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PAIN MEDICINE: Review Article

Persistent Pain as a Disease Entity: Implications for Clinical Management

Siddall, Philip J., MBBS, PhD, FFPMANZCA; Cousins, Michael J., MD, FANZCA, FFPMANZCA

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doi: 10.1213/01.ANE.0000133383.17666.3A
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Abstract

Persistent pain is a major health problem. An epidemiological study in Australia indicated that approximately 18% of people in a community sample have persistent pain defined as continuous pain for 3 of the last 6 months (1). Similar figures have been obtained from surveys in other countries (2) although others have reported prevalence figures closer to 50% (3,4). This frequent prevalence of persistent pain and disability has a significant impact on the community both economically and in terms of human suffering (5,6).

In addition to an increased awareness of the societal impact of pain, we are now more aware of the harmful effects of pain on the individual. There is accumulating evidence of the physiological benefits and improved outcomes associated with good pain relief after surgery (7,8). It has also been demonstrated in animals that postoperative analgesia with morphine can reduce the incidence of metastatic spread induced by surgery, suggesting that pain may be linked to an increased risk of tumor spread and survival (9).

Despite the growing recognition of the problem of persistent pain, clinical and research attention has often focused on understanding and treating the disease underlying the pain. This reflects a historical view of pain as a nonspecific symptom of a disease process. However, some have suggested that persistent pain should no longer be viewed as a symptom but should be considered as a disease in its own right. This article seeks to examine this proposition and addresses a number of questions. What does it mean that persistent pain is a disease entity? What is the evidence to support this assertion? If persistent pain is a disease entity, what are the implications for assessment and management?

Pain as a Symptom of Disease

The current approach to medicine is based largely on the disease model. A disease has been defined as “a disorder with a specific cause and recognizable signs and symptoms” (10). An entity is simply a thing that is real and exists (11). Therefore a disease entity is defined here as a real disorder with its own specific cause, symptoms, and signs. Therefore, if a disease is represented diagrammatically as below (Fig. 1), the traditional view of pain places it as one symptom of the primary pathology responsible for the disease. Pain simply serves as a nonspecific and passive warning signal of a specific disease process. The focus and goal of the practitioner is to identify and then deal with the primary disease pathology or cause of the pain.

Figure 1.
Figure 1.:
Model of pain as a symptom of disease.

This model of primary disease-oriented diagnosis and treatment works reasonably well as an approach to the assessment and management of acute pain. However, it works poorly in those with persistent pain. Therefore, it has been suggested that this model of persistent pain as a symptom is inadequate. We will seek to examine this issue further by considering an alternative conceptual model of persistent pain in which persistent pain itself is the disease. According to our definition above, persistent pain should then have its own pathology, symptoms, and signs, rather than simply be a nonspecific symptom of another disease process.

Definition of Persistent Pain

Before addressing this issue, however, it is necessary to first clarify what is meant by “persistent pain.” Pain is defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” (12). Persistent pain is sometimes defined as pain that persists beyond the expected healing time. For the purposes of this article, we have chosen the definition of persistent pain as “pain that persists beyond three months.” Although the time point is arbitrary, it should encompass the expected healing time in most situations of tissue injury but allows for situations in which there is no expected healing time.

There are two issues that are central to the consideration of persistent pain as a disease entity. First, as defined earlier, a disease not only has signs and symptoms but its own pathology. Does persistent pain have its own pathology? We will explore this issue and examine the evidence for a pathology of persistent pain. Second, in suggesting that persistent pain is a disease entity, it is sometimes taken to mean that not only does persistent pain have its own pathology but also that this pathology becomes independent of the initiating disease process. In this scenario, persistent pain becomes a self-perpetuating condition that continues beyond resolution of any underlying disease state. This second issue will be examined later, but first we will review the findings that indicate that pain has its own pathology. In other words, what disturbances are associated with the presence of pain and give rise to the constellation of signs and symptoms in the person with persistent pain?

Pain as a Disease Entity

As mentioned above, pain is often regarded as a passive symptom of a disease process. However, there is accumulating evidence that the transmission of nociceptive signals after injury has a rapid and sustained impact on the physiological environment at a number of levels (13–17). These influences commence in the periphery. Activation of nociceptive fibers has an almost immediate effect on the local environment that modifies responses to further stimuli. Release of neurotransmitters results in local peripheral inflammatory changes that make up the process of neurogenic inflammation (18). Nociceptive stimulation also results in the release of peptides, such as substance P, neurokinin A, and calcitonin gene-related peptide, from the peripheral terminals of nociceptive primary afferent fibers (19). Release of these peptides results in a changed excitability of sensory and sympathetic nerve fibers, vasodilatation, extravasation of plasma proteins as well as action on inflammatory cells to release chemical mediators. These interactions result in the release of a “soup” of inflammatory mediators that act to sensitize high-threshold nociceptors and the development of peripheral sensitization (20–22). Peripheral sensitization is associated with increased sensitivity to both mechanical and thermal stimuli at innocuous (allodynia) and noxious (hyperalgesia) levels.

Damage to the peripheral nervous system also results in further secondary changes in primary afferent nerves that in turn result in an increase in afferent signals. For example, peripheral nerve injury leads to the abnormal expression of receptors and channels that may result in ectopic discharges from neuromas and the dorsal root ganglion of both injured and uninjured primary afferents (23–27) (Fig. 2).

Figure 2.
Figure 2.:
Proposed mechanism of the generation of ectopic impulses after peripheral nerve injury. Abnormal sodium channel expression may lead to abnormal ectopic activity being generated at the site of injury and close to the dorsal root ganglion.

After injury to somatic, visceral, and neural structures, there may also be alterations to the responsiveness of the autonomic nervous system. Although the clinical significance remains uncertain, nerve injury can result in novel sprouting of sympathetic efferents and the formation of rings or “baskets” around large diameter dorsal root ganglion cells (Fig. 3) (28–30). Central neural mechanisms are also almost certainly involved. This may lead to a constellation of peripheral vasomotor and sudomotor changes that are collectively termed complex regional pain syndromes (31–33). These syndromes are evidenced by increased or decreased sweating, pallor or redness, temperature changes, abnormalities of hair and nail growth, and osteoporosis as well as sensory symptoms of spontaneous burning pain, hyperalgesia and allodynia, and often disturbance of motor function.

Figure 3.
Figure 3.:
Proposed mechanism of involvement of sympathetic nervous system after damage to primary afferent fibers. α-Adrenoceptors are expressed at the site of damage and are susceptible to activation by circulating catecholamines. Sympathetic fibers sprout to form “baskets” around the dorsal root ganglia after damage to primary afferent fibers. These sympathetic fibers then may release noradrenaline, which activates α-adrenoceptors on the dorsal root ganglion.

Increased inputs from the periphery from either stimulation of nociceptors or ectopic firing after neuropathy will then result in alterations within the spinal cord dorsal horn (34,35). Excessive neuronal firing may induce prolonged glutamate release and activation of metabotropic glutamate and ionotropic N-methyl-d-aspartate (NMDA) receptors (36). Activation of these receptors in turn leads to the initiation of intracellular events, such as oncogene induction (37), production of nitric oxide (38–41), and activation or production of a number of second messengers including phospholipases, polyphosphoinosites (inositol triphosphate, diacylglycerol), cyclic guanosine monophosphate, ecosanoids, and protein kinases (42,43). Peripheral nerve injury can also result in a number of dorsal horn effects, such as changes in the distribution and density of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (44,45), release of neurotrophins (46), and sprouting of central terminals (47,48). Disinhibition, either as a result of selective loss of inhibitory neurons containing γ-aminobutyric acid (49), receptor changes (50), or loss of inhibitory surround with deafferentation, may also result in increased responsiveness of central neurons.

These and other changes may contribute to the development of alterations in central neuronal responsiveness, which share features of wind-up (51,52) and long-term potentiation (17,53–56) and are collectively known as “central sensitization.” This increase in cell responsivity may be evidenced by phenomena, such as the development of expansion in receptive field size (57,58), afterdischarges (59), and increased spontaneous neuronal activity (59,60). These alterations in cell responsiveness may be evidenced by a number of symptoms and signs, including spontaneous pain and dysesthesia, spreading pain, and hypersensitivity to touch and extremes of temperature. This increased responsiveness to peripheral stimuli has been demonstrated in patients who have chronic pain associated with whiplash injury and fibromyalgia and suggests that the presence of pain and hyperalgesia in these conditions is associated with increased sensitivity of spinal neurons (61).

Not only do changes occur at a spinal level but, as nociceptive signals reach the brain, many other regions are activated that control a number of autonomic and homeostatic mechanisms. Pain activates brain structures, such as the periaqueductal gray matter of the midbrain, that are involved in blood pressure regulation, respiration, vasomotor control, and metabolic homeostasis. Therefore, continuing nociceptive inputs may have deleterious effects on any of these systems (7,8).

The thalamus acts as a major relay in the transmission of nociceptive information (62). However, it is not a passive relay station; downstream changes alter the way it responds to incoming signals. Nerve injury and inflammation result in several changes in the firing of neurons in both the lateral and medial thalamus. These include a lengthening of the response latencies of low threshold and wide dynamic range neurons, an increase in background activity, and afterdischarges in response to a low threshold stimulus (Fig. 4) (63–65).

Figure 4.
Figure 4.:
Single-cell recordings from thalamic neurons demonstrate novel afterdischarges to innocuous mechanical stimulation in a contusion model of neuropathic pain after spinal cord injury (65).

Functional imaging has also identified a widely distributed network of cortical and subcortical structures in the brain that are activated by noxious inputs (66–68). These studies have also demonstrated that persistent pain is associated with a change in pattern of brain activation that is different from acute pain responses. For example, in many studies, an acute experimental painful stimulus results in an increase of activity in the thalamus (69), while people with persistent pain due to cancer (70), fibromyalgia (single-photon emission tomography) (71), and chronic neuropathic pain (72) demonstrate a decrease in activity in the thalamus. Reorganization can also occur with shifts in cortical representation of body structures demonstrated to be associated with persistent pain (73–75).

Persistent nociceptive inputs can have a strong impact on psychological function (76–78). Peripheral nerve injury in animals is associated with consistent sensory disturbances in the affected limb, but a sub-population have either transient or persistent disturbances of sleep and social interactions that appear to correlate with functional disturbances observed in people with persistent pain (79). People often report mood disturbances, including irritability, helplessness, and depression (76). More complex cognitive responses can also develop, such as loss of belief in the ability to perform tasks and fear avoidance (78). These in turn can result in loss of employment, breakdown of family relationships, and loss of community status. If unsuccessfully addressed, those with unrelenting and unrelieved pain may see suicide as the only available option (77).

The foregoing description of the impact of continuing nociceptive and neuropathic inputs is broad-ranging and as yet still incomplete. It serves, however, to demonstrate that altered sensory inputs from the periphery, due either to increased inputs from stimulation of nociceptors or from nerve damage, result in a host of pathological changes that represent a “pain pathology.” These pathologies range from specific changes in receptor populations in primary afferents to mood dysfunction and social disruption, which are a consequence of persistent nociceptive inputs, regardless of the underlying disease. Therefore, in a real sense, these pathologies, symptoms, and signs are both dependent on and unique to the presence of pain. Their presence is evidence for considering persistent pain as a disease entity.

Pain as a Secondary Disease

In describing all these changes, it has been suggested that the induction of these changes leads to a state in which the perception of pain is maintained independently of inputs to the nervous system. While it is tempting to speculate that this is indeed the case in people who have persistent pain despite no evidence of pathology, there is little evidence to support this proposition. A hip replacement will usually lead to a substantial reduction, if not elimination, of pain arising from an osteoarthritic hip, no matter how long the pain has been present. Secondary pathological changes, such as central sensitization, mood changes, and disability, may occur as a result of persistent nociceptive inputs. However, they will generally all resolve after a procedure that results in resolution or removal of the underlying primary pathology.

It could also be argued that psychosocial factors may be responsible for the maintenance of persistent pain independently of a primary disease. For example, there is evidence for a lack of correlation between pain report and spinal pathology as demonstrated on magnetic resonance imaging (80). It is also well known that mood changes such as anxiety and depression alter both pain perception and expression (81,82). It is therefore tempting to speculate that some patients have persistent pain that is generated by psychosocial factors. However, with the exception of a conversion hysteria, there is no evidence to indicate that psychosocial factors can generate pain in the absence of continuing nociceptive inputs.

Therefore, we do not argue that pain is a disease entity because it somehow becomes self-perpetuating due to either physiological or psychological changes. Rather, we would argue that it meets the criteria for a disease entity in having its own pathology, signs, and symptoms. As described above, persistent pain does give rise to its own secondary pathology. This secondary pathology then gives rise to a constellation of symptoms and signs that are indicative of persistent pain and need to be addressed in their own right (Fig. 5).

Figure 5.
Figure 5.:
Model of persistent pain as a secondary disease

Pain as an Environmental Disease

Although helpful in taking pain medicine beyond the old view of pain as a symptom, the demonstration that pain has its own secondary pathology that gives rise to specific symptoms and signs is still not entirely adequate in providing a convincing model of pain as a disease entity. Both the primary and secondary pain pathology occur within an environment that has a multitude of factors, many of which will also have a direct impact on the pathology. These factors are not a consequence of pain and therefore are not secondary to the pain. They form the background environment (both internal and external) in which the pain occurs and can be considered as “tertiary” pathology. This tertiary pathology can include factors such as genetic makeup, level of spinal inhibition, psychological status, and the societal litigation system. These environmental factors may be crucial in explaining the variability in response to apparently similar levels of nociception and need to be considered as part of the assessment and treatment of persistent pain.

Several studies have indicated the importance of our innate, genetic environment or makeup in the way that we experience pain. Some researchers have suggested a genetic susceptibility to nociceptive and neuropathic pain with excessive and prolonged “normal” neuroplasticity responses to neuropathic and nociceptive stimuli (83,84). Transgenic and knockout mice show differences in the prevalence of nociceptive and neuropathic pain and differences in sensitivity to interventions and analgesics (85). Some pain disorders have also been shown to have a genetic link. These include hereditary sensory neuropathy type 1 (86), painful congenital myotonia (87), mutations of NTRK1 in people with congenital insensitivity to pain (88), or CACNL1A4 in people with familial hemiplegic migraine (89). Mu opioid receptor gene polymorphisms (Oprm) (90) cause abnormalities of sensation or changes in response to medication (e.g., differing CYP2D6 phenotype) (91). Although the complexity of pain suggests that it is extremely unlikely that a “pain gene” will be discovered, nevertheless genetic factors are clearly involved in the development of pain under certain conditions and are involved in response to treatment.

The role of the psychological environment is also very important. As mentioned previously, the evidence for a psychological cause as the basis for the presence of pain (so-called “psychogenic pain”) is weak (81,82). However, psychological factors have a strong influence on perception and expression of pain (92,93). Psychological factors may increase the perception of pain indirectly through several avenues, such as the effect of mood on descending controls of sensory and autonomic tone (92,94). As suggested by the gate theory, signals generated and transmitted along sensory pathways are modulated at many levels of the nervous system (95,96). This modulation is directly related to cognitive and emotional processes. It is bidirectional and, depending on psychological processes, can either lead to decreased or increased perception of pain (97). For example, fear and anxiety are two emotional states that appear to affect pain responses and may result in both decreased responsiveness to pain or analgesia (94,98) and increased pain and hyperalgesia through arousal and hypervigilance (99,100). Cognitive processes may also influence the pain experience, although they appear to affect pain processing differently from emotion. While both affect pain perception, it appears that emotional manipulation can alter pain unpleasantness more than intensity, whereas cognitive processes, such as attention, modulate both intensity and unpleasantness (101). Operant learning processes, such as excessive attention from a solicitous spouse, may also contribute to pain behaviors (102). These factors may all be influenced by the context in which the pain occurs. For example, a diagnosis of cancer may have a significant impact on the way that pain is experienced.

Social environmental processes may also affect the perception and expression of pain. This environment includes a host of relationships that surround the person in pain, including friends, family, colleagues, employers, health practitioners, lawyers, the media, and compensation or insurance systems. Pain expression or disability often appears to bear little relationship to the severity of injury and therefore presumed nociceptive inputs. Although these inputs are impossible to quantify, part of the reason for the large variation in disability may be a social environment that actively encourages or discourages the expression of pain behaviors.

In summary, persistent pain has its own pathology, symptoms, and signs and is therefore a disease entity. However, as with any disease, pain occurs within an environment that contributes to all of the components of the pain experience. This environment could be seen as a tertiary pathology that is an important factor in pain as a disease entity (Fig. 6).

Figure 6.
Figure 6.:
Model of persistent pain as an environmental disease

Implications for the Assessment and Management of Persistent Pain

Our approach to the assessment and management of persistent pain is very much determined by our conceptual framework. We will examine the implications of each of these pain models above (pain as a symptom, pain as a disease, pain as an environmental disease) for assessment and management.

A Symptom-Based Approach.

The traditional view that regards persistent pain as a symptom of another disease process has as its main aim the identification and removal or treatment of the primary pathology underlying the disease process. In other words, the practitioner seeks to identify and treat a cause for the pain. As described above, although the concept may be limited, in many situations this aim is appropriate and satisfactory results can be achieved. Even in persistent pain states, it is appropriate to first identify the primary pathology responsible for the generation of pain. The aims of this approach to pain management are illustrated and described in the figure and table below (Table 1).

Table 1
Table 1:
Implications for Assessment and Treatment Using a Symptom-Based Approach to Pain Management

However, problems can occur with the assessment and management of persistent pain if there is an exclusive emphasis on locating and dealing with another disease process and not recognizing pain “pathology.” It may either not be possible to identify primary pathology responsible for the pain, or more commonly, it can be identified, but there is no treatment available that will reverse the primary pathology. To maintain the symptom-based approach in these situations can lead to negative outcomes.

First, with regard to assessment, there may be a continuing chase to identify primary pathology even though the ability to detect the pathology that is generating pain is poor and unreliable. There may be no recognition or understanding of the secondary pathology associated with persistent pain or the treatments that are available to deal with the pathology. Patients may be dismissed or labeled with terms such as a malingerer or “functional” purely on the negative criteria that the practitioner is unable to find pathology that they feel explains the pain.

Second, with regard to treatment, the symptom-based view of pain also has a number of inherent dangers. It may result in the reliance on approaches that focus on treating the symptom of pain such as simple analgesics or opioids with little understanding of approaches that target secondary pathology. Alternatively, the patient is often told there is nothing that can be done or is left feeling that the practitioner feels that their pain is imaginary. It may also lead to the use of treatments that remove or disconnect the believed source of inputs with no recognition of the consequences of this approach. This leads to such treatments as removal of all teeth in people with facial pain, and peripheral nerve section. Even if a procedure can eliminate nociceptive signals arising from a structure, pain relief is often still transient. Focusing on a procedure to eliminate or reduce the symptoms may also fail to address the secondary pathology contributing to pain and disability that has developed.

A Disease-Based Approach.

Therefore, efforts to treat persistent pain on the basis of identification and treatment of the primary pathology may be impossible or inadequate. In these situations, the aim of the disease-based approach is to deal with the primary pathology as much as possible, as well as address the secondary pathology or consequences of persistent pain, many of which may be “feeding back” to enhance pain further. The aims of this approach to pain management are illustrated and described in the table above (Table 2).

Table 2
Table 2:
Implications for Assessment and Treatment Using the Disease-Based Approach to Pain Management

This disease-based approach means identifying the pathological changes described above using symptoms and signs that indicate specific pathology associated with persistent pain. It then means being familiar with and applying treatments that do not reverse the primary pathology but which address the secondary pathology and thus reduce the consequences of pain. This is done either by reducing inputs directly (nonsteroidal antiinflammatory drugs, local anesthetic blockade, sodium channel blockade, analgesics), or by reducing the effect of these inputs on central processes (analgesics, NMDA antagonists, anticonvulsants, tricyclic antidepressants, stimulation techniques, psychological measures). In addition to reducing inputs, the disease model recognizes that persistent pain is not just a symptom. Treatment may also then focus on directly addressing signs or behaviors associated with persistent pain independently of any attempt to reduce inputs.

Although addressing the secondary pathology induced by continuing nociceptive inputs may be more successful in managing pain than an approach that focuses solely on removing pathology or blocking a symptom, it may still not be adequate. The primary danger in this approach is that it focuses on the internal processes or secondary pathology of the person in pain. Treatment may be primarily directed toward correcting this pathology without any recognition of environmental influences that are serving to maintain it. Thus treatment may address the secondary pathology (e.g., NMDA receptor activation, central sensitization, amplification, fear of injury) but still not adequately deal with environmental issues that may maintain this or other pathologies (e.g., misinformation, oversolicitous relationships, litigation system).

An Environmental Approach to Treatment.

The view of persistent pain as an environmental disease means that other environmental factors need to be addressed to maximize the effectiveness of treatments. Therefore, treatment will involve three components: first, if possible, identifying and treating any primary pathology that may be causing pain; second, identifying and treating the secondary pathology or consequences of pain; and third, identifying and treating the environmental “tertiary” pathology that may act as contributors to persistent pain.

This may not only address the management of existing pain but also the prevention of persistent pain states. For example, the emergence of genetic factors in pain argues for the concept of genetic susceptibility and possible identification of “at risk” individuals prior to surgery. This could also include the prediction of postoperative analgesic requirements via preoperative DNA tests and choosing specific analgesic classes on the basis of genetic sensitivity (103). Further work may be needed in the area of preemptive analgesia. Although many studies have been disappointing (104–106) there is evidence from some studies that preemptive analgesia may be effective in preventing the development of persistent pain (107–110), and the concept is supported by basic research. Further exploration may reveal the optimal approach in terms of drugs and method and timing of administration.

Taking an environmental approach also means exploring and dealing with factors that may be contributing to the maintenance of persistent pain. Are there physical factors in the home or work environment that are serving to increase the generation of pain, such as posture, work schedule, or techniques used to perform tasks? Are there psychological factors that serve to increase the perception of pain, such as stress and anxiety? Are there social factors that serve to increase the expression of pain, such as the medicolegal system or oversolicitous relationships? If these factors are identified, then suitable approaches, such as cognitive behavioral interventions (111,112) altering the work environment and approach to work tasks, and even medicolegal reform, may be appropriate. There is now substantial evidence that the use of cognitive behavioral interventions in the context of a multidisciplinary pain center provides considerable cost savings over non-multidisciplinary treatment (111–113). Thus, the practice of effective pain management may incorporate an approach that ranges from an understanding and treatment of the complex intracellular biochemical cascades that give rise to increased neuronal responsiveness to tackling social structures that contribute to pain-related disability (Fig. 6, Table 3).

Table 3
Table 3:
Implications for Assessment and Treatment Using the Environmental Disease Approach to Pain Management

Conclusion

In summary, a disease entity has its own pathology, symptoms, and signs. Persistent pain meets all of these criteria. Continuing pain results in a number of pathophysiological changes from the periphery to the brain that are manifest in specific constellations of symptoms and signs that indicate pathology at these various levels. Pain ultimately is caused by primary pathology within the body. However, the presence of pain for any length of time results in these pathophysiological consequences that make up the secondary pathology of pain. Although secondary in one sense, and still dependent on the primary pathology, these consequences of pain are often of more importance than the primary pathology. This secondary pathology has a huge impact on the individual with persistent pain and is dependent not only on nociceptive inputs but is largely determined by the environment of the person with pain.

In some cases, it may be possible to address the primary pathology resulting in resolution of the pain and its associated consequences. However, in many people with persistent pain, it is impossible to adequately resolve their primary pathology. A sole focus on resolving primary pathology with inadequate recognition of the consequences of pain and secondary pathology will result not only in patients who are left in pain, but also in little recognition or treatment of these other issues. In these circumstances, satisfactory treatment depends on identification of secondary pain pathology and application of appropriate intervention that effectively targets this pathology. Finally, the best outcomes will be obtained when those involved in the treatment of persistent pain recognize and also tackle the variety of environmental factors that may be contributing to the presence of persistent pain.

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