Pain Management
Review For reprint orders, please contact: [email protected]
Persistent pain in chronically ill children without detectable disease activity Maggie H Bromberg1, Neil L Schechter2, Samuel Nurko3, William T Zempsky4 & Laura E Schanberg*,5 Practice points ●●
Children with painful organic diseases may experience persistent pain not adequately explained by disease processes.
●●
Assessing and treating pain as organic without evidence of increased disease activity may lead to unnecessary escalation of diagnostic evaluation and medical therapy.
●●
Clinicians should apply a biopsychosocial approach to diagnosis and treatment of
persistent pain in the presence of seemingly well-controlled organic disease, similar to approaches used with pain that is functional in etiology. ●●
Consistent with strategies used in treating functional pain, a comprehensive,
multimodal treatment approach incorporating physical therapy, cognitive behavioral therapy and pharmacotherapy may improve treatment outcomes.
SUMMARY: Children with organic diseases may experience persistent pain in the presence of controlled disease, as evidenced by little or no measurable disease activity or inflammation. Historically, dualistic definitions of pain have informed standard diagnostic approaches to persistent pain; aggressive investigation and treatment targeting underlying disease, even in the absence of evidence indicating disease escalation. Evidence across disease populations, in children with inflammatory bowel disease, sickle cell disease, and juvenile idiopathic arthritis indicates that persistent pain in these conditions may be better conceptualized as functional in nature, potentially resulting from disordered somatosensory processing including central sensitization. Applying a biopsychosocial understanding of persistent pain and multidisciplinary functional pain management strategies may lead to improved health outcomes. Background It is generally assumed that acute pain is caused by an underlying pathophysiologic aberration (trauma, inflammation and infection) [1] . Therefore, when this process is adequately treated or resolves, the pain should dissipate. The term, functional pain, evolved to describe pain that exists without an underlying biochemical or anatomical abnormality [2] . It is a core tenet of functional
Center for Child Health, Behavior, & Development, Seattle Children’s Research Institute, M/S CW8–6, PO Box 5371, Seattle, WA 98145, USA Department of Anesthesiology, Perioperative, & Pain Medicine, Boston Children’s Hospital, 300 Longwood Avenue Boston, MA 02115, USA 3 Center for Motility & Functional Gastrointestinal Disorders, Boston Children’s Hospital, 300 Longwood Avenue Boston, MA 02115, USA 4 Division of Pain & Palliative Medicine, Connecticut Children’s Medical Center, 282 Washington Street, Hartford, CT 06106, USA 5 Division of Pediatric Rheumatology, Duke University Medical Center, Box 3212 Med Ctr T0909, Durham, NC 27710, USA *Author for correspondence: Tel.: +1 919 684 6601; Fax: +1 919 684 6616; [email protected] 1 2
10.2217/PMT.14.6 © 2014 Future Medicine Ltd
Pain Management (2014) 4(3), 211–219
part of
ISSN 1758-1869
211
Review Bromberg, Schechter, Nurko, Zempsky & Schanberg pain, implicit in all definitions, that there is no underlying structural pathological process to explain the pain. Across a variety of chronic pediatric diseases, persistent pain may be present even when disease activity is not currently detectable. There are limitations in the ability of clinicians to detect low levels of inflammation that may impact nociception and contribute to central sensitization. However, the frequency, intensity, and degree of disability associated with persistent pain in chronic disease is suggestive of central sensitization and best treated from a biopsychosocial perspective rather than with anti-inflammatory or disease-modifying therapies alone. In this context, the persistent pain is not fully attributable to a disease process. We propose that lessons for assessing and treating functional pain may be borrowed to guide decisions in caring for children with chronic disease who experience pain that is disproportionate to their current detectable disease activity. At present, there is no ideal term for describing the process that is the topic of this review. ‘Functional pain’ has historically been applied to pain conditions without a clear underlying disease basis, often implying a primarily psychogenic etiology and pejorative connotations. Nevertheless, it remains the best available term to describe pain out of proportion to detectable disease activity. However, it has been shown in inflammatory arthritis and other contexts that low grade inflammatory processes can, and often do, continue below the threshold for detection by clinical examination, laboratory tests, even MRIs. Such low level inflammation may play a role in the maintenance of pain and central sensitization, but aggressive treatment with expensive, potentially risky anti-inflammatory and immunomodulatory medications may not be the best treatment approach. Persistent pain in chronically ill children when disease activity is not detectable by clinical examination or laboratory testing is best assessed and managed from a biopsychosocial perspective, as is routinely employed in the context of functional pain. Additionally, persistent pain intensity and functional impairment may seem disproportionate, even in the possible presence of ongoing, undetectable disease activity. In this situation, employing a biopsychosocial approach and pain management techniques aimed at functional pain rehabilitation is warranted. It is clear that many individuals diagnosed with chronic organic disease report significant,
212
Pain Management (2014) 4(3)
persistent discomfort resembling functional pain often in the face of seemingly well-controlled disease, which impacts health outcomes in multiple ways, particularly activity engagement. This topic is of increasing interest to healthcare providers caring for children with chronic illness, as well as pain researchers. In this review, we discuss current understanding about functional pain focusing on its implications for children with persistent pain with organic disease when disease activity is no longer detectable, using inflammatory bowel disease (IBD), sickle cell disease (SCD) and juvenile idiopathic arthritis (JIA) as models of a more general concept. Etiology of functional pain There has been a significant shift in the understanding of functional pain over the past 10 years [2] . Although in theory the term functional pain implies that pain stems from ‘organ dysfunction’ without organic disease but with no implication of underlying etiology, it has been commonly assumed that functional pain results from or has been strongly influenced by psychological factors. This is evident in the recent definition of functional disease in Stedman’s Medical Dictionary (“not organic in origin; denoting a disorder with no known or detectable or organic basis to the symptoms; See Neurosis”) [3] . The historical mind–body dichotomy is manifest in the standard erroneous diagnostic approach to persistent pain – extensive organic evaluation followed by referral to a mental health professional if no pathology is identified. Pain in an individual with a previously identified organic disease initiates an aggressive hunt for disease or the empiric escalation of medical therapy even if disease markers and physical exam demonstrate remission or minimal disease activity. If the investigative journey does not yield evidence of hidden new or recurrent disease, then psychological factors are assumed responsible and the child or adolescent is unceremoniously scheduled for the next available psychology or psychiatry appointment. Unfortunately, not only are these services hard to access, but often families are not compliant with the recommendation as they do not believe the psyche is responsible for their suffering [4] . There is now strong evidence that functional pain stems from a complex interaction of biological, psychological, and sociocultural factors which influence neuronal hyper-responsiveness [5] . This nociceptive hypersensitivity may result
future science group
Persistent pain in chronically ill children without detectable disease activity from ‘central sensitization’, defined by Woolf [6] as an increase in synaptic efficacy in nociceptive pathways in the central nervous system and/or from reduced descending inhibition of pain leading to enhanced pain. Factors including genetic susceptibility, repeated trauma, inflammation, and infections may yield central sensitization while anxiety, depression, and stress may produce reduced descending inhibition. The combination of central sensitization and reduced descending inhibition results in increased pain from non- or minimally-noxious stimuli as well as producing an intensified and prolonged response. Changes in pain reactivity may persist long after the initial stimulus dissipates. Neuronal hyper-responsiveness is likely at the core of functional abdominal pain [7] , fibromyalgia [8] and chronic daily headaches [9] . In addition to a shared etiology, the overlapping clinical characteristics including abnormalities on quantitative sensory testing [10] , female predominance [11] , sleep problems [12] , POTS [13] , fatigue [14] , mood disorders [15] and responsiveness to behavioral interventions and neuro-modulating drugs such as antidepressants and anticonvulsants provide evidence that functional pain problems are interrelated. It is clear that functional pain is complex and the overly simplistic characterization as either organic or psychological is not only incorrect, but often harmful, as treatment adherence decreases if children and their families perceive that providers attribute symptoms solely to psychological origins. Although it is typically assumed that the presence of diagnosed organic disease in an individual by definition precludes functional disease, in fact, many features associated with chronic disease may make the individual at risk for functional pain. Children with chronic illness commonly experience inflammation, infection, or medically induced trauma which may predispose them to the development of central sensitization [16] . Likewise, anxiety, depression, and stress are common in children experiencing the social isolation, stigmatization, and fear that accompany chronic diseases [17] . Furthermore, there is no reason to believe that children with inflammatory bowel disease (IBD), sickle cell disease (SCD), or juvenile idiopathic arthritis (JIA), are less likely than the general public to be genetically predisposed to the development of persistent pain. In fact, it appears that many factors that predispose an individual to central sensitization and resultant persistent pain are more,
future science group
Review
rather than less, likely to be present in children with chronic organic disease (Figure 1) . As documented subsequently in this review, mounting evidence demonstrates that persistent pain in children with disease-related pain (inflammatory bowel disease, sickle cell disease and juvenile idiopathic arthritis) has many characteristics in common with functional pain, likely resulting from biopsychosocial processes contributing to central sensitization, and may benefit from approaches that have been successful in addressing it. Persistent pain in inflammatory bowel disease Abdominal pain is a common complaint in children with IBD, often accompanying active disease and inflammation [18–20] . Children with IBD and pain are therefore presumed to have an underlying exacerbation of their disease, leading to invasive and costly testing, and escalation of therapy [18,19,21] . Persistence of pain in IBD represents a diagnostic and therapeutic dilemma, particularly when there is no objective evidence of inflammation. Patients with IBD, particularly Crohn’s disease (CD), in apparent remission report varying degrees of gastrointestinal symptoms (e.g., bloating, diarrhea, urgency, constipation and incomplete bowel movements) as well as abdominal pain that overlap with symptoms reported by children with irritable bowel syndrome (IBS), suggesting that some symptoms reported by IBD patients may in fact be related to functional gastrointestinal disorders (FGIDs), mainly IBS [18,20–23] . The overlap between IBD and IBS is beginning to be recognized [18,21,22] . One challenge in identifying the overlap of symptoms has been the absence of biomarkers to aid in the diagnosis of IBS, which instead relies on a system-based approach [21,23] . Diagnostic criteria for IBS are well established (ROME III criteria [23]), but one criterion is the absence of ‘organic pathology’, excluding patients with underlying well defined ‘organic’ diseases such as IBD. Ignoring the possible role of functional pain often leads to potentially unnecessary testing and intensification of therapy in symptomatic IBD patients, even when there is no objective evidence of ongoing inflammation [19,21,22] . Recent studies have documented evidence of low grade inflammation or alterations in symptomatic patients with IBD, or with those with symptomatic IBD in the absence of traditional markers of active disease [24] . The exact role that
www.futuremedicine.com
213
Review Bromberg, Schechter, Nurko, Zempsky & Schanberg
Psychosocial Stress Anxiety Depression Reinforcement of pain behaviors
Biomedical Genetic susceptibility Inflammation Infections Repeated medical trauma
Pathogenetic mechanisms Central sensitization Reduced descending noxious inhibition
Pain characteristics Persistent Intensity disproportionate to detected disease activity Pain from minimally or non-noxious stimuli Low pain threshold Sleep disruptions Fatigue
Figure 1. Model of biopsychosocial factors occurring in the context of organic disease that contribute to a pain hypersensitivity/centralization process, resulting in persistent pain in organic disease. Italicized items are those that are increased in the context of organic illness. This broad theoretical model is applicable across a variety of diseases.
those subtle abnormalities play in the pathogenesis of the pain needs to be determined, but there is no clinical evidence that its treatment has an effect on outcome [18,19] . In recent years it has become clear that IBD patients report symptoms in the absence of objective disease, leading to the recognition that a subgroup of patients may have symptoms that are functional, rather than inflammatory, in nature [19,21,22] . A recent meta-analysis in adults showed that IBS is common in IBD affecting approximately 39% of patients with an OR of 4.89 compared with controls [22] . In our own prospective study of 307 children, 139 reported abdominal pain [21] . Of this group, 18 out of 139 (13%) children met the criteria for functional abdominal pain. These patients had a higher rate of depression than patients with CD in remission reporting no abdominal pain (55.6 vs 29.9%; p
Review For reprint orders, please contact: [email protected]
Persistent pain in chronically ill children without detectable disease activity Maggie H Bromberg1, Neil L Schechter2, Samuel Nurko3, William T Zempsky4 & Laura E Schanberg*,5 Practice points ●●
Children with painful organic diseases may experience persistent pain not adequately explained by disease processes.
●●
Assessing and treating pain as organic without evidence of increased disease activity may lead to unnecessary escalation of diagnostic evaluation and medical therapy.
●●
Clinicians should apply a biopsychosocial approach to diagnosis and treatment of
persistent pain in the presence of seemingly well-controlled organic disease, similar to approaches used with pain that is functional in etiology. ●●
Consistent with strategies used in treating functional pain, a comprehensive,
multimodal treatment approach incorporating physical therapy, cognitive behavioral therapy and pharmacotherapy may improve treatment outcomes.
SUMMARY: Children with organic diseases may experience persistent pain in the presence of controlled disease, as evidenced by little or no measurable disease activity or inflammation. Historically, dualistic definitions of pain have informed standard diagnostic approaches to persistent pain; aggressive investigation and treatment targeting underlying disease, even in the absence of evidence indicating disease escalation. Evidence across disease populations, in children with inflammatory bowel disease, sickle cell disease, and juvenile idiopathic arthritis indicates that persistent pain in these conditions may be better conceptualized as functional in nature, potentially resulting from disordered somatosensory processing including central sensitization. Applying a biopsychosocial understanding of persistent pain and multidisciplinary functional pain management strategies may lead to improved health outcomes. Background It is generally assumed that acute pain is caused by an underlying pathophysiologic aberration (trauma, inflammation and infection) [1] . Therefore, when this process is adequately treated or resolves, the pain should dissipate. The term, functional pain, evolved to describe pain that exists without an underlying biochemical or anatomical abnormality [2] . It is a core tenet of functional
Center for Child Health, Behavior, & Development, Seattle Children’s Research Institute, M/S CW8–6, PO Box 5371, Seattle, WA 98145, USA Department of Anesthesiology, Perioperative, & Pain Medicine, Boston Children’s Hospital, 300 Longwood Avenue Boston, MA 02115, USA 3 Center for Motility & Functional Gastrointestinal Disorders, Boston Children’s Hospital, 300 Longwood Avenue Boston, MA 02115, USA 4 Division of Pain & Palliative Medicine, Connecticut Children’s Medical Center, 282 Washington Street, Hartford, CT 06106, USA 5 Division of Pediatric Rheumatology, Duke University Medical Center, Box 3212 Med Ctr T0909, Durham, NC 27710, USA *Author for correspondence: Tel.: +1 919 684 6601; Fax: +1 919 684 6616; [email protected] 1 2
10.2217/PMT.14.6 © 2014 Future Medicine Ltd
Pain Management (2014) 4(3), 211–219
part of
ISSN 1758-1869
211
Review Bromberg, Schechter, Nurko, Zempsky & Schanberg pain, implicit in all definitions, that there is no underlying structural pathological process to explain the pain. Across a variety of chronic pediatric diseases, persistent pain may be present even when disease activity is not currently detectable. There are limitations in the ability of clinicians to detect low levels of inflammation that may impact nociception and contribute to central sensitization. However, the frequency, intensity, and degree of disability associated with persistent pain in chronic disease is suggestive of central sensitization and best treated from a biopsychosocial perspective rather than with anti-inflammatory or disease-modifying therapies alone. In this context, the persistent pain is not fully attributable to a disease process. We propose that lessons for assessing and treating functional pain may be borrowed to guide decisions in caring for children with chronic disease who experience pain that is disproportionate to their current detectable disease activity. At present, there is no ideal term for describing the process that is the topic of this review. ‘Functional pain’ has historically been applied to pain conditions without a clear underlying disease basis, often implying a primarily psychogenic etiology and pejorative connotations. Nevertheless, it remains the best available term to describe pain out of proportion to detectable disease activity. However, it has been shown in inflammatory arthritis and other contexts that low grade inflammatory processes can, and often do, continue below the threshold for detection by clinical examination, laboratory tests, even MRIs. Such low level inflammation may play a role in the maintenance of pain and central sensitization, but aggressive treatment with expensive, potentially risky anti-inflammatory and immunomodulatory medications may not be the best treatment approach. Persistent pain in chronically ill children when disease activity is not detectable by clinical examination or laboratory testing is best assessed and managed from a biopsychosocial perspective, as is routinely employed in the context of functional pain. Additionally, persistent pain intensity and functional impairment may seem disproportionate, even in the possible presence of ongoing, undetectable disease activity. In this situation, employing a biopsychosocial approach and pain management techniques aimed at functional pain rehabilitation is warranted. It is clear that many individuals diagnosed with chronic organic disease report significant,
212
Pain Management (2014) 4(3)
persistent discomfort resembling functional pain often in the face of seemingly well-controlled disease, which impacts health outcomes in multiple ways, particularly activity engagement. This topic is of increasing interest to healthcare providers caring for children with chronic illness, as well as pain researchers. In this review, we discuss current understanding about functional pain focusing on its implications for children with persistent pain with organic disease when disease activity is no longer detectable, using inflammatory bowel disease (IBD), sickle cell disease (SCD) and juvenile idiopathic arthritis (JIA) as models of a more general concept. Etiology of functional pain There has been a significant shift in the understanding of functional pain over the past 10 years [2] . Although in theory the term functional pain implies that pain stems from ‘organ dysfunction’ without organic disease but with no implication of underlying etiology, it has been commonly assumed that functional pain results from or has been strongly influenced by psychological factors. This is evident in the recent definition of functional disease in Stedman’s Medical Dictionary (“not organic in origin; denoting a disorder with no known or detectable or organic basis to the symptoms; See Neurosis”) [3] . The historical mind–body dichotomy is manifest in the standard erroneous diagnostic approach to persistent pain – extensive organic evaluation followed by referral to a mental health professional if no pathology is identified. Pain in an individual with a previously identified organic disease initiates an aggressive hunt for disease or the empiric escalation of medical therapy even if disease markers and physical exam demonstrate remission or minimal disease activity. If the investigative journey does not yield evidence of hidden new or recurrent disease, then psychological factors are assumed responsible and the child or adolescent is unceremoniously scheduled for the next available psychology or psychiatry appointment. Unfortunately, not only are these services hard to access, but often families are not compliant with the recommendation as they do not believe the psyche is responsible for their suffering [4] . There is now strong evidence that functional pain stems from a complex interaction of biological, psychological, and sociocultural factors which influence neuronal hyper-responsiveness [5] . This nociceptive hypersensitivity may result
future science group
Persistent pain in chronically ill children without detectable disease activity from ‘central sensitization’, defined by Woolf [6] as an increase in synaptic efficacy in nociceptive pathways in the central nervous system and/or from reduced descending inhibition of pain leading to enhanced pain. Factors including genetic susceptibility, repeated trauma, inflammation, and infections may yield central sensitization while anxiety, depression, and stress may produce reduced descending inhibition. The combination of central sensitization and reduced descending inhibition results in increased pain from non- or minimally-noxious stimuli as well as producing an intensified and prolonged response. Changes in pain reactivity may persist long after the initial stimulus dissipates. Neuronal hyper-responsiveness is likely at the core of functional abdominal pain [7] , fibromyalgia [8] and chronic daily headaches [9] . In addition to a shared etiology, the overlapping clinical characteristics including abnormalities on quantitative sensory testing [10] , female predominance [11] , sleep problems [12] , POTS [13] , fatigue [14] , mood disorders [15] and responsiveness to behavioral interventions and neuro-modulating drugs such as antidepressants and anticonvulsants provide evidence that functional pain problems are interrelated. It is clear that functional pain is complex and the overly simplistic characterization as either organic or psychological is not only incorrect, but often harmful, as treatment adherence decreases if children and their families perceive that providers attribute symptoms solely to psychological origins. Although it is typically assumed that the presence of diagnosed organic disease in an individual by definition precludes functional disease, in fact, many features associated with chronic disease may make the individual at risk for functional pain. Children with chronic illness commonly experience inflammation, infection, or medically induced trauma which may predispose them to the development of central sensitization [16] . Likewise, anxiety, depression, and stress are common in children experiencing the social isolation, stigmatization, and fear that accompany chronic diseases [17] . Furthermore, there is no reason to believe that children with inflammatory bowel disease (IBD), sickle cell disease (SCD), or juvenile idiopathic arthritis (JIA), are less likely than the general public to be genetically predisposed to the development of persistent pain. In fact, it appears that many factors that predispose an individual to central sensitization and resultant persistent pain are more,
future science group
Review
rather than less, likely to be present in children with chronic organic disease (Figure 1) . As documented subsequently in this review, mounting evidence demonstrates that persistent pain in children with disease-related pain (inflammatory bowel disease, sickle cell disease and juvenile idiopathic arthritis) has many characteristics in common with functional pain, likely resulting from biopsychosocial processes contributing to central sensitization, and may benefit from approaches that have been successful in addressing it. Persistent pain in inflammatory bowel disease Abdominal pain is a common complaint in children with IBD, often accompanying active disease and inflammation [18–20] . Children with IBD and pain are therefore presumed to have an underlying exacerbation of their disease, leading to invasive and costly testing, and escalation of therapy [18,19,21] . Persistence of pain in IBD represents a diagnostic and therapeutic dilemma, particularly when there is no objective evidence of inflammation. Patients with IBD, particularly Crohn’s disease (CD), in apparent remission report varying degrees of gastrointestinal symptoms (e.g., bloating, diarrhea, urgency, constipation and incomplete bowel movements) as well as abdominal pain that overlap with symptoms reported by children with irritable bowel syndrome (IBS), suggesting that some symptoms reported by IBD patients may in fact be related to functional gastrointestinal disorders (FGIDs), mainly IBS [18,20–23] . The overlap between IBD and IBS is beginning to be recognized [18,21,22] . One challenge in identifying the overlap of symptoms has been the absence of biomarkers to aid in the diagnosis of IBS, which instead relies on a system-based approach [21,23] . Diagnostic criteria for IBS are well established (ROME III criteria [23]), but one criterion is the absence of ‘organic pathology’, excluding patients with underlying well defined ‘organic’ diseases such as IBD. Ignoring the possible role of functional pain often leads to potentially unnecessary testing and intensification of therapy in symptomatic IBD patients, even when there is no objective evidence of ongoing inflammation [19,21,22] . Recent studies have documented evidence of low grade inflammation or alterations in symptomatic patients with IBD, or with those with symptomatic IBD in the absence of traditional markers of active disease [24] . The exact role that
www.futuremedicine.com
213
Review Bromberg, Schechter, Nurko, Zempsky & Schanberg
Psychosocial Stress Anxiety Depression Reinforcement of pain behaviors
Biomedical Genetic susceptibility Inflammation Infections Repeated medical trauma
Pathogenetic mechanisms Central sensitization Reduced descending noxious inhibition
Pain characteristics Persistent Intensity disproportionate to detected disease activity Pain from minimally or non-noxious stimuli Low pain threshold Sleep disruptions Fatigue
Figure 1. Model of biopsychosocial factors occurring in the context of organic disease that contribute to a pain hypersensitivity/centralization process, resulting in persistent pain in organic disease. Italicized items are those that are increased in the context of organic illness. This broad theoretical model is applicable across a variety of diseases.
those subtle abnormalities play in the pathogenesis of the pain needs to be determined, but there is no clinical evidence that its treatment has an effect on outcome [18,19] . In recent years it has become clear that IBD patients report symptoms in the absence of objective disease, leading to the recognition that a subgroup of patients may have symptoms that are functional, rather than inflammatory, in nature [19,21,22] . A recent meta-analysis in adults showed that IBS is common in IBD affecting approximately 39% of patients with an OR of 4.89 compared with controls [22] . In our own prospective study of 307 children, 139 reported abdominal pain [21] . Of this group, 18 out of 139 (13%) children met the criteria for functional abdominal pain. These patients had a higher rate of depression than patients with CD in remission reporting no abdominal pain (55.6 vs 29.9%; p
