, in patients with IBD—almost double those of
abdominal pain intensity, but does support the contention healthy individuals.43 Anxiety and depression were re-
that chronic pain is likely more associated with dysregula- ported in higher proportions of patients with active than
tion and reorganization of the central nervous system.21,22 inactive IBD, and of patients with CD than UC. In children,
Chronic visceral pain is mediated by nociceptors in the anxiety and depression were often present before the onset
intestinal wall that respond to different stimuli (mechanical of IBD; in adults, anxiety was reported before a diagnosis of
such as stretch and distention; chemical, and thermal).23 IBD, whereas depression was reported before and after a
The signal is transmitted to the brainstem via the spinal diagnosis of IBD. Among 152,461 female participants in the
cord by unmyelinated nerve fibers.24 Unlike primary so- Nurse’s Health Study, depressive symptoms were associated
matic afferent fibers originating from the skin, muscles, or with an increased risk for onset of CD (170 cases) but not
peritoneum, which are often characterized as sudden, sharp, UC (203 cases).44
localized pain due to their dermatome distribution, visceral Certain disease-related variables have been correlated
afferents arborize throughout the spinal cord and brain, with these psychiatric symptoms. For example, anxiety in
contributing to a more diffuse, and poorly localized pain.25 patients with IBD has been associated with reduced adher-
Visceral pain is often associated with autonomic activation ence to medications, increased risk of surgery, perceived
linked to symptoms such as profuse sweating and changes stress, and lower quality of life.45–48 Symptoms of depression
in body temperature, blood pressure, and heart rate.26 among patients with IBD have been associated with inflam-
In patients with IBD, there are multiple plausible etiol- mation, pain, IBD relapse, and a poorer response to IBD
ogies for chronic visceral pain or hyperalgesia. These include treatment in most, but not all, studies.49–53 In a prospective
sensitization of primary sensory afferents from the GI tract study, short-term perceived stress, but not depression or
by inflammatory proteins, sensitization of spinal ascending degree of mucosal healing, predicted relapse among patients
nerves, and dysregulation of modulating descending path- with IBD in clinical remission at baseline.54 In patients from
ways from the brain.7,27 Stress and emotional dysregulation Korea with inactive IBD, severity of anxiety and depression
(anxiety and depression) can cause efferent stimulation and were associated with greater socioeconomic adversity.55
amplify the pain signal in humans.28,29 In fact, chronic stress A study assessed the odds of generalized anxiety disor-
can modify brain circuitry, change motility and permeability der among IBD patients.56 Based on data on 22,522 in-
in the GI tract, and interact with gut microbiota; all leading to dividuals from the nationally representative 2012 Canadian
an intensified visceral pain perception.5 One hypothesized Community Health Survey-Mental Health (68.9% response
mechanism for pain amplification is via the brain-derived rate), the estimated odds ratios of generalized anxiety dis-
nerve factor, an activity-dependent neuromodulator order were calculated among those with (n ¼ 269) and
involved in the development and maintenance of inflam- without IBD. Even when the authors controlled for
matory and neuropathic pain.30 Social attachment style and numerous potential confounders, individuals with IBD had a
early childhood adversity all influence intestinal nociception, >2-fold increase in risk of anxiety compared with persons
motility, and inflammation, but need to be better studied in without IBD. Generalized anxiety disorder was equally likely
patients with IBD.15,31,32 Thus, for the health care provider among patients with CD vs UC. The strongest correlates
explaining the causes of chronic abdominal pain to patients, of anxiety among patients with IBD were a history of
it is important to emphasize that the pain they are experi- childhood sexual abuse, female sex, and chronic pain.
encing is likely multimodal and involves a cascade of Symptoms of depression and anxiety also occur in a
neurobiological alterations from the gut to the brain. portion of patients with quiescent IBD suggesting that these
Chronic pain has been associated with greater use of may be comorbid psychiatric conditions unrelated to IBD
medicinal cannabis by patients with IBD.33 Additionally, activity status. It is important to note that depression is a
Etiology and Treatment of Pain and Psychosocial Issues
in Patients With Inflammatory Bowel Diseases
Miguel Regueiro1 Julia B. Greer1 Eva Szigethy1,2
1
Division of Gastroenterology, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and 2Department of
Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania
There is increasing evidence that brainLgut interactions as an “unpleasant sensory and emotional experience,”9
are altered during development of inflammatory bowel becomes chronic, there is growing evidence of functional
diseases (IBDs). Understanding the relationship between reorganization of the brain.10 While acute abdominal pain is
the neurobiology, psychological symptoms, and social ram- an important clinical correlate of IBD activity, chronic
ifications of IBD can guide comprehensive care for the whole abdominal pain is different and involves both central nervous
patient. The most common psychological conditions in pa- system reorganization and dysregulation of the braingut
tients with IBD are chronic abdominal pain, anxiety, and axis.11 This braingut dysregulation predisposes patients
depression. We review the evidence-based data and rates of with chronic IBD pain to anxiety and depression.12,13 When
these conditions and their respective relationship to IBD chronic abdominal pain occurs in the absence of measurable
and the diagnostic approaches to identify patients with objective IBD activity, for example, elevated C-reactive
these conditions. Different treatment options for pain and protein or endoscopic evidence of inflammation, it has been
psychosocial conditions are discussed, and new models of
called comorbid irritable bowel syndrome (IBS-IBD). This
team-based IBD care are introduced. Providing the health
IBS-IBD nomenclature does not necessarily imply, however,
care provider with tools to diagnose and manage psycho-
that IBD and IBS are the same condition.7,14
logical conditions in patients with Crohn’s disease or
ulcerative colitis is necessary for their total care and should The incidence of IBS-IBD has been reported to be as high
be part of quality-improvement initiatives. as 59% in patients with Crohn’s disease (CD) and 38% in
patients with ulcerative colitis (UC).6 In a study of 149
patients with IBD (44 with UC and 105 with CD) who
Keywords: CD; UC; Psychology; Behavioral Therapy. reported inactive IBD during the previous 12 months,
IBS-like symptoms were common; additionally, 27.3% of the
A lterations in braingut interactions are an impor-
tant component of inflammatory bowel diseases
(IBD).1 There is a complex communication system con-
patients with UC and 31.3% of those with CD, with inactive
disease, met the criteria for major depression.15 These
findings were consistent with the larger-scale SONIC trial,
necting the brain with the gastrointestinal (GI) tract. This where 1 of 3 of patients with a diagnosis of moderate to
system involves modulating interactions among the hypo- severe IBD on the Crohn’s Disease Activity Index, did not
thalamicpituitary adrenal axis, autonomic nervous system, have evidence of inflammation on colonoscopy.16 In a meta-
GI immune system, and intestinal barrier and microbiota. analysis examining the prevalence of IBS-IBD, the pooled
Dysregulation of this braingut axis can lead to an exacer- prevalence of IBS-IBD in all patients was 39%; 35%
bation of GI processes, including inflammation and motility, described in remission and 44% with active IBD. IBS-like
particularly under conditions of stress.2–5 In patients with symptoms were higher overall in patients with CD (46%
IBD, the most common psychosocial and modifiable condi- vs 36% for UC).8 The range of rates of IBS-IBD from 27% to
tions are chronic abdominal pain, anxiety, and depression.
We review clinically relevant information related to the
neurobiological etiology, and the rates, diagnosis, and Abbreviations used in this paper: BAS, behavioral activation system; BIS,
treatment of these nervous system correlates of IBD. behavioral inhibition system; CBT, cognitive behavioral therapy; CD,
Crohn’s disease; GI, gastrointestinal; IBD, inflammatory bowel disease;
IBS, irritable bowel syndrome; PROMIS, Patient-Reported Outcomes
Pain, Anxiety, and Depression Measurement Information System; UC, ulcerative colitis.
Most current article
Pain
© 2017 by the AGA Institute
Abdominal pain is common in patients with IBD and can 0016-5085/$36.00
be present with active or inactive IBD.6–8 When pain, defined http://dx.doi.org/10.1053/j.gastro.2016.10.036
, January 2017 BrainGut Interactions and Development of Inflammatory Bowel Disease 431
59% is largely due the different criteria used to define approximately one-quarter of all outpatients with IBD take
remission and abdominal pain and differences in the IBD opioid medications on a chronic basis.34–37 Narcotic use in
type examined. It is important to note that abdominal pain is IBD patients has been associated with female sex, moderate
often a subscore of IBD activity scores used in clinical to severe pain, anxiety, depression, substance abuse, clinical
research trials, as well as an important clinical end point in disease activity, as well as histories of 2 or more surgeries
patient-reported outcomes. In fact, abdominal pain will be or sexual, emotional, and/or physical abuse.34 There is no
required by the US Food and Drug Administration as a evidence that narcotic analgesics are effective treatments
patient-reported outcome for CD in future IBD trials. One for IBD, and they pose numerous health risks, including
way to differentiate more functional chronic pain is to opioid-induced constipation, worsening pain (narcotic
measure pain beliefs and pain interference.17 bowel syndrome), and an increased risk of infection and
In UC patients with IBS-IBD, higher levels of serum death.38,39
cytokines, such as interleukin-6, have been reported and
may be related both to visceral hypersensitivity and the
increased psychopathology reported.12 Cytokines and Anxiety and Depression
immune modulators have been implicated in other models Rates of anxiety and depression are higher among pa-
of inflammatory depression in humans.18 IBS-IBD has also tients with IBD compared with other diseases as well as the
been associated with increased health care use.19,20 Collec- general population.40–42 Pooled incidence values for anxiety
tively, the existing literature shows no definitive causal and depression were reported to be 19% and 21%,
relationship between the degree of IBD activity and respectively, in patients with IBD—almost double those of
abdominal pain intensity, but does support the contention healthy individuals.43 Anxiety and depression were re-
that chronic pain is likely more associated with dysregula- ported in higher proportions of patients with active than
tion and reorganization of the central nervous system.21,22 inactive IBD, and of patients with CD than UC. In children,
Chronic visceral pain is mediated by nociceptors in the anxiety and depression were often present before the onset
intestinal wall that respond to different stimuli (mechanical of IBD; in adults, anxiety was reported before a diagnosis of
such as stretch and distention; chemical, and thermal).23 IBD, whereas depression was reported before and after a
The signal is transmitted to the brainstem via the spinal diagnosis of IBD. Among 152,461 female participants in the
cord by unmyelinated nerve fibers.24 Unlike primary so- Nurse’s Health Study, depressive symptoms were associated
matic afferent fibers originating from the skin, muscles, or with an increased risk for onset of CD (170 cases) but not
peritoneum, which are often characterized as sudden, sharp, UC (203 cases).44
localized pain due to their dermatome distribution, visceral Certain disease-related variables have been correlated
afferents arborize throughout the spinal cord and brain, with these psychiatric symptoms. For example, anxiety in
contributing to a more diffuse, and poorly localized pain.25 patients with IBD has been associated with reduced adher-
Visceral pain is often associated with autonomic activation ence to medications, increased risk of surgery, perceived
linked to symptoms such as profuse sweating and changes stress, and lower quality of life.45–48 Symptoms of depression
in body temperature, blood pressure, and heart rate.26 among patients with IBD have been associated with inflam-
In patients with IBD, there are multiple plausible etiol- mation, pain, IBD relapse, and a poorer response to IBD
ogies for chronic visceral pain or hyperalgesia. These include treatment in most, but not all, studies.49–53 In a prospective
sensitization of primary sensory afferents from the GI tract study, short-term perceived stress, but not depression or
by inflammatory proteins, sensitization of spinal ascending degree of mucosal healing, predicted relapse among patients
nerves, and dysregulation of modulating descending path- with IBD in clinical remission at baseline.54 In patients from
ways from the brain.7,27 Stress and emotional dysregulation Korea with inactive IBD, severity of anxiety and depression
(anxiety and depression) can cause efferent stimulation and were associated with greater socioeconomic adversity.55
amplify the pain signal in humans.28,29 In fact, chronic stress A study assessed the odds of generalized anxiety disor-
can modify brain circuitry, change motility and permeability der among IBD patients.56 Based on data on 22,522 in-
in the GI tract, and interact with gut microbiota; all leading to dividuals from the nationally representative 2012 Canadian
an intensified visceral pain perception.5 One hypothesized Community Health Survey-Mental Health (68.9% response
mechanism for pain amplification is via the brain-derived rate), the estimated odds ratios of generalized anxiety dis-
nerve factor, an activity-dependent neuromodulator order were calculated among those with (n ¼ 269) and
involved in the development and maintenance of inflam- without IBD. Even when the authors controlled for
matory and neuropathic pain.30 Social attachment style and numerous potential confounders, individuals with IBD had a
early childhood adversity all influence intestinal nociception, >2-fold increase in risk of anxiety compared with persons
motility, and inflammation, but need to be better studied in without IBD. Generalized anxiety disorder was equally likely
patients with IBD.15,31,32 Thus, for the health care provider among patients with CD vs UC. The strongest correlates
explaining the causes of chronic abdominal pain to patients, of anxiety among patients with IBD were a history of
it is important to emphasize that the pain they are experi- childhood sexual abuse, female sex, and chronic pain.
encing is likely multimodal and involves a cascade of Symptoms of depression and anxiety also occur in a
neurobiological alterations from the gut to the brain. portion of patients with quiescent IBD suggesting that these
Chronic pain has been associated with greater use of may be comorbid psychiatric conditions unrelated to IBD
medicinal cannabis by patients with IBD.33 Additionally, activity status. It is important to note that depression is a
