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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
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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
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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
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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
Table 1. Types of Pain and Neuropathic Pain in Relationship to Inflammatory Pain Based on the Underlying
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-
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
790 MEDICAL INTELLIGENCE BACKONJA ANESTH ANALG
DEFINING NEUROPATHIC PAIN 2003;97:785–90
proceed, nor would it be possible to find consensus at 12. Kidd BL, Urban LA. Mechanisms of inflammatory pain. Br J
the present time. 13. Mitchell SW, Morehouse G, Keen W. Gunshot wounds, and
Advances in basic and clinical science, together with other injuries of nerves. Philadelphia: Lippincott, 1864.
further differentiation of the influences that various 14. Dejerine JRG. La syndrome thalamique. Rev Neurol Fasc 1906;
mechanisms have on the genesis and maintenance of 12:521–32.
15. Lindblom U, Ochoa J. Somatosensory function and dysfunction.
different subtypes of pain, will certainly result in a In: Asbury AK, McKhann GM, McDonald WI, eds. Diseases of
better and more precise definition of this type of pain- the nervous system: clinical neurobiology. Philadelphia: WB
ful disorder and lead ultimately to more specific di- Saunders Co, 1986:283–98.
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classification of impaired temperature sensibility in patients
that this simple crude distinction will be replaced with with diabetic polyneuropathy. J Neurol Neurosurg Psychiatry
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patients who have neuropathic pain. Neurol Clin 1998;16:
Progress in clinical pain research will be made only 775–90.
when open debate and productive cooperative work 18. Janig W, Levine JD, Michaelis M. Interactions of sympathetic
in the form of translational research take place. It is the and primary afferent neurons following nerve injury and tissue
goal of this article to initiate and to frame this impor- trauma. Prog Brain Res 1996;113:161– 84.
19. Weber M, Birklein F, Neundorfer B, Schmelz M. Facilitated
tant debate. neurogenic inflammation in complex regional pain syndrome.
20. Veldman PH, Reynen HM, Arntz IE, Goris RJ. Signs and symp-
The author would like to thank Drs. Andrew Waclawik, John Farrar, toms of reflex sympathetic dystrophy: prospective study of 829
Robert Dworkin, and Alan Basbaum for their constructive feedback patients. Lancet 1993;342:1012– 6.
on earlier drafts of this manuscript. 21. Sack K, Fey KH. Rheumatic diseases. In: Parslow TG, Stites DP,
Terr AI, Imboden JB, eds. Medical immunology. New York:
Lange Medical Books/McGraw-Hill Medical, 2001.
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sensation testing of hypoesthesia and hyperalgesia are predic-
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