Abstract
At the pain workshop held prior to the Outcome Measures in Rheumatology (OMERACT) 12 conference, chronic nonmalignant pain (CP) as a “disease” was discussed, in response to growing interest in this concept and in terms of the effect on the OMERACT Filter 2.0 framework. CP is often assessed as a unidimensional outcome measure; however, if CP is a disease, then outcome measures need to define the disease state and identify all its manifestations as well as its effects, as specified by Filter 2.0. The aim was to write a discussion piece, reflecting the workshop contributions and debate, as an important step in opening a dialogue around future OMERACT Filter 2.0 Framework developments.
The Outcome Measures in Rheumatology (OMERACT) Filter 2.01 requires a definition of the area/domain of interest before selecting outcome measures for a disease, and currently sees chronic pain (CP) as a domain under Pathophysiologic Manifestations or as an element under Life Impact. Given that pain is now being considered a disease in its own right by some, it was decided at a pre-OMERACT workshop to discuss how CP should be classified (see Table 1 for working definitions shared with participants).
Definitions.
A number of presentations were given at the workshop including one that proposed that CP should be reclassified because it can no longer be seen as just a symptom. Participants were then asked to informally vote (Figure 1), and this showed widespread opinions on what pain represented. Admittedly, this poll was difficult to interpret, participants could not respond to more than 1 statement, and there was no option to explain choices. However, it provided a stimulus for the discussions that followed.
Results of an informal poll conducted at the pre-OMERACT workshop on participants’ opinions of how to define chronic pain.
This workshop, although sponsored by OMERACT, was not characteristic of OMERACT workshops: It was not informed by a prior, systematic, and methodologic approach normally taken; thus participants (healthcare professionals, scientists, and patient research partners) could air opinions, network, and lay foundations to inform the newly created pain subgroup regarding future OMERACT workshops and activity. If CP is considered a disease in its own right, this will have an effect on future OMERACT work streams in terms of the Filter 2.0 framework. Therefore this exploratory article starts the process of reflecting on whether CP remains a symptom or should be considered a disease.
The Challenge
Several individuals and organizations have suggested that CP is a disease in its own right2,3,4; however, others disagree5,6. At the outset, it must be stressed that untangling all the strands of the “CP, a disease” debate is a complex and nuanced task; for this reason, neuropathy is not included because it is seen as part of an ongoing pathophysiologic process of damage, especially, for example, diabetic painful neuropathy, which is already regarded as a disease. Cancer pain was also omitted because it is viewed as part of palliative care; pain in cancer is directly related to the ongoing presence of disease rather than a chronic condition without further input. The complexities under consideration, for example, include the fact that pathophysiological manifestations are different (central vs peripheral mechanisms); there are varying degrees of neurobiology that are not specific to a pain condition; some patients have very complex central pain changes and others appear not to; and finally, there are issues surrounding the grouping of all pain conditions into a disease model given the differing assessment needs and outcome measures. Following this and other such articles, OMERACT may need to reconceptualize CP in terms of the OMERACT Filter 2.0.
What Does the Literature Describe?
A number of literature reviews have explored the issue of whether CP is a disease. All have used relatively recent neuroimaging research to either support or refute its disease status.
Cousins7 and Siddall and Cousins3 both contended that CP is a disease entity, proposing that it has recognizable signs and symptoms and its own specific cause. Both reviews provide comprehensive discussions regarding functional and structural central nervous system (CNS) changes associated with CP. However, CP can manifest in different ways, have different signs and symptoms, and may not have a specific cause. For instance, differences can be seen in how individuals describe their pain8, in how pain is modulated by the CNS9, and in how individuals can respond to treatment: all suggesting different pathophysiological processes.
Cousins7 and Siddall and Cousins3 list a number of psychosocial sequelae that lead to structural and functional changes in the brain: the “pain pathology.” These include mood disturbances, loss of self-belief in abilities, fear avoidance, and loss of social roles and relationships, as specific changes in physiological mechanisms. Siddall and Cousins3 state, in support of CP as a disease, that these pathologies and signs and symptoms are dependent on, and unique to, the presence of pain. This proposition can be challenged; many of these are not pathological in a true sense, nor unique to chronic pain, in that the majority can be seen in people living with various chronic conditions unrelated to the presence of pain.
Tracey and Bushnell10 reviewed the evidence from neuroimaging studies, presenting functional, anatomical, and neurochemical evidence that people with CP have altered brains compared to healthy controls. What they could not identify is whether these changes were the result of an adaptive response to the continuing nociceptive barrage, or a real disease-specific process, which would support the conclusion that neuroimaging research has established CP as a true disease state. It is not surprising that pain results in brain changes, given that it is a sensory and emotional experience; other sensory and emotional experiences (meditation11, exercise12, pleasant touch13) are known to alter the brain. Therefore, caution is required when using altered CNS processes to define a disease state.
Tracey and Bushnell’s review10, in which support is given for CP as a disease, mentions that one motivation for their review was that CP treatment options are pharmacologically and behaviorally similar for many patients despite different etiologies, thereby suggesting that similar mechanisms generate the pain, in turn supporting the claim that CP is a disease. It is agreed that common interventions are used across diverse groups of people living with pain, but these interventions have only moderate success rates14 in low back pain, for example, and are even more variable across a range of pain conditions; this may reflect different outcome measures used in the studies, however. Not one treatment option works for all cases of CP; instead, a wide range of treatment options is advocated and used to address the complex biopsychosocial aspects that can be present.
Cohen, et al5 argue that CP is not a disease; they examine the evolutionary models used to explain CP and comment upon propositions in other reviews. They cite May15, who concluded that it was not clear whether structural changes in CP were due to pain, the consequences of pain, or both; and that other factors may have contributed to the findings. A number of studies have examined cortical structural changes accompanying chronic musculoskeletal pain16,17,18, and while different regions appear to be implicated in different CP states, there appears to be consistency in the involvement of the cingulate cortex, insula, and dorsolateral prefrontal cortex. Some researchers have controlled for other variables (anxiety and depression10, opioid use13, reduction in physical activity19, general drug consumption10) to account for structural loss but still found significant differences in CP patients versus controls.
Chronic Pain, a Disease?
Previous reviews have included rigorous debate concerning CP as a disease. Neuroimaging research has certainly provided rich detail regarding changes that occur as a result of pain, leading the debate supporting the idea that CP may indeed be a disease. Given that patients with CP are a large heterogeneous group, perhaps what qualifies chronic pain as a disease is a set of underlying mechanisms (central sensitization) or a particular type of pain (neuropathic).
Central sensitization can develop as a result of nociceptive inputs causing a reversible increase in the excitability and synaptic efficacy of neurons in the central nociceptive pathways20. It manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctuate or pressure hyperalgesia, enhanced temporal summation, and after-sensations20. Central sensitization and brain changes have been identified through neuroimaging studies10, and it has been proposed that CP is associated with cortical remodeling, specifically, primary somatosensory cortex (S1) functional reorganization21. However, it appears that pain itself does not result in S1 reorganization22; neuropathic pain appears to lead to cortical reorganization and associated changes in somatosensory cortex activity and anatomy, where nonneuropathic pain does not22. Unfortunately, there are no absolute diagnostic criteria for identifying the presence of central sensitization in patients; Woolf contends that pain hypersensitivity by itself is not sufficient to make an irrefutable diagnosis of central sensitization20. However, studies have putatively identified that central sensitization has contributed to patients’ pain phenotype (see Woolf20).
Central Sensitization and Common Rheumatologic Conditions
In osteoarthritis (OA), Woolf has suggested that the degree of central sensitization correlates with clinical pain reports but not with radiographic findings20. While this is supported by some23,24, others disagree and suggest a strong correlation25,26 between self-reported pain and radiographic changes. Central sensitization has been offered as an explanation for these differences, as described below.
In patients with hip OA accompanied by referred pain, hyperalgesia detected by quantitative sensory testing (QST) in the referred pain areas correlates with central pain modulation regions in the brain, including the anterior cingulate cortex27. In those with knee OA, patients vary in local and diffuse sensitization by QST — those reporting severe pain being more sensitive to local pressure stimulation than healthy controls28. Central sensitization was especially apparent among knee OA patients who reported high levels of clinical pain in the absence of moderate-to-severe radiographic evidence of pathologic changes29. Results were significant even after adjusting for differences on psychosocial measures, as well as age, sex, and race.
In rheumatoid arthritis (RA), self-reports of pain have been shown not to correlate with clinical, observable findings30. In some patients, symptoms persist even when RA flares have apparently subsided30. It has been suggested that pain processing in the CNS is impaired, and the continuous barrage of nociceptive activity in RA can lead to peripheral and subsequently persistent central sensitization31,32. Peripheral sensitization does not account for enhanced responses to sensory stimuli seen in non-inflamed regions adjacent to and even remote from the inflamed joint31. A number of studies have reported hyperalgesia or allodynia in patients with RA, signs of central sensitization33,34,35 compared with healthy controls, and increased pain sensitivity appears to be related to longer disease duration35.
Functional Pain Disorders
There are conditions in which pain appears not to be driven by noxious stimuli, inflammation, or direct damage to the nervous system; they present with pain hypersensitivity but no clear etiological factors, which may reflect a primary dysfunction of the nervous system20. In a review of functional disorders36, various mechanisms were proposed to explain the cause of conditions such as irritable bowel syndrome, fibromyalgia, temporomandibular joint disorder, and interstitial cystitis, including enhanced pain perception, altered brain activation, dysregulations in immunologic and neuroendocrine function, and genetic factors. It does appear that heightened sensitivity of the CNS and an increased propensity to develop central sensitization are common features20.
Defining the underlying pathophysiology of CP remains elusive; several reports now show evidence for peripheral nerve abnormalities in patients with fibromyalgia that could contribute to their chronic pain37,38. Discussing peripheral sensitization as a disease entity is outside the realm of this article, but further exploration is recommended.
Other unifying factors include functional disorders that overlap within the same individual, common pathophysiologic disturbances, responsiveness to similar treatment interventions36, and a possible hereditary component20. Woolf20 concludes that CP hypersensitivity in the absence of inflammation or nerve damage results in apparently phenotypically different syndromes depending on the tissue/organ affected.
DISCUSSION
There is still a great deal of uncertainty about whether CP is a disease. In the United Kingdom, CP is considered a longterm (chronic) condition (LTC); however, CP is not recognized as such globally. This conceptualization appears to succinctly reflect our present level of understanding around CP and would appear to be an acceptable middle ground until further research offers greater insight (Table 1)39,40,41.
If CP is a symptom, what is it a symptom of? Traditionally, acute pain has been seen as a symptom of an underlying disease or an event such as trauma or surgery; treatment of the disease or cause would improve or eradicate the pain. In people diagnosed with a primary disease such as OA or RA, it may be relatively straightforward in that CP in the affected joint(s) is a symptom of the disease. However, as described, central sensitization and neuropathic changes can occur.
It appears that the medical paradigm in which the person presenting with pain is ultimately assessed and managed is important. For a rheumatologist presented with someone complaining of CP, a more biomedical model approach may initially be used in aiding a diagnosis. The focus is on biological factors responsible for the pain and less on psychological, environmental, and social influences. Once a diagnosis is reached, pain becomes a symptom of the disease diagnosed, with the assumption that if the disease is managed, the symptom of pain will improve or disappear.
Conversely, patients are referred to pain specialists by other medical specialists who have either diagnosed but are unable to treat them, or have failed to diagnose. In these instances, the biomedical model is no longer useful. Pain specialists would be expected to explore the biopsychosocial issues associated with CP, including pain-related disability and distress. Some argue that because it is managed from a biopsychosocial perspective, CP is a disease. However, being a disease and using a biopsychosocial model are not synonymous; and given its complexity, CP may not be well served by a disease model. Figure 2 illustrates the issues with trying to fit CP as a disease into the biomedical model approach to RA.
Illustrating the problems with trying to fit chronic pain as a disease into the biomedical model approach to rheumatoid arthritis (RA; used as an example).
Current research is focused on producing diagnostic criteria and biomarkers with good sensitivity and specificity for identifying neuropathic pain, as well as development of new therapies42,43. If these were available, central sensitization could be the diagnosis of a disease of the CNS. Similarly, given that cortical reorganization can be seen in important pain regions in neuropathic pain but not nociceptive pain, is neuropathic pain the disease?
CP has historically been regarded as a symptom although the International Association of Pain has defined over 500 CP syndromes41. Given the burden of CP44, we need to consider how to define and manage it, and a good start may be to identify how we conceptualize it. There has been a groundswell of opinion, based upon emerging neuroimaging evidence, that CP needs to be reclassified; Table 2 summarizes the debate presented here. If we accept, for instance, that CP is an LTC or disease, then the philosophy of care may change from a biomedical model that views CP as a symptom to that of a biopsychosocial one that views CP as a disease or LTC. The implications for further refinement of the OMERACT Filter 2.0 is that the biopsychosocial aspects of pain as an LTC/disease must be included in measurement outcomes; measuring pain-related distress and disability, physical functioning and participation, for instance, and not just measuring physical pain.
Synopsis of the debate for and against the concept of chronic pain as a disease.
The authors propose that CP is definitely an LTC or chronic condition and would like to see continued debate around central sensitization and neuropathic pain. However, a similar exploratory report is required to examine whether peripheral sensitization should be seen as a disease and to address other factors such as work undertaken in genetic factors (not included here) to inform future OMERACT work streams and research activity (see Table 3 for future OMERACT CP activity).
Future OMERACT CP activity
Footnotes
Authors were funded as follows: Dr. Conaghan, in part by Arthritis Research UK; Dr. Singh, by grants from the Agency for Health Quality and Research Center for Education and Research on Therapeutics U19 HS021110, US National Institute of Arthritis and Musculoskeletal and Skin Diseases P50 AR060772 and U34 AR062891, US National Institute on Aging U01 AG018947, US National Cancer Institute U10 CA149950; by resources and use of facilities at the VA Medical Center at Birmingham, Alabama; and by research contract CE-1304-6631 from the Patient Centered Outcomes Research Institute; Dr. Choy, from the Arthritis Research UK and National Institute for Social Care and Health Research; and Dr. Kaiser, by a grant from the German Ministry of Education and Research (BMBF 01GY1326).
Financial disclosures are as follows: Dr. Singh, research grants from Takeda and Savient and consultant fees from Savient, Takeda, Regeneron, and Allergan; on the executive of OMERACT, which receives arms-length funding from 36 companies; member of the American College of Rheumatology’s Guidelines Subcommittee of the Quality of Care Committee; and member of the Veterans Affairs Rheumatology Field Advisory Committee. Dr. Choy, research grants, membership on advisory boards and speaker bureaus of Abbott Laboratories, Allergan, Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Chelsea Therapeutics, Chugai Pharma, Daiichi Sankyo, Eli Lilly, Ferring Pharmaceutical, GSK, Hospita, ISIS, Jazz Pharmaceuticals, MedImmune, Merrimack Pharmaceutical, MSD, Napp, Novimmune, Novartis, Pfizer, Pierre Fabre Medicament, Regeneron, Roche, Sanofi-Aventis, Schering Plough, Synovate, Tonix, and UCB. Lee Simon: Nicox, Fidelity, Extera, Wyeth, Asahi, Sammuded, Metabolex, SarCode, Anthera, Antares, Vical, Daiichi Sankyo, Rigel, Bayer, Solace, Puretechventures, Abbott, Omeros, Jazz, Takeda, Teva, Zydus, Alder, Cephalon, Purdue, EMDSerono, Altea, Talagen, Tigenix, Agenus, Forest, Genzyme, Horizon, Pozen, ILPharma, Analgesic Solutions, Creabilis, Kowa, Array, JRX Biopharm, Imprimis, Dara, Genco, Neos, Bayer Consumer, Sanofi, Lilly, Idera, Medac, Inotec, Osteoanalgesia, and Akron.
