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Anesth Analg 2003;97:785-790 © 2003 International Anesthesia Research Society
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Abstract |
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 Top Abstract IntroductionNP as a Clinical...Proposal for Categorical...Challenges and Possible...ConclusionReferences |
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IMPLICATIONS: A practical definition of neuropathic pain based on the distinction between neuropathic and inflammatory pain mechanisms is suggested. Neuropathic pain is in this case is defined as pain occurring in an area of the body affected by neurological disease. In addition to pain, the patient is likely to have weakness and numbness at the same time.
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Introduction |
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TopAbstractIntroductionNP as a Clinical...Proposal for Categorical...Challenges and Possible...ConclusionReferences |
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The current definition of neuropathic pain (NP) as proposed by the International Association for the Study of Pain (IASP) is "pain initiated or caused by a primary lesion or dysfunction of the nervous system" (1). This definition has been criticized by many as vague, particularly the "dysfunction" component, and too frequently assigned to chronic pain disorders such as complex regional pain syndrome (CRPS). "Dysfunction" blurs the distinction between NP and the other possible types of pain that may result from specific and distinctly different underlying mechanisms, such as inflammatory pain (IP) mechanisms, but that have a component of neurological dysfunction, such as peripheral and central sensitization (2). This lack of specificity in the diagnosis of NP stands in the way of developing a mechanism-based diagnosis and treatment of pain.
In addition to conceptual difficulties, there is a clinical need for more specificity in making pain diagnoses. This clinical need is best illustrated by the observation that NP responds to certain specific pharmacological treatments, such as anticonvulsants, and not to others, such as nonsteroidal antiinflammatories, whereas other types of pain, such as IP, respond readily to nonsteroidal antiinflammatories and not to anticonvulsants (3,4). Another problem in clinical practice is that many clinicians tend to diagnose as neuropathic any clinical pain presentation that is difficult to categorize (5). Therefore, there is a strong and even urgent need for pain clinicians and researchers to address the NP definition and find a workable model.
The definition of NP should be viewed in the larger context of pain mechanisms as understood from the currently available data. Studies in animal models—assuming that animal models mimic human painful disorders reasonably well—describe a number of peripheral and central pathophysiological processes after nerve injury that would be the basis of underlying NP mechanisms. Peripheral processes that are best described include ectopic and spontaneous discharges, ephaptic transmission, alterations in ion channel expression, collateral sprouting of primary afferent neurons, sprouting of sympathetic neurons into the dorsal root ganglia, and nociceptor sensitization (2). Central processes include segmental central sensitization, spinal receptive field reorganization, cerebral cortical reorganization, and changes in descending modulatory mechanisms (6,7). After the success of animal pain research, human studies of the pain mechanisms with NP have increased in sophistication but are still limited in number. These studies underscore the complexity of NP and the multiplicity of mechanisms and implicate the involvement of peripheral and central mechanisms (8–11). Activation of the pain system is associated with demonstrable neuroplasticity, many steps of which are reversible, such as in case of inflammatory reactions to acute injuries (12). Because multiple biological reactions are the rule for pain, regardless of how pain is initiated, it is crucial to always specify the circumstances under which the pain occurs. The underlying pain mechanisms can be differentiated in the general sense as inflammatory, which is the most common result of continuing tissue disease or injury, and as neuropathic, in cases when neural tissue is affected by the disease or injury.
This article is the first step in the process of updating the definition of NP on the basis of modern concepts of pain mechanisms and relative to other types of pain, particularly to IP. From the basic science perspective, NP and IP are definable by the specific and controlled methods used to induce those models—nerve injury and inflammation, respectively. In contrast, trauma- or disease-related injuries seen in the clinical setting do not occur under specific and controlled conditions. Clinicians face the inverse problem: a situation in which they have to make a conclusion about underlying mechanisms on the basis of manifestations of the disease. Proposed herein is a definition of NP based on the premise that NP can be understood only when viewed as a part of the spectrum of pathophysiological processes that occur as a result of disease or injury. It should be understood that this is only a proposal that invites further discussion and research.
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NP as a Clinical Phenomenon and as a Categorical Designation |
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TopAbstractIntroductionNP as a Clinical...Proposal for Categorical...Challenges and Possible...ConclusionReferences |
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More than a century ago, it was recognized that a number of neurological disorders are characterized by pain in the area affected by those neurological diseases (13,14). Since then, it has been observed that pain and other neurological symptoms due to peripheral or central nervous system disease or injury present in very similar ways, and this observation has led to a group designation of NP (1). Most characteristically, the disorders that are included in this diagnostic group are post-herpetic neuralgia (PHN), painful diabetic neuropathy (PDN) and other polyneuropathies, traumatic neuralgia, and central pain syndromes. In almost all of these, painful manifestations are very similar regardless of the underlying disease. They include spontaneous continuing pain, spontaneous paresthesia and paroxysms, and various types of hyperalgesia, which are present at various degrees of symptomatology even within a single disease diagnosis—such as diabetic distal sensory painful neuropathy—and, as a rule, are associated with various degrees of sensory and motor deficits (15–17). This degree of variability in the presentation has always posed a difficulty to researchers and clinicians. This contradiction that etiologically different NP disorders have similar symptoms and signs and that patients with the same etiology of NP have a very wide scope of symptoms and signs will be elucidated only through further systematic quantitative studies.
An added difficulty in dealing with the issue of NP is the categorical designation of disorders that have some but not all symptoms and signs of NP. An example is CRPS Type I (CRPS-I) (previously known as reflex sympathetic dystrophy). For chronic pain disorders, it is postulated that they are due to nervous system dysfunction in a pathophysiological sense, rather than to a disease in a pathoanatomical sense. Many investigators provide strong arguments, primarily based on a large number of clinical studies, that even pain disorders assumed to be due to dysfunction are of the neuropathic type. However, many others strongly oppose this designation, arguing that the evidence is "too soft." There is evidence that would suggest that other mechanisms, such as autonomic (18) or inflammatory (19,20) processes, play an important role in the case of CRPS-I. The number of mechanisms contributing to manifestations of NP is increasing as the body of knowledge related to underlying mechanisms grows, and this adds to the complexity of how we have to view NP disorders. Consequently, the increase in our understanding requires a more comprehensive and data-driven approach when we study these pain disorders.
We need to seize the opportunities that basic science and clinical research offer for advancing our diagnosis and treatment of NP. For that reason, suggestions for a more stringent and specific diagnosis of NP are offered here. It is proposed that NP be designated on the basis of the type of clinical evidence. NP is due to disease or injury of the thermonociceptive component of the nervous system, and the disease or injury can be at any level of the nervous system, regardless of etiology. In this case, there is demonstrable evidence of a neurological disorder or injury as assessed by clinical tools appropriate for each clinical situation, including clinical history, neurological pain examination, electrophysiology, and neuroimaging.
Characteristics that would define NP and differentiate it from other types of pain include the following:
- Pain and sensory symptoms that persist beyond the healing period.
- Presence, in variable degree, of neurological sensory signs manifesting as negative and positive sensory phenomena.
- Presence, in variable degree, of other neurological signs, including motor, manifesting as negative and positive motor phenomena or autonomic signs.
Examples of NP include PHN, central pain syndrome, PDN, causalgia, and painful radiculopathy. The presence of NP does not exclude the concurrent presence of other types of pain and pain mechanisms. For example, a patient with PDN could have a foot ulcer, where the major component of pain is inflammatory, in addition to the continuing burning NP.
In contrast, chronic pain disorders with less-specific symptoms and signs that are suggestive of NP mechanisms, similar to the previous classification of "dysfunction," manifesting primarily with varying degrees and types of allodynia and hyperalgesia, would be, then, termed as hypersensitivity pain disorders. Examples of the patients in this category would be those with fibromyalgia, among others. An analogy for this mechanism-based strategy would be the diagnosis of systemic lupus erythematosus in a patient who meets all the recognized criteria (21) but the diagnosis of mixed connective tissue disease for another patient with less-specific, but abnormal, clinical findings. The type of pain given the categorical designation hypersensitivity pain disorders does not imply that it is any less real. This designation implies that the best our diagnostic tools can offer at this time is the acknowledgment that mechanisms other than currently well defined neurological processes are responsible. It is certainly clear that as our tools for evaluation, assessment, and diagnosis of these patients improve, this distinction between neuropathic types of pain and other pain disorders would take yet a different form or even disappear. In addition, the influence of other pain (in particular, inflammatory) mechanisms on the presentation of patients with any NP will be further discussed in the next section.
Because the definition of NP is based on the presence of neurological disease, it is also important to acknowledge that most neurological disorders affecting the thermonociceptive component of the nervous system do not have pain as a part of their presentation (22,23). This observation would suggest that NP occurs only in patients who are predisposed to it, probably as a matter of genetic makeup. These patients, with disorders of the thermonociceptive nervous system but without pain, could serve as a control group in studies of NP mechanisms as much as patients with pain caused by other mechanisms. Another possible outcome of neurological disease is not only NP, but also other disagreeable sensations, which many patients clearly identify as "not pain but something very disturbing." This group of positive sensory symptoms and signs is categorized as dysesthesia, which can be present in isolation without pain in a classical sense. Most of these positive sensory phenomena, including paresthesia and dysesthesia, are proposed to be due to underlying mechanisms similar to those of NP (15).
NP in a clinical setting never occurs in isolation, but rather as a part of a disease or injury that affects other tissues and initiates other mechanisms, such as inflammation. In general, large clinical experience has shown us that most patients with NP have other types of pain, most frequently musculoskeletal related. A better characterization of the relationship of NP to those other types of pain can only help to define NP more specifically. By clarifying these more general relationships, we can then proceed with further categorical classification of pain disorders. Certainly, it is likely that certain aspects of NP mechanisms play an important role in other types of pain, such as visceral pain, cancer pain, or headaches, but those will not be addressed here. Discussion in the following section will focus on somatic pain and provide suggestions for the terminology and conceptual framework regarding NP.
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Proposal for Categorical Classification of Major Types of Somatic Pain |
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TopAbstractIntroductionNP as a Clinical...Proposal for Categorical...Challenges and Possible...ConclusionReferences |
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The amount of information about pain mechanisms has grown rapidly with each new laboratory discovery, including the expression of novel receptors in the relationships between major pain categories and their mechanism at the clinical level. This is because the ultimate issue regarding those mechanisms is whether they operate in patients and whether, by correcting those mechanisms, we can obtain better pain therapy. In addition, by studying the relationships of pain mechanisms in patients, we could generate new hypotheses (Fig. 1).
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We may begin with the simplest type of pain from the standpoint of mechanisms, i.e., pain initiated in a healthy subject with an intact nervous system to whom highly controlled painful stimuli are applied (24,25). This is the standard and common means for anatomic and physiological pain studies in laboratories, regardless of whether the subjects are human or animal. In this case, all of the aspects of stimulation are controlled with the goal of activating the pain-transmitting nervous system. Because it is a physiological activation, the suggested designation for it is "physiological pain" (26). Stimuli such as pinprick or heat pulses result in activation of the pain- and temperature-transmitting nervous system, including all of the structures involved in transduction, transmission, modulation, perception, and reaction. Once the stimulus is terminated, the subject no longer feels any pain. This is in contrast to clinical types of pain, which persist for the duration of healing, long after injury is over, or, in some cases, may persist even after the healing period, as in the chronic painful disorders.
Within the mechanism-based concept and terminology of pain, there is no place for the term "nociceptive pain" (1). It is redundant. Nociceptive means "painful," and nociceptive pain would mean "painful pain." The term is, for the most part, an artifact of laboratory investigation of pain during which pain-transmitting components of the nervous system, justifiably termed "nociceptive," are studied. As discussed previously, pain from controlled application of painful stimuli in the laboratory setting is best termed "physiological pain," because the physiological characteristics and mechanisms of the pain system are studied under these conditions. The term "nociceptive pain" does not carry any information about mechanisms or the disease process, so it should be abandoned.
The most commonly studied clinical types of pain—IP and NP—will be the primary subject of this discussion. However, it should be recognized that there are many other types of pain, such as migraine headaches and cancer-related bone pain, to mention only two. Research in those areas is making significant progress. Consequently, productive discussions can be expected regarding them, as well.
IP is the result of tissue response to those pathologic processes that lead to tissue destruction, such as an abscess or fresh wound. There is mounting evidence that intense IP results in changes of the pain-transmitting nervous system, called peripheral and central sensitization (12). In most instances, subjects with IP experience various types of hyperalgesia and other symptoms and signs, which are all manifestations of peripheral and central sensitization related to IP. In most of these cases, once the disease process is healed, the nervous system returns to its normal state and function. As long as the disease or injury that causes the IP does not affect the nervous system, the neurological evaluation is normal.
NP, as discussed previously, is the result of injury and disease of the nervous system, most frequently beyond the healing period, and manifests with positive and negative neurological symptoms and signs. Any injury involving the nervous system causes inflammatory responses (27–30), and in this case, there is an inflammatory component adding to the complexity of the process, although it is still possible to make specific distinctions between IP and NP. In most cases, the inflammatory responses are direct and occur at the site of injury, although there are distant responses, manifesting with central nervous system inflammatory responses from peripheral nervous system injury, as well (27,30). The relationship of these two types of inflammatory responses—direct and distant—and the final manifestation of NP is far from clear. However, this additional inflammatory mechanism could account for some of the secondary NP disorders, such as CRPS-I (31).
Recent knowledge about pain mechanisms blurs the margins of where IP stops and NP begins, suggesting that the process from IP to NP is a continuum rather than a strict categorical distinction (Fig. 2). However, from the perspective of pain mechanisms, as well as from the clinical standpoint, it is still necessary to continue making this distinction between IP and NP.
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Clearly, this paradigm addresses only one set of relationships between the two best-described types of mechanisms: inflammatory and neuropathic. The other mechanisms still need to be better defined before their relationships to these two can be addressed. The spectrum of somatic pain mechanisms can generally be presented as suggested in Table 1.
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Neuropathic and inflammatory mechanisms have been proposed as contributing to some of the more common painful disorders, such as myofascial pain, fibromyalgia, and low back pain, although some would argue that both types of mechanisms are at work. However, the current state of clinical and basic science research does not provide us with tools to make this categorization.
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Challenges and Possible Solutions for Classification of Pain on the Basis of Mechanism |
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TopAbstractIntroductionNP as a Clinical...Proposal for Categorical...Challenges and Possible...ConclusionReferences |
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Certainly, this proposal is only a first effort to apply pain mechanisms to clinical pain syndromes, and it is not meant to be all inclusive. There are many NP disorders that would not easily fit in this paradigm, such as trigeminal neuralgia, and this difficulty would not be unusual, because clinical diagnostic methods and tools have limitations. In addition, the dynamic natural course of many neuropathic clinical pain disorders, as in the case of radiculopathy and PDN, would deem these disorders to be painless neuropathies at one stage and NP at the other stages, and vice versa.
Even the naming of many types of pain is difficult, and many defy simple definition. Examples of pain that escape eloquent naming would be the pain from bearing weight or pain on movement, just to mention two. When the attempt is made to develop a classification protocol based on mechanisms, and where the system is complex and dozens of potential mechanisms operate at any given time and on multiple levels, it is important to change the paradigm. A possible solution is not only to catalogue mechanisms, as has been done thus far, but more importantly, to determine the temporal sequence and relationship of those mechanisms in the genesis and maintenance of chronic painful disorders. The explosion of information in both basic science and clinical research is characterized by large volumes of data. For those data to be useful, the application of methods designed for analyzing large datasets, such as dynamic principle component analysis, is necessary (32). The only way that we will be able to make progress is by a close and coordinated working relationship between basic science and clinical research in the form of translational research. Thus far, the predominant approach in pain translational research has been of trying to apply basic science findings to clinical practice, known as going from bench to bedside, and the other important step in this process (of going from bedside to bench) has been missing. For translational research to be successful, the process of a two-way communication has to be established.
At this point, we are considering NP as only one end of the "pain mechanisms" spectrum. However, as our understanding of pain mechanisms advances, additional dimensions will have to be considered. One additional aspect of NP that has to be considered early in the process of developing the definition is its dynamic nature. Although symptoms and signs of most readily recognized NP syndromes, PHN and PDN, may appear stable and consistent from visit to visit, they tend to change over time as a result of many factors.
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Conclusion |
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TopAbstractIntroductionNP as a Clinical...Proposal for Categorical...Challenges and Possible...ConclusionReferences |
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There are many theoretical, conceptual, and practical clinical reasons to improve methods for distinguishing NP from other nonneuropathic painful disorders. The conceptual distinction between neuropathic and IP mechanisms is provided here, as is the distinction between NP due to neurological dysfunction and NP due to neurological disorder. NP is in this case defined as pain occurring in the area or body part associated with neurological disease or injury. This type of pain manifests not only with positive sensory phenomena, such as pain, dysesthesia, and different types of hyperalgesia, but also with negative sensory phenomena and negative and positive motor symptoms and signs. It is acknowledged here that to separate and to define any symptom as pain due to neurological dysfunction does not necessarily clarify the issue, because this is still a vague term. With advancing knowledge of mechanisms, we may one day resolve this problem. The distinction between NP and pain due to neurological dysfunction would be analogous to the distinction that rheumatologists make between lupus and connective tissue disease. It is not possible to provide any further solution regarding the definition of NP, or any type of pain for that matter, beyond what is presented here because there are no data with which to proceed, nor would it be possible to find consensus at the present time.
Advances in basic and clinical science, together with further differentiation of the influences that various mechanisms have on the genesis and maintenance of different subtypes of pain, will certainly result in a better and more precise definition of this type of painful disorder and lead ultimately to more specific diagnosis and therapy. It is possible, and even likely, that this simple crude distinction will be replaced with more specific mechanism-based definitions of pain diagnoses.
Progress in clinical pain research will be made only when open debate and productive cooperative work in the form of translational research take place. It is the goal of this article to initiate and to frame this important debate.
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Acknowledgments |
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The author would like to thank Drs. Andrew Waclawik, John Farrar, Robert Dworkin, and Alan Basbaum for their constructive feedback on earlier drafts of this manuscript.
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