Defining Neuropathic Pain


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Defining Neuropathic Pain

  1. 1. PAIN MEDICINE SECTION EDITOR MICHAEL J. COUSINS MEDICAL INTELLIGENCE Defining Neuropathic Pain Misha-Miroslav Backonja, MD Departments of Neurology, Anesthesiology, and Rehabilitation Medicine, University of Wisconsin Medical School, University of Wisconsin, Madison T he current definition of neuropathic pain (NP) as NP mechanisms. Peripheral processes that are best proposed by the International Association for the described include ectopic and spontaneous dis- Study of Pain (IASP) is “pain initiated or caused charges, ephaptic transmission, alterations in ion by a primary lesion or dysfunction of the nervous channel expression, collateral sprouting of primary system” (1). This definition has been criticized by afferent neurons, sprouting of sympathetic neurons many as vague, particularly the “dysfunction” com- into the dorsal root ganglia, and nociceptor sensitiza- ponent, and too frequently assigned to chronic pain tion (2). Central processes include segmental central disorders such as complex regional pain syndrome sensitization, spinal receptive field reorganization, ce- (CRPS). “Dysfunction” blurs the distinction between rebral cortical reorganization, and changes in descend- NP and the other possible types of pain that may ing modulatory mechanisms (6,7). After the success of result from specific and distinctly different underlying animal pain research, human studies of the pain mech- mechanisms, such as inflammatory pain (IP) mecha- anisms with NP have increased in sophistication but nisms, but that have a component of neurological are still limited in number. These studies underscore dysfunction, such as peripheral and central sensitiza- the complexity of NP and the multiplicity of mecha- tion (2). This lack of specificity in the diagnosis of NP nisms and implicate the involvement of peripheral stands in the way of developing a mechanism-based and central mechanisms (8 –11). Activation of the pain diagnosis and treatment of pain. system is associated with demonstrable neuroplastic- In addition to conceptual difficulties, there is a clin- ity, many steps of which are reversible, such as in case ical need for more specificity in making pain diag- of inflammatory reactions to acute injuries (12). Be- noses. This clinical need is best illustrated by the ob- cause multiple biological reactions are the rule for servation that NP responds to certain specific pain, regardless of how pain is initiated, it is crucial to pharmacological treatments, such as anticonvulsants, always specify the circumstances under which the and not to others, such as nonsteroidal antiinflamma- pain occurs. The underlying pain mechanisms can be tories, whereas other types of pain, such as IP, respond differentiated in the general sense as inflammatory, readily to nonsteroidal antiinflammatories and not to which is the most common result of continuing tissue anticonvulsants (3,4). Another problem in clinical disease or injury, and as neuropathic, in cases when practice is that many clinicians tend to diagnose as neural tissue is affected by the disease or injury. neuropathic any clinical pain presentation that is dif- This article is the first step in the process of updat- ficult to categorize (5). Therefore, there is a strong and ing the definition of NP on the basis of modern con- even urgent need for pain clinicians and researchers to cepts of pain mechanisms and relative to other types address the NP definition and find a workable model. of pain, particularly to IP. From the basic science The definition of NP should be viewed in the larger perspective, NP and IP are definable by the specific context of pain mechanisms as understood from the and controlled methods used to induce those mod- currently available data. Studies in animal models— els—nerve injury and inflammation, respectively. In assuming that animal models mimic human painful contrast, trauma- or disease-related injuries seen in the disorders reasonably well— describe a number of pe- clinical setting do not occur under specific and con- ripheral and central pathophysiological processes af- trolled conditions. Clinicians face the inverse problem: ter nerve injury that would be the basis of underlying a situation in which they have to make a conclusion about underlying mechanisms on the basis of mani- Accepted for publication January 30, 2003. festations of the disease. Proposed herein is a defini- Address correspondence and reprint requests to Misha-Miroslav Backonja, MD, Department of Neurology, H6-550, University of tion of NP based on the premise that NP can be Wisconsin-Madison, 600 Highland Ave., Madison, WI 53792. Ad- understood only when viewed as a part of the spec- dress e-mail to trum of pathophysiological processes that occur as a DOI: 10.1213/01.ANE.0000062826.70846.8D result of disease or injury. It should be understood ©2003 by the International Anesthesia Research Society 0003-2999/03 Anesth Analg 2003;97:785–90 785
  2. 2. 786 MEDICAL INTELLIGENCE BACKONJA ANESTH ANALG DEFINING NEUROPATHIC PAIN 2003;97:785–90 that this is only a proposal that invites further discus- increase in our understanding requires a more com- sion and research. prehensive 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 NP as a Clinical Phenomenon and as a and treatment of NP. For that reason, suggestions for a more stringent and specific diagnosis of NP are Categorical Designation offered here. It is proposed that NP be designated on More than a century ago, it was recognized that a the basis of the type of clinical evidence. NP is due to number of neurological disorders are characterized by disease or injury of the thermonociceptive component pain in the area affected by those neurological diseases of the nervous system, and the disease or injury can be (13,14). Since then, it has been observed that pain and at any level of the nervous system, regardless of eti- other neurological symptoms due to peripheral or ology. In this case, there is demonstrable evidence of a central nervous system disease or injury present in neurological disorder or injury as assessed by clinical very similar ways, and this observation has led to a tools appropriate for each clinical situation, including group designation of NP (1). Most characteristically, clinical history, neurological pain examination, elec- the disorders that are included in this diagnostic trophysiology, and neuroimaging. group are post-herpetic neuralgia (PHN), painful dia- Characteristics that would define NP and differen- betic neuropathy (PDN) and other polyneuropathies, tiate it from other types of pain include the following: traumatic neuralgia, and central pain syndromes. In almost all of these, painful manifestations are very 1. Pain and sensory symptoms that persist beyond similar regardless of the underlying disease. They in- the healing period. clude spontaneous continuing pain, spontaneous par- 2. Presence, in variable degree, of neurological sen- esthesia and paroxysms, and various types of hyper- sory signs manifesting as negative and positive algesia, which are present at various degrees of sensory phenomena. symptomatology even within a single disease diagno- 3. Presence, in variable degree, of other neurologi- sis—such as diabetic distal sensory painful neuropa- cal signs, including motor, manifesting as nega- thy—and, as a rule, are associated with various de- tive and positive motor phenomena or auto- grees of sensory and motor deficits (15–17). This nomic signs. degree of variability in the presentation has always Examples of NP include PHN, central pain syn- posed a difficulty to researchers and clinicians. This drome, PDN, causalgia, and painful radiculopathy. contradiction that etiologically different NP disorders The presence of NP does not exclude the concurrent have similar symptoms and signs and that patients presence of other types of pain and pain mechanisms. with the same etiology of NP have a very wide scope For example, a patient with PDN could have a foot of symptoms and signs will be elucidated only ulcer, where the major component of pain is inflam- through further systematic quantitative studies. matory, in addition to the continuing burning NP. An added difficulty in dealing with the issue of NP In contrast, chronic pain disorders with less-specific is the categorical designation of disorders that have symptoms and signs that are suggestive of NP mech- some but not all symptoms and signs of NP. An ex- anisms, similar to the previous classification of “dys- ample is CRPS Type I (CRPS-I) (previously known as function,” manifesting primarily with varying degrees reflex sympathetic dystrophy). For chronic pain disor- and types of allodynia and hyperalgesia, would be, ders, it is postulated that they are due to nervous then, termed as hypersensitivity pain disorders. Ex- system dysfunction in a pathophysiological sense, amples of the patients in this category would be those rather than to a disease in a pathoanatomical sense. with fibromyalgia, among others. An analogy for this Many investigators provide strong arguments, pri- mechanism-based strategy would be the diagnosis of marily based on a large number of clinical studies, that systemic lupus erythematosus in a patient who meets even pain disorders assumed to be due to dysfunction all the recognized criteria (21) but the diagnosis of are of the neuropathic type. However, many others mixed connective tissue disease for another patient strongly oppose this designation, arguing that the ev- with less-specific, but abnormal, clinical findings. The idence is “too soft.” There is evidence that would type of pain given the categorical designation hyper- suggest that other mechanisms, such as autonomic sensitivity pain disorders does not imply that it is any (18) or inflammatory (19,20) processes, play an impor- less real. This designation implies that the best our tant role in the case of CRPS-I. The number of mech- diagnostic tools can offer at this time is the acknowl- anisms contributing to manifestations of NP is increas- edgment that mechanisms other than currently well ing as the body of knowledge related to underlying defined neurological processes are responsible. It is mechanisms grows, and this adds to the complexity of certainly clear that as our tools for evaluation, assess- how we have to view NP disorders. Consequently, the ment, and diagnosis of these patients improve, this
  3. 3. ANESTH ANALG MEDICAL INTELLIGENCE BACKONJA 787 2003;97:785–90 DEFINING NEUROPATHIC PAIN distinction between neuropathic types of pain and those mechanisms, we can obtain better pain therapy. other pain disorders would take yet a different form or In addition, by studying the relationships of pain even disappear. In addition, the influence of other mechanisms in patients, we could generate new hy- pain (in particular, inflammatory) mechanisms on the potheses (Fig. 1). presentation of patients with any NP will be further We may begin with the simplest type of pain from discussed in the next section. the standpoint of mechanisms, i.e., pain initiated in a Because the definition of NP is based on the pres- healthy subject with an intact nervous system to ence of neurological disease, it is also important to whom highly controlled painful stimuli are applied acknowledge that most neurological disorders affect- (24,25). This is the standard and common means for ing the thermonociceptive component of the nervous anatomic and physiological pain studies in laborato- system do not have pain as a part of their presentation ries, regardless of whether the subjects are human or (22,23). This observation would suggest that NP oc- animal. In this case, all of the aspects of stimulation are curs only in patients who are predisposed to it, prob- controlled with the goal of activating the pain- ably as a matter of genetic makeup. These patients, transmitting nervous system. Because it is a physio- with disorders of the thermonociceptive nervous sys- logical activation, the suggested designation for it is tem but without pain, could serve as a control group “physiological pain” (26). Stimuli such as pinprick or in studies of NP mechanisms as much as patients with heat pulses result in activation of the pain- and pain caused by other mechanisms. Another possible temperature-transmitting nervous system, including outcome of neurological disease is not only NP, but all of the structures involved in transduction, trans- also other disagreeable sensations, which many pa- mission, modulation, perception, and reaction. Once tients clearly identify as “not pain but something very the stimulus is terminated, the subject no longer feels disturbing.” This group of positive sensory symptoms any pain. This is in contrast to clinical types of pain, and signs is categorized as dysesthesia, which can be which persist for the duration of healing, long after present in isolation without pain in a classical sense. injury is over, or, in some cases, may persist even after Most of these positive sensory phenomena, including the healing period, as in the chronic painful disorders. paresthesia and dysesthesia, are proposed to be due to Within the mechanism-based concept and terminol- underlying mechanisms similar to those of NP (15). ogy of pain, there is no place for the term “nociceptive NP in a clinical setting never occurs in isolation, but pain” (1). It is redundant. Nociceptive means “pain- rather as a part of a disease or injury that affects other ful,” and nociceptive pain would mean “painful pain.” tissues and initiates other mechanisms, such as inflam- The term is, for the most part, an artifact of laboratory mation. In general, large clinical experience has shown investigation of pain during which pain-transmitting us that most patients with NP have other types of components of the nervous system, justifiably termed pain, most frequently musculoskeletal related. A bet- “nociceptive,” are studied. As discussed previously, ter characterization of the relationship of NP to those pain from controlled application of painful stimuli in other types of pain can only help to define NP more the laboratory setting is best termed “physiological specifically. By clarifying these more general relation- pain,” because the physiological characteristics and ships, we can then proceed with further categorical mechanisms of the pain system are studied under classification of pain disorders. Certainly, it is likely these conditions. The term “nociceptive pain” does that certain aspects of NP mechanisms play an impor- not carry any information about mechanisms or the tant role in other types of pain, such as visceral pain, disease process, so it should be abandoned. cancer pain, or headaches, but those will not be ad- The most commonly studied clinical types of dressed here. Discussion in the following section will pain—IP and NP—will be the primary subject of this focus on somatic pain and provide suggestions for the discussion. However, it should be recognized that terminology and conceptual framework regarding there are many other types of pain, such as migraine NP. headaches and cancer-related bone pain, to mention only two. Research in those areas is making significant progress. Consequently, productive discussions can Proposal for Categorical Classification of be expected regarding them, as well. IP is the result of tissue response to those pathologic Major Types of Somatic Pain processes that lead to tissue destruction, such as an The amount of information about pain mechanisms abscess or fresh wound. There is mounting evidence has grown rapidly with each new laboratory discov- that intense IP results in changes of the pain- ery, including the expression of novel receptors in the transmitting nervous system, called peripheral and relationships between major pain categories and their central sensitization (12). In most instances, subjects mechanism at the clinical level. This is because the with IP experience various types of hyperalgesia and ultimate issue regarding those mechanisms is whether other symptoms and signs, which are all manifesta- they operate in patients and whether, by correcting tions of peripheral and central sensitization related to
  4. 4. 788 MEDICAL INTELLIGENCE BACKONJA ANESTH ANALG DEFINING NEUROPATHIC PAIN 2003;97:785–90 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. 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. Figure 1. Thick arrows indicate established relationships between diseases of the nervous system and pain symptoms and signs, Challenges and Possible Solutions for thinner arrows represent proposed and evolving relationships and processes, and dashed arrows indicate uncertain relationships. Solid Classification of Pain on the Basis of line boxes represent established and published types of information, and dashed boxes represent steps that would further define pain Mechanism mechanisms and complement the information from basic science Certainly, this proposal is only a first effort to apply regarding mechanisms. CNS central nervous system; PNS peripheral nervous system. 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, IP. In most of these cases, once the disease process is such as trigeminal neuralgia, and this difficulty would healed, the nervous system returns to its normal state not be unusual, because clinical diagnostic methods and function. As long as the disease or injury that and tools have limitations. In addition, the dynamic causes the IP does not affect the nervous system, the natural course of many neuropathic clinical pain dis- neurological evaluation is normal. orders, as in the case of radiculopathy and PDN, NP, as discussed previously, is the result of injury and would deem these disorders to be painless neuropa- disease of the nervous system, most frequently beyond thies at one stage and NP at the other stages, and vice the healing period, and manifests with positive and neg- versa. ative neurological symptoms and signs. Any injury Even the naming of many types of pain is difficult, involving the nervous system causes inflammatory re- and many defy simple definition. Examples of pain sponses (27–30), and in this case, there is an inflamma- that escape eloquent naming would be the pain from tory component adding to the complexity of the process, bearing weight or pain on movement, just to mention although it is still possible to make specific distinctions two. When the attempt is made to develop a classifi- between IP and NP. In most cases, the inflammatory cation protocol based on mechanisms, and where the system is complex and dozens of potential mecha- responses are direct and occur at the site of injury, al- nisms operate at any given time and on multiple lev- though there are distant responses, manifesting with els, it is important to change the paradigm. A possible central nervous system inflammatory responses from solution is not only to catalogue mechanisms, as has peripheral nervous system injury, as well (27,30). The been done thus far, but more importantly, to deter- relationship of these two types of inflammatory respons- mine the temporal sequence and relationship of those es— direct and distant—and the final manifestation of mechanisms in the genesis and maintenance of NP is far from clear. However, this additional inflamma- chronic painful disorders. The explosion of informa- tory mechanism could account for some of the second- tion in both basic science and clinical research is char- ary NP disorders, such as CRPS-I (31). acterized by large volumes of data. For those data to Recent knowledge about pain mechanisms blurs the be useful, the application of methods designed for margins of where IP stops and NP begins, suggesting analyzing large datasets, such as dynamic principle that the process from IP to NP is a continuum rather component analysis, is necessary (32). The only way than a strict categorical distinction (Fig. 2). However, that we will be able to make progress is by a close and from the perspective of pain mechanisms, as well as coordinated working relationship between basic sci- from the clinical standpoint, it is still necessary to ence and clinical research in the form of translational continue making this distinction between IP and NP. research. Thus far, the predominant approach in pain
  5. 5. ANESTH ANALG MEDICAL INTELLIGENCE BACKONJA 789 2003;97:785–90 DEFINING NEUROPATHIC PAIN Figure 2. The hypothetical relationship be- tween inflammatory and neuropathic pain mechanisms that may account for mani- festation of some of the common inflam- matory and neuropathic painful disorders is illustrated in this figure. It should be noted that this is a proposed abstracted presentation of the concept. The actual de- gree of involvement of the neuropathic pain mechanisms and that of inflamma- tory pain mechanisms will be possible only when specific markers or assessment tools for those two types of pain are de- veloped and become available. OA os- teoarthritis; RA rheumatoid arthritis; PHN post-herpetic neuralgia; PDN painful diabetic neuropathy; CIDP chronic inflammatory demyelinating polyneuropathy. Table 1. Types of Pain and Neuropathic Pain in Relationship to Inflammatory Pain Based on the Underlying Mechanisms Type of pain Examples Physiological pain Pinprick, heat pulse Acute inflammatory pain Abscess, surgical incision Chronic inflammatory pain Rheumatoid arthritis Neurogenic inflammation Intradermal capsaicin, Complex Regional Pain Syndrome Inflammatory neuropathic pain Inflammatory demyelinating polyneuropathy (i.e., Guillian-Barre) ´ Neuropathic pain Phantom pain, Central pain translational research has been of trying to apply basic NP from other nonneuropathic painful disorders. The science findings to clinical practice, known as going conceptual distinction between neuropathic and IP from bench to bedside, and the other important step in mechanisms is provided here, as is the distinction this process (of going from bedside to bench) has been between NP due to neurological dysfunction and NP missing. For translational research to be successful, the due to neurological disorder. NP is in this case defined process of a two-way communication has to be as pain occurring in the area or body part associated established. with neurological disease or injury. This type of pain At this point, we are considering NP as only one manifests not only with positive sensory phenomena, end of the “pain mechanisms” spectrum. However, as such as pain, dysesthesia, and different types of hy- our understanding of pain mechanisms advances, ad- peralgesia, but also with negative sensory phenomena ditional dimensions will have to be considered. One and negative and positive motor symptoms and signs. additional aspect of NP that has to be considered early It is acknowledged here that to separate and to define in the process of developing the definition is its dy- any symptom as pain due to neurological dysfunction namic nature. Although symptoms and signs of most does not necessarily clarify the issue, because this is readily recognized NP syndromes, PHN and PDN, still a vague term. With advancing knowledge of may appear stable and consistent from visit to visit, mechanisms, we may one day resolve this problem. they tend to change over time as a result of many The distinction between NP and pain due to neuro- factors. logical dysfunction would be analogous to the distinc- tion that rheumatologists make between lupus and connective tissue disease. It is not possible to provide Conclusion any further solution regarding the definition of NP, or There are many theoretical, conceptual, and practical any type of pain for that matter, beyond what is pre- clinical reasons to improve methods for distinguishing sented here because there are no data with which to
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