Translation of symptoms and signs into mechanisms in neuropathic pain
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Pain 102 (2003) 1–8
www.elsevier.com/locate/pain
Topical review
Translation of symptoms and signs into mechanisms in neuropathic pain
Troels S. Jensen a,b,*, Ralf Baron c
a
Department of Neurology, Aarhus University, DK 8000 Aarhus C, Denmark
b
Danish Pain Research Center, Aarhus University, DK 8000 Aarhus C, Denmark
c
Klinik für Neurologie, Christian-Albrechts-Universität, Kiel, Germany
Keywords: Neuropathic pain; Symptoms; Signs; Mechanisms; Assessment
1. Introduction pain has strengthened the demand for other ways to treat
pain. Woolf and other authors (Woolf et al., 1998; Woolf
For centuries, clinicians have been taught to examine and and Decosterd, 1999; Sindrup and Jensen, 1999) have
classify patients on the basis of topographical lesion and the emphasised the rational for a treatment approach directed
underlying pathology. In most clinical specialities, such an at mechanism(s) rather than at diseases because new treat-
approach has been a key element in understanding the ments are being developed on basis of the biological
pathophysiology of diseases and has led to progress in mechanisms that underlie the pain. One area that needs
terms of finding disease modifying or even disease curing such a new approach is neuropathic pain.
therapies. Examples are multiple including bacterial menin-
gitis, painful neuroborrelosis, osteoarthrosis, cancer, rheu-
matoid arthritis, ischaemic heart disease etc. In most of 2. Neuropathic pain classification problems
these disorders, pain can be a major complaint, which
then rapidly disappears after the relevant therapy has been According to the current International Association for
given. the Study of Pain (IASP) definition of neuropathic pain,
But what happens when the symptom itself becomes a these disorders are characterised by lesions or dysfunction
disease? When pain persists and becomes a chronic problem of the system(s) that under normal conditions transmit
and when the underlying diseases such as diabetes, cancer, noxious information to the central nervous system. Thus
vasculitis are known, or cannot be cured? Are we then in theory, neuropathic pain should be easy to distinguish
helped by the classical ‘Sherlock Holmes’ approach, first, from other conditions, but in practise, they are both diffi-
to look for the ‘crime site’ (topography of lesion) and cult to identify and to treat and there are several reason
second, for the ‘criminal’ (the disease) that caused this why this is the case:
pain? The short answer is: no. Clinical experience and
decades of rather discouraging systematic research mainly † There is rarely one diagnostic test that can confirm or
related to therapy in chronic pain have shown that a strategy refute the hypothesis of nerve lesion/dysfunction.
directed at examining, classifying and treating pain on basis † The perception of neuropathic (and other types of) pain
of anatomy or underlying disease is of limited help to these is a pure subjective phenomenon, which despite use of
patients and their pain. These observations have then raised the most sophisticated equipment can’t be measured;
the question whether an entirely different strategy in which only correlates to the perceived content can be obtained.
pain is analysed on the basis of underlying mechanisms † The borderland between definite, probable, possible and
could be an alternative approach to examine and classify unlikely diagnoses is not clear. Prevalent disorders such
patients to obtain a better outcome. Our increasing under- as cancer, low back pain, traumatic injuries may contain
standing of mechanisms underlying chronic pain together a considerable (although as yet undetermined) neuro-
with the discovery of new molecular targets for modifying pathic component.
† In contrast to other sensory systems, the pain system is
not static, but changes in a dynamic and somewhat
* Corresponding author. Tel.: 145-8949-3283; fax: 145-8949-3300. unpredictable fashion whenever the system has been
E-mail address: tsj@akhphd.au.dk (T.S. Jensen). activated.
0304-3959/03/$20.00 q 2003 International Association for the Study of Pain. Published by Elsevier Science B.V. All rights reserved.
doi:10.1016/S0 304-3959(03)00 006-X2 T.S. Jensen, R. Baron / Pain 102 (2003) 1–8
† Signs and symptoms of neuropathic pain may change horn neurons. At the cellular level formation of new chan-
during the course of the disease and if it becomes nels, upregulation of certain receptors and downregulation
chronic. of others, altered local or descending inhibition are some of
† There is at present no agreement on whether a restrictive the biological features that can contribute to a hyperexcit-
or a broader definition of neuropathic should be used; ability, which is assumed to be a sine qua non for chronic
the latter including dysfunctional disorders. pain. The neuronal hyperexcitability has a wide spectrum
† Systematic reviews of neuropathic pain treatment of manifestations including increase in cellular excitability,
(excluding simple entrapment disorders such as carpal expansion of neuronal receptive fields, change of modality
tunnel syndrome, meralgia paraesthetica or radial nerve to which neurons respond, recruitment of silent neurons or
compression on the dorsal forearm) show that a moder- circuits and a neuronal reorganisation in the dorsal horn
ate or better pain relief is found only in approximately and further upstream (for review, see Woolf and Salter,
one-third of the patients regardless of underlying disease 2000). It is, therefore, not surprising that these cellular
or anatomy of such disease (McQuay and Moore, 1998; alterations subsequently give rise to neuroplastic changes
Sindrup and Jensen, 1999). in which the somatosensory information can be distorted in
several ways including reorganisation of structures partici-
These constraints and limitations in our current concept pating in the processing of noxious information. At this
of neuropathic pain calls for another approach: to group point of time, we do not know the exact sequence of
suspected neuropathic pain patients. There are specific changes in mechanisms and how they may influence each
requirements to such a grouping as emphasised previously other. After lesioning central pathways, neurons in the
(Woolf et al., 1998): it should be ‘valid’ (the grouping spinal cord and the brain with lost normal input may also
correspond to a specific pathological mechanism) and ‘reli- change their response characteristics and exhibit signs of
able’ (correspondence between examiners and between hyperexcitability in a fashion, mimicking that seen after
results from one time point to the next), and the classifica- peripheral nerve injury (Vierck et al., 2000).
tion should be ‘universal’ (applicable to all conditions,
mild as well as severe) The latter point may be difficult
to ascertain because of the dynamic nature of the nocicep- 4. Symptoms, signs and mechanisms in neuropathic pain
tive system particularly under abnormal conditions. It
should be stressed that at this point of time, no studies The core in neuropathic pain is a lesion of the afferent
have provided a classification of symptoms and signs and transmission system resulting in partial or complete loss of
a scoring system, where the requirements are accounted input to the nervous system and a corresponding sensory
for. loss with negative sensory symptoms. The reduction of
When diseases and disorders are dominated by symp- afferent input caused by the nerve lesion is at the same
toms, which are merely subjective and the associated clin- time the starting point for regeneration and disinhibition
ical signs are few or non-existing the requirement for with secondary development of hypersensitivity resulting
validity and reliability becomes even more demanding. If in various positive symptoms. Negative and positive
the correspondence between symptoms and signs on one phenomena can be demonstrated either at the bedside or
side and mechanism(s) on the other is understood, the in the laboratory. Combined with a pharmacological modu-
possibility for targeting neuropathic pain in a rational lation aimed at specific sites or at specific molecular targets,
way should be better. We will, in the forthcoming para- it will be possible to gain some insight into mechanisms
graphs, briefly review the possibilities for such an approach participating in neuropathic pain.
and consider the practical requirements on how to pursue Most likely symptoms, signs and mechanisms are
in this avenue. related, but probably not directly. For example, a diabetic
patient may have: steady pain, touch evoked pain, parox-
ysms and non-painful paraesthesia. In these cases, several
3. Mechanisms of neuropathic pain mechanisms can be involved such as tissue injury due to
ischaemia, sensitisation of peripheral receptors, ectopic
Pathophysiological mechanisms underlying neuropathic activity in sprouting regenerating fibres, phenotypic
pain have been reviewed extensively within recent years changes in dorsal root ganglion (DRG) cells, spinal reor-
(Baron, 2000; Besson, 1999; Woolf and Salter, 2000; ganisation etc. In other pain states, one mechanism may
Jensen et al., 2001; Hansson et al., 2001; Koltzenburg give rise to different symptoms and signs. For example, a
and Scadding, 2001). The peripheral mechanism occurring peripheral nerve entrapment may cause paroxysms due to
after peripheral nerve damage has been characterised in ectopic activity from the lesioned nerve and an associated
great (although still incomplete) detail. Injured peripheral (extra)-territorial brush evoked pain due to C-fibre evoked
nerve fibres give rise to an intense and prolonged input of central sensitisation. Thus symptoms and mechanisms
ectopic activity to the central nervous system and in some involved in a particular pain condition cannot always be
cases also secondary changes of the excitability of dorsal predicted. Is it then impossible to dissect pathophysiologi-T.S. Jensen, R. Baron / Pain 102 (2003) 1–8 3
cal mechanisms? It is probably not possible. As patients abolished touch-evoked A-b allodynia. The functional
report symptoms and ‘not’ mechanisms and assessors remodelling of synaptic organisation produced by afferent
disclose signs and ‘not’ mechanisms, the starting point C-fibre activity was considered reversed by the peripheral
should be the patient with a focus on how symptoms and C-fibre block. Moreover, in CRPS I, physiological sympa-
signs translate into mechanisms rather than the vice versa. thetic activity and norepinephrine release enhances pain
indicating a pathological adrenergic sensitivity of nocicep-
4.1. Symptoms tive fibres (Baron et al., 2002).
Fields et al. (1998), along a similar line of thinking in
An important point concerns the possible classification
patients with postherpetic neuralgic (PHN), proposed the
of pain just on the basis of symptoms. There are at present
existence of sensitised C-nociceptors as being a major
no data documenting such a classification. It has been
contributing factor to brush-evoked allodynia seen in
claimed that certain symptoms such as burning, smarting,
these patients. They observed an inverse relationship
shock-like pains are characteristic for neuropathic pain, but
between heat pain deficit and ongoing pain indicating
studies are not unanimous on this issue. The symptoms and
that C-nociceptors may be a contributing factor to ongoing
signs resulting from one particular mechanism cannot
pain (Rowbotham and Fields, 1996). In other neuropathic
always (if at all) be predicted because the plasticity gener-
pain states such as traumatic nerve injury and postmastect-
ated in the nervous system implies an unpredictable chain
omy syndrome, similar peripheral sensitisation can be
of events.
demonstrated (Gottrup et al., 2000) showing that sensitised
More recently, there has been suggestions that symptoms
C-nociceptors may indeed be the culprits for generating
also may have some bearing value in clarifying pain
certain types of spontaneous and evoked pains. Chabal et
mechanisms. Paroxysms are generally considered to be of
al. (1989a) showed that modulating peripheral output by
peripheral origin due to spontaneous firing in peripheral
local anaesthetizing stump neuromas with lidocaine
nociceptive afferents. In tic doulourex, it has been
produced a reduction of tap evoked stump pain. In contrast,
suggested that compression of the trigeminal root leads
perineuromal injection of a potassium channel blocker,
to a hyperexcitability in a group of trigeminal ganglion
gallamine produced clear exacerbation of pain (Chabal et
cells which then sets off an ‘ignition focus’ that spreads
al., 1989b). Local anaesthetics applied to the painful skin
to other parts of the ganglion (Devor et al., 2002). New
in PHN patients produced significant pain relief, supporting
observations (Otto et al., 2003) suggest that paroxysms also
the notion of an abnormal input from peripheral nocicep-
could represent more central disturbance. These authors
tors as an important pain generator.
found in patients with painful neuropathy that paroxysms
were related to a reduced function of small fibre activity.
4.2.2. Central sensitisation
Other studies have been less successful in demonstrating
A series of animal studies have shown the importance of
relationship between symptoms and mechanisms. Two
central mechanisms in maintaining pain and in generating
introduced neuropathic pain scales: the neuropathic pain
pain by non-noxious input. Human studies confirm that
scale (NPS) (Galer and Jensen, 1997) and the Leeds assess-
activity in large myelinated A-b fibres can maintain neuro-
ment of neuropathic symptoms and signs (LANSS) scale
pathic pain. After nerve injury, innocuous tactile stimuli get
(Bennett, 2001) need further evaluation in neuropathic pain
access to dorsal horn neurons via low-threshold mechanor-
patients.
eceptors from A-b fibres. If this A-b fibre input is blocked,
4.2. Signs the allodynia disappears, but burning spontaneous pain
persists indicating that the latter probably is mediated by
4.2.1. Peripheral sensitisation C-nociceptors.
Classical studies in patients with complex regional pain While there is evidence that increasing activity in C-
syndrome (CRPS) type II have shown that a local anaes- nociceptors in certain neuropathic pain conditions produces
thetic block of an injured stump can reduce severe allody- an increase in central sensitisation, there are also indica-
nia and signs of autonomic dysfunction (Livingston, 1998). tions that some patients can have severe loss of C-fibre
A large body of evidence obtained within the last decades functions despite the presence of extensive allodynia in
show that sensitisation of peripheral nociceptors can be the the area corresponding to C-fibre loss and pain. Baron
fuel for generating activity in central connecting noxious and Saguer (1993) in a study of PHN patients using C-
responding systems (Fields et al., 1998; Koltzenburg and fibre mediated histamine axon reflexes to determine C-
Scadding, 2001). Nystrom and Hagbarth (1981) in micro- fibre activity showed abolished responses in areas with
electrode recordings from transected nerves in amputees marked allodynia suggesting that in this case, the allodynia
showed spontaneous activity from stumps and blockade is a pure central phenomenon. In central pain conditions,
of such activity with lidocain at the stump also relieves observations are less easy to interpret because of the
the pain. Gracely et al. (1992) demonstrated in patients increasing complexity in ascending transmitting somato-
with peripheral nerve injury that local anaesthetic block sensory systems and the multitude of modulating circuits.
of presumed ongoing C-fibre activity in the injured region Findings in post-stroke pain show that pain occurs in body4 T.S. Jensen, R. Baron / Pain 102 (2003) 1–8
areas that have lost their normal patterned input and that tual responses to noxious stimuli. Intravenously adminis-
areas of pain occupy only a fraction of the area with abnor- tered lidocaine can reduce ongoing and different types of
mal sensory function. These findings indicate similar to evoked pain both in experimental conditions and in various
peripheral neuropathic pain conditions that lost input neuropathic pain conditions peripheral as well as central.
causes a secondary sensitisation in populations of central The use of topical administration of lidocaine has been
neurons, which then are both responsible for the pain and one of the tools used to classify mechanisms in PHN (Fields
the combination of negative and positive sensory findings et al., 1998).
(Boivie et al., 1999; Finnerup et al., 2003). In agreement
with such central sensitisations either in the spinal cord or
5. Assessment of neuropathic pain
more rostrally pharmacological agents with an action on
cellular hyperexcitability such as opioids, gabapentin, lido-
Assessment of neuropathic pain involves a series of
caine and lamotrigine (Attal et al., 2000, 2002; Vestergaard
systematic steps. A key problem in the existing literature
et al., 2001; Finnerup et al., 2002) can reduce pain and
is that the diagnostic work-up of patients apparently varies
abnormal sensitivity.
from one laboratory to another. Trivial as it may be, simple
differences in questioning, differences in equipment used
4.3. Pharmacological tests and changes in sequence of testing are obvious sources for
variability among examiners in the same patient (Hansson
An additional approach for classifying pain involves the
et al., 2001; Jensen et al., 2001). Other confounding factors
use of specific pharmacological agents. Based on their mode
may contribute to an unclear picture of what is and what is
of action and their different molecular targets, pharmacolo-
not neuropathic pain. The diagnostic work-up of patients
gical drugs may be used to determine whether a particular
can be exceedingly complex including sophisticated quan-
symptom can be modulated by a drug with a specific action
titative sensory testing, neurophysiological studies,
(Attal et al., 2000; Jensen et al., 2001). By using different
imaging and pharmacological tests. While this may be of
modes of administration of the same agent (topical,
interest in some cases, the key question is whether we can
systemic, epidural, intrathecal etc.), the site of action can
obtain a meaningful classification of patients also in terms
be determined and the pain-generating site identified.
of mechanisms in a large group of patients in a reasonable
Several agents have been used. In particular the use of
time using simple bedside equipment.
opioids, N-methyl d-aspartate (NMDA) antagonist and
We propose that this is possible. Below, we have listed a
anticonvulsants have provided insight into the pharmacol-
framework on how this can be done in the clinic. The propo-
ogy of various phenomena encountered in neuropathic pain.
sal is for obvious reasons open to criticism. The important
The NMDA antagonist ketamine in subanaesthetic
point here is not whether this is complete or not, or whether
concentrations has by systemic administration been shown
it is correct or not. The important thing is that basically,
to reduce ongoing pain, brush-, pinprick-evoked pain in
scientists and clinicians need to join together and find a
traumatic nerve injuries in amputees, posttraumatic nerve
consensus about how these patients should be assessed
injuries and PHN (Eide et al., 1994; Nikolajsen et al., 1996).
both for clinical and research purposes. By doing so, a clas-
Interestingly, the NMDA antagonist dextromethorphane
sification can be established and proper epidemiological,
was effective in diabetic painful neuropathy and not in
clinical, genetic, therapeutic and other trials can be
PHN indicating different underlying mechanisms (Sang et
performed – also on a large scale.
al., 2002).
NMDA receptors have also been demonstrated in the skin 5.1. Medical history
with a location on unmyelinated and myelinated axons
(Carlton et al., 1995). Topical administration has in some The history should clarify pain location, distribution,
studies been able to demonstrate a reduction in experimental intensity, quality and time course as well as the underlying
mechanical hyperalgesia, while others have failed to find disease and possibly document the nervous system lesion
such an effect. There are no indications at this point that responsible for pain. Separation into stimulus-independent
peripheral NMDA receptors are involved in clinical neuro- and stimulus-dependent pain is useful because it allows
pathic pain. separating ongoing activity from provoked activity. Careful
Local and intravenous administered fast acting opioids history will allow such separation. Patients may describe
such as fentanyl are likewise useful in clarifying the possi- their pains in a variety of ways: unpleasant, pricking, stick-
ble involvement of peripheral as opposed to systemic opioid ing, burning, scalding, aching or deep sore pain. Therefore,
receptors in neuropathic pain (Eide et al., 1994; Attal et al., comparison across patient’s assessors and laboratories
2002). requires similarities in applied definitions, questioning
Local anaesthetics are widely used in treating neuropathic and symptom presentation. A characteristic in many neuro-
pain. Local anaesthetics, in addition to their ability to block pathic pain conditions is the presence of allodynia follow-
nerve impulse traffic, have an effect on damaged nociceptive ing exposure to non-painful cold. In such cases, patients
neurons without affecting nerve conduction and the percep- may describe their pain in a variety of ways: cold, wet, ice-T.S. Jensen, R. Baron / Pain 102 (2003) 1–8 5
Table 1
Medical history in neuropathic pain
Pain complaint Duration Interference with Character Average intensity Nerve territory Extraterritorial
(most prevalent) daily activity (burning, shock-like, pins last week/last day (based on anatomic spread (based on
(0–10) and needles, aching etc.) (0–10) drawing) anatomic drawing)
1
2
3
4
like or even in a paradox manner like burning-hot or ice thermal stimulus e.g. thermorollers kept at 20 and 458C,
burning (like holding a snow-ball in the hand). Some respectively. Cold sensation can also be assessed by the
patients with central pain complain of pain by movement response to acetone or menthol. Vibration can be assessed
in which the movement itself elicit a tightening, squeezing by a tuning fork placed at strategic points (malleol, inter-
or burning sensation in the skin. At other times, the pain is phalangeal joints etc.). At present, there is no consensus
one of paroxysms with stabbing, shooting, lancinating about what, where and how to measure and what to compare
types of pain. Unless patients are questioned in the same with. It is generally agreed that assessment should be carried
manner, comparison will not be possible. The use of out in the area with maximal pain using the contralateral
various scales such as the McGill pain questionnaire, area as control. However, contralateral segmental changes
NPS and the LANSS scale are undoubtedly important following a unilateral nerve or root lesion cannot be
steps in the direction of finding the most suitable neuro- excluded so an examination at mirror sites may not neces-
pathic pain questionnaire. Table 1 presents a suggestion of sarily represent a true control site.
history parameters that need to be recorded. The underly- At bedside, the response can be graded as: ‘normal,
ing disease is, of course, also important even in terms decreased or increased’ (Andersen et al., 1995). This is a
mechanisms of pain. As recently pointed out in an animal simple way to determine whether negative or positive
experimental neuropathic study, the pain behaviour asso- phenomena are involved.
ciated with a nerve crush is different form that seen after a If hyperaesthetic, the response is classified as dysaes-
nerve ligation (Decosterd et al., 2002.) thetic, hyperalgesic or allodynic. A correlation of sponta-
neous pain and sensory response in the painful area suggest
that the two phenomena are reflections of the same phenom-
5.2. Clinical examination enon: a central sensitisation of dorsal horn neurons (Rowbo-
tham and Fields, 1996; Gottrup et al., 2003).
The sensory examination should assess negative sensory
A more sophisticated sensory testing has been proposed
symptoms and findings as well as positive sensory symp-
using neurophysiological and imaging techniques to assess
toms and signs (Tables 2 and 3). By using careful sensory
the various positive phenomena (Table 3). When present,
testing, the characteristic sensory findings corresponding to
allodynia or hyperalgesia can be quantitated by measuring
such symptoms can be detected and quantified. The stimu-
intensity, threshold for elicitation, duration and area of allo-
lus-evoked pains are classified according to its dynamic or
dynia.
static character. A sensory examination at bedside will often
include: pinprick, touch, pressure, cold, heat and vibration.
Pinprick sensation can be assessed by the response to 5.2.1. Windup-like pain and aftersensations
pinprick stimuli, touch by gently applying cotton wool to Windup-like pain or abnormal temporal summation is the
the skin, deep pain by gentle pressure, cold and warm sensa- clinical equivalent to increasing neuronal activity following
tion by measuring the response to a specific cold or warm repetitive C-fibre stimulation .0.3 Hz (Mendell and Wall,
Table 2
Assessment of negative sensory symptoms or signs in neuropathic pain
Negative sensory symptoms/ Bedside examination Laboratory examination Mechanism
signs
Reduced touch Touch skin with cotton wool Graded von Frey hair A-b fibres
Reduced pin prick Prick skin with a pin single stimuli von Frey hair specific (e.g. 100–g) A d fibres
Reduced cold/warm Thermal response to cold 20 and 45 Detection/pain threshold cold warm A d/C-fibres
Reduced vibration Tuning fork on malleol Vibrameter A-b fibres6
Table 3
Assessment of positive sensory symptoms or signs in neuropathic pain
Positive sensory symptoms/signs Bedside exam Laboratory test Specific test (topical, systemical) Mechanism(s)
Spontaneous
Paraesthesia Grade (0–10) Area in cm 2 grade (0–10) None Spontaneous activity in LT A-b afferents
Dysaesthesia Grade (0–10) Area in cm 2 grade (0–10) Pharmacological Spontaneous activity in C/A-d afferents
Paroxysms Number Grade (0–10) Threshold for evocation Pharmacological Spontaneous activity in C-nociceptors
Superficial burning pain Grade (0–10) Area in cm 2 grade (0–10) Capsaicin provocation pharmacological Spontaneous activity in C-nociceptors?
Deep pain Grade (0–10) Area in cm 2 grade (0–10) Pharmacological Spontaneous activity in joint/muscle nociceptors?
T.S. Jensen, R. Baron / Pain 102 (2003) 1–8
Evoked
Touch evoked hyperalgesia Stroking skin with painters brush Block (ischaemia, compression) Central sensitisation:
pharmacological
1. C-fibre input
2. Lost C-fibre input
Static hyperalgesia Gentle mechanical pressure Evoked pain to pressure Peripheral sensitisation
Punctate hyperalgesia Pricking skin with pin von Frey hair Pharmacological Central sensitisation:
A-d fibre input
Punctate repetitive hyperalgesia Pricking skin with pin 2/s for von Frey hair Block (ischaemia, compression) Central sensitisation: A-d fibre input
(windup-like pain) 30 s pharmacological
Aftersensation Measure pain duration after Measure pain duration after Block (ischaemia, compression) Central sensitisation
stimulation stimulation pharmacological
Cold hyperalgesia Stim skin with cool metal roller Evoked pain to cold stimuli Pharmacological 1. Central sensitisation
2. Central disinhibition
Heat hyperalgesia Stim skin with warm metal roller Evoked pain to heat stimuli Pharmacological Peripheral sensitisation
Chemical hyperalgesia Topical capsaicin Topical capsaicin Menthol/Capsaicin/histamine test Peripheral sensitisation
Sympathetic maintained pain none Sympathetic blockade, Sympathetic-afferent coupling
Modulation of sympathetic
outflowT.S. Jensen, R. Baron / Pain 102 (2003) 1–8 7
1965). The windup-like pain can be produced by a variety of References
stimuli including mechanical, thermal and electrical types.
Aftersensations – the persistence of pain long after termina- Andersen G, Vestergaard K, Ingeman-Nielsen M, Jensen TS. The incidence
tion of a painful stimulus – is another characteristic feature of central post-stroke pain. Pain 1995;61:187–193.
Attal N, Gaude V, Brasseur L, Dupuy M, Guirimand V, Parker F, Bouhas-
of neuropathic pain, which is closely related to a coexistent sira D. Intravenous lidocaine in central pain: a double-blind, placebo-
dynamic or static hyperalgesia (Gottrup et al., 2003). controlled psychophysical study. Neurology 2000;54:564–574.
Consistent with this notion, windup-like pain and aftersen- Attal N, Guirimand F, Brasseur L, Gaude V, Chauvin M, Bouhassira D.
sations may both reflect neuronal discharges in wide Effects of iv morphine in central pain: a randomised placebo-controlled
dynamic range neurons. study. Neurology 2002;58:554–563.
Baron R, Schattschneider J, Binder A, Siebrecht D, Wasner G. Relation
By combining symptoms and signs and disease cate-
between sympathetic vasoconstrictor activity and pain and hyperalgesia
gories, it can be tested whether certain symptom clusters in complex regional pain syndrome: a case–control study. Lancet
across disease categories or within the same disease cate- 2002;359:1655–1660.
gory are linked to specific mechanisms (see above). Baron R, Saguer M. Postherpetic neuralgia. Are C-nociceptors involved in
signalling and maintenance of tactile allodynia. Brain 1993;116:1477–
1496.
5.3. Pharmacological testing Baron R. Peripheral neuropathic pain: from mechanisms to symptoms. Clin
J Pain 2000;16:s12–s20.
Acute pharmacological tests using a double-blind placebo Bennett M. The LANSS pain scale: the Leeds assessment of neuropathic
symptoms and signs. Pain 2001;92:147–157.
controlled technique with either different drugs or different Besson JM. The neurobiology of pain. Lancet 1999;353:1610–1615.
administration forms of the same substance permit an exam- Boivie J. Central pain. In: Wall PD, Melzack R, editors. Textbook of pain,
ination of the location of the ‘pain generator’ and the mole- 3rd ed.. Edinburgh: Churchill Livingstone, 1999. pp. 871–902.
cular mechanism involved in pain. If testing further is Chabal C, Russell LC, Burchiel KJ. The effect of intravenous lidocaine,
separated into an examination of ongoing pain and various tocainide and mexiletine on spontaneously active fibers originating in
rat sciatic neuromas. Pain 1989a;38:333–338.
evoked responses (see Table 3) insight can also be obtained
Chabal C, Jacobson L, Russell LC, Burchiel KJ. Pain responses to perineur-
into the molecular mechanisms involved in a particular omal injection of normal saline, galamine and lidocaine in humans. Pain
phenomenon or mechanism. 1989b;36:321–325.
Carlton SM, Hargett GL, Coggeshall RE. Localization and activation of
glutamate receptors in unmyelinated axons of rat glabrous skin.
Neurosci Lett 1995;197:25–28.
6. Conclusion Decosterd I, Allchorne A, Woolf CJ. Progressive tactile hypersensitivity
after a peripheral nerve crush: non-noxious mechanical stimulus-
A mechanism-based analysis and eventually classifica- induced neuropathic pain. Pain 2002;100:155–162.
tion of neuropathic pain is an attractive approach for several Devor M, Amir R, Rappaport ZH. Pathophysiology of trigeminal neuralgia:
reasons. However, at present it is unclear if this in the daily the ignition hypothesis. Clin J Pain 2002;18:4–13.
Eide PK, Jørum E, Stubhaug A. Relief of post-herpetic neuralgia with the
clinic will result in a better treatment outcome of pain N-methyl-d-aspartic receptor antagonist ketamine: a double-blind,
patients. It will be of interest to determine the possible addi- cross-over comparison with morphine and placebo. Pain
tional yield provided by a hierarchical structured system 1994;54:347–354.
that classifies pain on the basis of: (1) symptoms, (2) Fields HL, Rowbotham M, Baron R. Postherpetic neuralgia: irritable noci-
symptoms 1 signs, (3) symptoms 1 signs 1 mechanisms ceptors and deafferentation. Neurobiol Dis 1998;5:209–227.
Finnerup BN, Sindrup SH, Bach FW, Johannesen IL, Jensen TS. Lamotri-
and (4) symptoms 1 signs 1 mechanisms 1
gine in spinal cord injury pain: a randomised controlled clinical trial.
pharmacological analysis (Rasmussen et al. unpublished Pain 2002;96:375–383.
observations). This can be done once there is consensus Finnerup NB, Johannesen IL, Fuglsang-Federiksen A, Bach FW, Jensen
about what the content should be in the examination ‘pack- TS. Sensory function in spinal cord injury patient with and without
age’. central pain. Brain 2003;126:57–70.
Galer BS, Jensen MP. Development and preliminary validation of a pain
measure specific to neuropathic pain. The neuropathic pain scale.
Neurology 1997;48:332–338.
Acknowledgements Gottrup H, Andersen J, Arendt-Nielsen L, Jensen TS. Psychophysical
examination in patients with postmastectomy pain. Pain
2000;87:275–284.
The studies on which the present paper is based have in
Gottrup H, Kristensen AD, Bach FW, Jensen TS. Aftersensations in experi-
part been supported by grants from Danish Pain Research mental and clinical hyperalgesia. Pain 2003; (in press).
Center, Danish Medical Research Council (No. 9502209), Gracely RH, Lynch SA, Bennett GJ. Painful neuropathy: altered central
the Cancer Society (No. 78004), Institute for Experimen- processing, maintained dynamically by peripheral input. Pain
tal. Clinical Research University of Aarhus, Karen Elise 1992;51:175–194.
Hansson P, Lacerenza M, Marchettini P. Aspects of clinical and experi-
Jensens Foundation, the German Research Foundation (Ba
mental neuropathic pain: the clinical perspective. In: Hansson PT,
1921), the German Research Network on Neuropathic Pain Fields HL, Hill RG, Marchettini P, editors. Neuropathic pain: patho-
(BMBF) and the German–Danish Commission of Kiel physiology and treatment, progress in pain research and management
University. vol. 21. Seattle, WA: IASP Press, 2001. p. 1–18.8 T.S. Jensen, R. Baron / Pain 102 (2003) 1–8 Jensen TS, Gottrup H, Bach FW, Sindrup SH. The clinical picture of Sang CN, Booher S, Gilron I, Parada S, Max MB. Dextromethorphan neuropathic pain. Eur J Pharmacol 2001;429:1–11. and memenatine in painful diabetic neuropathy and postherpetic neur- Koltzenburg M, Scadding J. Neuropathic pain. Curr Opin Neurol algia: efficacy and dose–response trials. Anesthesiology 2002;96: 2001;14:641–647. 1053–1061. Livingston WK. In: Fields HL, editor. Pain and suffering. Seattle, WA: Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuro- IASP Press, 1998. p. 1–250. pathic pain: an update and effect related to mechanism of drug action. McQuay HJ, Moore RA. An evidence-based resource for pain relief. Pain 1999;83:389–400. Oxford: Oxford University Press, 1998. Vestergaard K, Andersen G, Gottrup H, Kristensen BT, Jensen, TS. Lamo- Mendell LM, Wall PD. Responses of single dorsal cord cells to peripheral trigine for central post-stroke pain: a randomised controlled trial. cutaneous unmyelinated fibers. Nature. 1965;206:97–99. Neurology 2001;56:184–190. Nikolajsen L, Hansen C., Nielsen J, Keller J, Arendt-Nielsen L, Jensen TS. Vierck CJ, Siddall P, YezierskiRP. Pain following spinal cord injury: The effect of ketamine on phantom pain: a neuropathic disorder main- animal studies and mechanistic studies. Pain 2000;89:1–5. tained by peripheral input. Pain 1996;67:69–77. Woolf CJ, Bennett GJ, Doherty M, Dubner, R, Kidd, B, Koltzenburg, M, Nystrom B, Hagbarth KE. Microelectrode recordings from transected nerves Lipton, R, Loeser JD, Payne R, Torebjork E. Towards a mechanism- in amputees with phantom limb pain. Neurosci Lett 1981;27:211–216. based classification of pain? Pain 1998;77:227–229. Otto et al., 2003Otto M, Bak S, Bach FW, Jensen TS, Sindrup SH. Pain Woolf CJ, Decosterd I. Implications of recent advances in the understand- phenomena and possible mechanisms in patients with painful poly- ing of pain pathophysiology for the assessment of pain in patients. Pain neuropathy. Pain 2003;101:187–192. 1999;(Suppl. 6):s141–148. Rowbotham, MC, Fields HL. The relationship of pain, allodynia and ther- Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain mal sensation in post-herpetic neuralgia. Brain 1996;119:347–354. Science 2000;288:1765–1768.
You can also read
