Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3111_Библиотеки_им_академика_М_И_Перельмана
.pdf
230 Milton L. COHEN
neuroanatomical relationships) is not disputed.
Clearly “trigger points” are also candidates to be
regions of secondary hyperalgesia. e anatomical
concordance of myofascial “trigger points” and
peripheral nerve trunks has been noted [45],
raising the possibility that the phenomena may
be attributable to nerve trunk hyperalgesia
[5], but whether that in itself reflects central
nociceptive changes remains to be explored. As
with fibromyalgia syndrome, the initiating and
maintaining mechanisms await elucidation.
Principles of Management
of Muscular and Regional
Musculoskeletal Pain
Implications from neurobiology
e diagnostic emphasis on trying to identify the
mechanism of production of pain experienced in
musculoskeletal tissues is the basis for developing
rational therapy. Clearly if there is an identifiable
nociceptive process, such as inflammation or nerve
compression, that is considered to be responsible
for the pain, then the biomedical model demands
that that process be targeted as specifically
as possible. If clinical assessment leads to an
inference of nociceptive pain, therapy is relatively
uncontroversial (although formal evidence of
efficacy is wanting).
However, if nociceptive pain is not readily or
reasonably identifiable, then an alternative
mechanism needs to be postulated. e possibility
that an alteration in function of nociceptive
networks themselves may be responsible for the
pain may need to be considered. is immediately
raises the issue of whether such alteration is
“driven” by ongoing afferent (“upward”) input or by
“downward” processes from higher centres, or what
may be the “balance” between these influences. In
the present state of knowledge, this issue cannot be
determined with confidence.
If on clinical grounds it is inferred that central
changes in nociceptive function have occurred,
specifically central sensitisation, such that a clinical
diagnosis of neuropathic (or neuroplastic) pain may
be made, then certain principles of management
follow.
• Assess the patient in a biopsychosocial
framework
Identification of secondary hyperalgesia as the
relevant pathophysiological mechanism should
place the clinical problem in a biopsychosocial
framework. In addition to somatic assessment, an
evaluation of function and behaviour is required,
as is identification of affective, cognitive, cultural
and environmental contributions to distress.
Treatment strategies need to focus on modifying
central sensitisation, other sites of nociception and
distress.
• Avoid chasing nociception in region of pain
e absence of a peripheral nociceptive lesion
implies that peripherally directed investigation
or therapy is not rational. Identification of
neuroanatomically related sites of nociception may
be more efficacious. at may not lead directly to
therapeutic intervention at such sites but it may
indicate what therapy should not be introduced.
Diagnostico-therapeutic manoeuvres in the region
of pain such as focal injections of local anaesthetic
may appear to benefit. However, any such benefit
may well be attributable to contextual (placebo)
effect rather than to the specific therapy itself [12].
• Mechanical modalities may be painful and
sensitising
If central sensitisation is the relevant mechanism,
then non-noxious movement may be associated
not only with pain (and its behavioural sequelae)
but also with maintaining the abnormal function
of central nociceptive networks. Passive physical
therapeutic techniques in this situation are unlikely
to be helpful (as indeed is not contradicted by the
evidence). An emphasis on graded active movement
with symptom modification can be defended.
Similarly, therapies (mechanical or chemical) which
directly involve the region of pain, thus eliciting
mechanical hyperalgesia, are likely to fail or indeed
to exacerbate the pain.
• Pharmacological modification of sensitisation
Major current challenges in the practice of pain
medicine include the identification of mechanisms
which underlie neuropathic pain, the rational
development of therapies which can influence
such mechanisms and the assessment of their
clinical effectiveness. e therapeutic effort to
date has depended upon the empirical usage of
anticonvulsant and antidepressant medication.
https://t.me/medicina_free
Muscular Pain Conditions 231
In a systematic review of randomised, double-blind
placebo controlled trials examining therapeutic
responses of evoked neuropathic pain phenomena,
including dynamic mechanical allodynia, pin-prick
hyperalgesia and thermal allodynia, a wide variety
of methods used to evaluate these phenomena was
found. ere was some evidence for the efficacy
of intravenous ketamine, alfentanil and morphine
in modifying dynamic mechanical allodynia. For
other agents and other evoked pain phenomena,
there was insufficient evidence to draw firm
conclusions [22]. Furthermore, at the level of
diagnosis of neuropathic pain syndromes (which
is highly relevant to discussions of musculoskeletal
pain), a review of meta-analyses and randomised,
double-blind placebo controlled clinical trials in
trigeminal neuralgia, polyneuropathy, nerve injury,
central pain and complex regional pain syndrome
found little difference between agents which
might enable recommendations to be made in a
given neuropathic pain state [20]. ese findings
do not constitute arguments against trying to
modify phenomena suggestive of altered central
nociception, but they do call for standardisation
of clinical methodology and more rigorous clinical
trials.
• Pharmacological modification of symptoms
as an adjunct to other therapy
If a mechanism for pain production cannot be
influenced by pharmacotherapy, the emphasis is to
treat the pain itself, although which medications to
use is an area of controversy.
e role of the placebo effect is highlighted in
this situation. Not only may apparent responses
to commonly used physical therapies in myalgia
and arthralgia be indistinguishable from placebo
but also the cumulative effect of repeated
ineffective therapies may extinguish responses to
later more powerful therapies [12, 43]. is may
apply also to inadequate symptom modification
with analgesic drugs. However, at present, the
mainstays of management of persistent myalgia are
symptom modification and cognitive-behavioural
approaches.
Rational therapy
A general approach to the medical management of
muscular and regional musculoskeletal pain includes
consideration of rest, modification of activities, use
of external supports, exercises, analgesic medications,
“anti-inflammatory” medications (topical and oral),
other drugs and injections.
Rest
Rest has intuitive appeal in the acute situation
and may include immobilisation or support of the
painful part, and avoidance of certain activities
or postures. ere is an inherent conflict between
reducing activity-related pain in pursuit of comfort
and increasing activity to facilitate maintaining
function of musculoskeletal tissues. ere is no
consensus regarding this issue and little evidence
on which to base recommendations.
Attention to biomechanical stressors
Modification of activities to reduce biomechanical
stressors addresses established or predictable risk
factors, especially those applicable to an individual
patient’s predicament. Intuitive principle here tends
not to be matched by evidence.
Aids and devices
e use of slings, supports, braces or bandages may
modify biomechanical stressors, in conjunction
with other measures. eir prescription is based on
individual preference rather than evidence. When
they are associated with benefit, whether such
devices work through biomechanical mechanisms or
through placebo effect has not been determined.
Physical modalities
Exercises, active and passive, and a variety of
physical modalities including heat and cold,
are usually prescribed. Two review articles have
found it difficult to draw conclusions [8, 18]. e
underlying principle is to facilitate and maintain
movement of the part despite the discomfort.
Pharmacotherapy
e aim of drug therapy in musculoskeletal pain
is symptom control, to facilitate movement and
function.
• Paracetamol
e mainstay of analgesic drugs is paracetamol,
which is effective, safe and attended by few
precautions or interactions at doses up to 4 g
per day [44]. It is also used in combination
with weak opioid agonists such as codeine or
dextropropoxyphene or stronger opioid drugs such
as immediate-release morphine or oxycodone. In
acute pain, single doses of paracetamol 600–650
https://t.me/medicina_free
232 Milton L. COHEN
mg are effective and the addition of codeine 60 mg
enhances pain relief although at the expense of side
effects [39].
• Opioids
Apart from some single-dose efficacy studies,
there are no controlled trials of opioid analgesics
in muscular or regional musculoskeletal pain. is
does not detract from their potential effectiveness.
ere is no a priori reason for not considering
their use in situations where simple analgesics have
failed. A recent review of opioids in chronic pain
found a mean decrease in pain intensity of “at least
30%” in “neuropathic” and “musculoskeletal” pain
in the short term; however, most of the patients in
this review did not go on to long term management
with opioids [30].
• Non-steroidal anti-inflammatory drugs
(NSAIDs)
Despite the lack of evidence that inflammation is
the relevant mechanism in the majority of cases
of regional musculoskeletal pain, NSAIDs are
used both topically and systemically. In acute
(mechanical) musculoskeletal conditions, topical
ketoprofen, ibuprofen and piroxicam have been
shown to be significantly better than placebo over
1 week and associated with no excess of adverse
events [40]. ere is little to choose between
paracetamol and NSAIDs in efficacy, whilst the
morbidity of NSAIDs is greater than that of
paracetamol [13].
Injections
e rationale for the use of local injections is that
pain is attributable to an anatomically localisable
nociceptive process. When a local anaesthetic
agent is used, the aims are to help with diagnosis
and, if positive, with treatment. When depot
corticosteroid agents are used, the presumption
is that inflammation is the relevant mechanism.
Although injection therapy is widely practised,
there is little support for its efficacy. e rational use
of this approach is confronted by three problems:
the question of which structure(s) is being injected,
which is of course linked with uncertainty of
diagnosis; whether any observed outcome of the
injection is due to the pharmacological property of
the substance or due to physical effects; and the issue
of the potential contextual (placebo) effect of an
invasive procedure itself [12]. Despite these major
challenges to rationale, it is clinical experience that
injections appear to help some patients. Unresolved
issues include volume, dose and technique of
injection. Complications of injection include
allergic reactions, local haemorrhage and infection
and, in the case of corticosteroid injections, local
tissue atrophy.
Evidence base
e need for an evidence base to support the
practice of pain medicine meets a nemesis in the
case of muscular or regional musculoskeletal pain,
where, for the most part, inflammation is not the
relevant mechanism but there is no agreement
that neuropathic or neuroplastic processes may
be responsible. Reference can be made to the
Australian Acute Musculoskeletal Pain Guidelines
Group [6] and to site-specific Cochrane reviews.
Summary
A biopsychosocial approach to the assessment
of patients presenting with muscular or regional
musculoskeletal pain integrates insights from
the neurobiology of nociception and pain with
evaluation of function and other contributions to
distress. e neurobiological approach emphasises
identification of the origin and of the mechanism
of pain. ese remain daunting challenges, with
implications for diagnostic nomenclature and
rational therapy. Most examples of such pain are
not threatening but tend to have natural histories
of incomplete resolution or of recurrence. erapy
to date has been largely empirical and not soundly
based either on mechanism or on evidence. e
potential of using older established drugs and of
developing newer agents specifically to gain insight
into mechanisms and thus to lead to rational
pharmacotherapy is there to be tapped. Reference
has been made to the importance of assessing the
cognitive dimension in diagnosis and addressing
cognitive issues in therapy.
https://t.me/medicina_free
Muscular Pain Conditions 233
References
Arendt-Nielsen L. Induction and assessment of experimental pain from human skin, muscle, and viscera. In Jensen
TS, Turner JA, Wiesenfeld-Hallin Z, eds. Proceedings of the 8th World Congress on Pain, Seattle: IASP press, 1997:393–
425.
Arendt-Nielsen L, Graven-Nielsen T, Svensson P, et al. Temporal summation in muscles and referred pain areas: An
experimental human study. Muscle Nerve 1997;20:1311–3.
Arendt-Nielsen L. Assessing muscle pain in humans. In Justins DM, ed. Pain 2005 — An Updated Review. Seattle: IASP
Presss, 205:355–65.
Arroyo JF, Cohen ML. Abnormal responses to electrocutaneous stimulation in fibromyalgia. J Rheumatol 1993;20:1923–
33.
Asbury AK, Fields HL. Pain due to peripheral nerve damage: An hypothesis. Neurology 1984;34:1587–90.
Australian Acute Musculoskeletal Pain Guidelines Group. Evidence-based Management of Acute Musculoskeletal Pain.
[Online. Available at http://www.nhmrc.gov.au. Brisbane: Australian Academic Press, 2003.
Bajaj P, Graven-Nielsen T, Arendt-Nielsen L. Osteoarthritis and its association with muscle hyperalgesia: An experimental
controlled study. Pain 2110; 93:107–14.
Beckerman H, Bouter LM, van der Heijden BRA, et al. Efficacy of physiotherapy for musculoskeletal disorders: What
can we learn from research? Br J Gen Pract 1993;43:73–7.
Blyth FM, March LM, Brnabic AJ, et al. Chronic pain in Australia: A prevalence study. Pain 2001;89:127–34.
Coderre J, Katz J, Vaccarino AL, et al. Contribution of central neuroplasticity to pathological pain: Review of clinical
and experimental evidence. Pain 1993;52:259–85.
Cohen ML, Quintner JL. Fibromyalgia syndrome: A problem of tautology. Lancet 1993;342:904–8.
Cohen ML. Placebo theory. In Ellis R, Hutson M, eds. Textbook of Musculoskeletal Medicine. Oxford: Oxford University
Press, 2006:109–14.
Courtney P, Doherty M. Key questions concerning paracetamol and NSAIDs for osteoarthritis. Ann Rheum Dis 2002;
61:767–73.
Croft P, Schollum J, Silman A. Population study of tender point counts as evidence of fibromyalgia. BMJ 1994;309:696–
9.
Davis KD, Meyer RA, Campbell JN. Chemosensitivity and sensitization of nociceptive afferents that innervate the
hairy skin of monkeys. J Neurophysiol 1993;69:1071–81.
Dujovne CA. Expanded clinical evaluation of lovastatin (EXCEL) study results: III. Efficacy in modifying lipoproteins
and implications for managing patients with moderate hypercholesterolemia. Amer J Med 1991;91:18S–24S.
Engel GL. e clinical application of the biopsychosocial model. Am J Psychiatry 1980;137:535–44.
Feine JS, Lund JP. An assessment of the efficacy of physical therapy and physical modalities for the control of chronic
musculoskeletal pain. Pain 1997;71:5–23.
Filosto M, Tonin P, Vattemi G, et al. e role of muscle biopsy in investigating isolated muscle pain. Neurology
2007;68:181–6.
Finnerup NB, Otto M, McQuay HJ, et al. Algorithm for neuropathic pain treatment: An evidence-based proposal.
Pain 2005;118:289–305.
Gerwin RD. A study of 96 subjects examined both for fibromyalgia and myofascial pain. J Musculoskelet Pain
1995;3(Suppl 1):121.
Granot R, Day RO, Cohen ML, et al. Targeted pharmacotherapy of evoked phenomena in neuropathic pain: A review
of the current evidence. Pain Med 2007;8:48–64.
Graven-Nielsen T, Segerdahl M, Svensson P, et al. Methods for induction and assessment of pain in humans with clinical
and pharmacological examples. In Kruger L, ed. Methods in Pain Research. Boca Raton: CRC Press, 2001:264–304.
Graven-Nielsen T, Arendt-Nielsen L. Peripheral and central sensitization in musculoskeletal pain disorders: An
experimental approach. Curr Rheumatol Rep 2002;4:313–21.
Graven-Nielsen T, Jansson Y, Segerdahl M, et al. Experimental pain by ischaemic contractions compared with pain by
intramuscular infusions of adenosine and hypertonic saline. Eur J Pain 2003;7:93–102.
Graven-Nielsen T, Mense S, Arendt-Nielsen L. Painful and non-painful pressure sensations from human skeletal muscle.
Exp Brain Res 2004;159(3):273–83.
Hardy JD, Wolff HG, Goodell H. Experimental evidence on the nature of cutaneous hyperalgesia. J Clin Invest
1950;29:115–40.
Harth M, Nielson WR. e fibromyalgia tender points: Use them or lose them? A brief review of the controversy. J
Rheumatol 2007;54:914–22.
Howell JN, Chleboun G, Conatser R. Muscle stiffness, strength loss, swelling and soreness following exercise-induced
injury in humans. J Physiol (Lond) 1993;464:183–96.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
https://t.me/medicina_free
234 Milton L. COHEN
Kalso E, Edwards JE, Moore RA, et al. Opioids in chronic non-cancer pain: Systematic review of efficacy and safety.
Pain 2004;112:372–80.
Kellgren JH. Observations on referred pain arising from muscle. Clin Sci 1938; 3:175–90.
Kidd BL. Pain mechanisms in musculoskeletal disease. In Justins DM, ed. Pain 2005 — An Updated Review. Seattle:
IASP Press, 2005:349–54.
Laursen RJ, Graven-Nielsen T, Jensen TS, et al. e effect of compression and regional anaesthetic block on referred
pain intensity in humans. Pain 1999;80:257–63.
Lewis T. Experiments relating to cutaneous hyperalgesia and its spread through somatic nerves. Clin Sci 1936;2:373–
421.
Lewis T, Kellgren JH. Observations relating to referred pain, viscero-motor reflexes and other associated phenomena.
Clin Sci 1942;4:47–71.
Marchettini P, Simone DA, Caputi G, et al. Pain from excitation of identified muscle nociceptors in humans. Brain Res
1996;740:109–16.
Mense S. Nociception from skeletal muscle in relation to clinical muscle pain. Pain 1993;54:241–89.
Merskey H, Bogduk N. Classification of Chronic Pain. Seattle: IASP Press, 1994:210.
Moore A, Collins S, Carroll D, et al. Paracetamol with and without codeine in acute pain: A quantitative systematic
review. Pain 1997;70:193–201.
Moore RA, Tramer MR, Carroll D, et al. Quantitative systematic review of topically applied non-steroidal anti-
inflammatory drugs. BMJ 1998;316:333–8.
Morris VH, Cruwys SC, Kidd BL. Characterisation of capsaicin-induced mechanical hyperalgesia as a marker for
altered nociceptive processing in rheumatoid arthritis. Pain 1997;71:179–86.
Newham DJ. e consequences of eccentric contractions and their relation to delayed onset muscle pain. Eur J Appl
Physiol 1988;57:353–9.
Peck C, Coleman C. Implications of placebo theory for clinical research and practice in pain management. eor Med
1991;12:247–70.
Prescott LF. Paracetamol: Past, present and future. Amer J er 2000;7:143–7.
Quintner JL, Cohen ML. Referred pain of peripheral neural origin: An alternative to the “myofascial pain” construct.
Clin J Pain 1994;10:243–51.
Quintner JL, Cohen ML. Fibromyalgia falls foul of a fallacy. Lancet 1999;353:1092–4.
Raja SN, Meyer RA, Campbell JN. Peripheral mechanisms of somatic pain, Anesthesiology 1988;68:571–90.
Rooks DS. Fibromyalgia treatment update. Curr Opin Rheumatol 2007;19:111–7.
Schaible H-G, Ebersberger A, Von Banchet GS. Mechanisms of pain in arthritis. Ann NY Acad Sci 2002;966:343–54.
Simone DA, Marchettini P, Caputi G, et al. Identification of muscle afferents subserving sensation of deep pain in
humans. J Neurophysiol 1994;72:883–9.
Simons DG. Neurophysiological basis of pain cause by trigger points. APS Journal 1994;3;17–9.
Smythe HA, Gladman D, Dagenais P, et al. Relationship between fibrositic and control site tenderness: Effects of
dolorimeter scale length and footplate size. J Rheumatol 1992;19:284–9.
Steig RL, Williams RC. Chronic pain as a biosociocultural phenomenon. Semin Neurol 1983;3:370–6.
Stewart WF, Ricci JA, Chee E, et al. Lost productive time and cost due to common pain conditions in the workforce.
JAMA 2003;290:2443–54.
Svensson P, Arendt-Nielsen L. Induction and assessment of experimental muscle pain. J Electromyogr Kinesiol
1995;5:131–40.
Tough EA, White AR, Richards S, et al. Variability of criteria used to diagnose myofascial trigger point pain syndrome
— evidence from a review of the literature. Clin J Pain 2007;23:278–86.
Travell J, Simons DG. Myofascial pain and Dysfunction. e trigger point manual. Baltimore: Williams and Wilkins,
1992.
Treede R-D, Meyer RA, Raja SN, et al. Peripheral and central mechanisms of cutaneous hyperalgesia. Progr Neurobiol
1992;38:397–421.
Treede R-D, Rolke R, Andrews K, et al. Pain elicited by blunt pressure: Neurobiological basis and clinical relevance.
Pain 2002;98:235–40.
Vierck CJ Jr. Mechanisms underlying the development of spatially distributed chronic pain (fibromyalgia). Pain
2006;124:242–63.
Wolfe F, Smythe HA, Yunus MB, et al. e American College of Rheumatology 1990. Criteria for the classification of
fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33:160–72.
Wolfe F, Simons DG, Fricton J, et al. e fibromyalgia and myofascial pain syndromes: A preliminary study of
tender points and trigger points in persons with fibromyalgia, myofascial pain syndrome and no disease. J Rheumatol
1992;19:944–51.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
https://t.me/medicina_free
Introduction
Both acute and chronic pain can occur after injury or damage
to the nervous system. “Neuropathic pain” is a collective term
used to describe these pain conditions. Neuropathic pain is a
common and important entity in pain medicine with unique
pathophysiological mechanisms, and frequently presents as
challenging diagnostic and management problems clinically.
Denition
According to the International Association for the Study of
Pain (IASP), neuropathic pain is defined as “Pain initiated
or caused by a primary lesion or dysfunction in the nervous
system” (IASP Pain Terminology, 1994). [52]. is definition
includes pain which is initiated or caused by a lesion or
dysfunction in the peripheral nervous system, known as
peripheral neuropathic pain; and pain initiated or caused by a
lesion or dysfunction in the central nervous system, which is
called central pain.
Some other related terms used in the IASP Pain Terminology
include:
1. Neuropathy. Defined as “A disturbance of function
or pathological change in a nerve: in one nerve,
mononeuropathy; in several nerves, mononeuropathy
multiplex; in diffuse and bilateral nerves,
polyneuropathy.”
2. Neuritis. Defined as “Inflammation of a nerve or
nerves.”
e term neuropathic pain was introduced in the 1994
IASP Pain Terminology. Prior to this, the name neurogenic
pain was used. e definition of neurogenic pain differs
Neuropathic Pain
15
Kwok Fu Jacobus NG
INTRODUCTION
Definition
Symptomatology
Neuropathic and nociceptive
pain
EPIDEMIOLOGY
P
A
THOPHYSIOLOGY
Peripheral disturbances
Central disturbances
CLINICAL PRESENT
ATION AND
MANAGEMENT
Classification of neuropathic pain
syndromes
IMPORT
ANT SYNDROMES
Postherpetic neuralgia
Phantom pain
Complex regional pain syndrome
Central pain
SUMMARY
REFERENCES
https://t.me/medicina_free
236 Kwok Fu Jacobus NG
from that of neuropathic pain in that neurogenic
pain also includes “transitory perturbation” in
the central or peripheral nervous system as a
cause of pain. e definition of neuropathy does
not include “transitory perturbation”, such as
neuropraxia, neurotmesis, section of a nerve, or
a transitory impact like a blow, stretching, or an
epileptic discharge. Similarly, neuropathic pain
also excludes pain caused by these perturbations.
e reason for this change in terminology is that
conditions causing genuine neuropathic pain
have unique pathophysiological mechanisms (see
Pathophysiology section below) which are rather
distinct from those seen in transitory perturbations
in nerves.
Neuritis is a special form of neuropathy and by
definition all pain initiated or caused by neuritis
is neuropathic pain. However, it is worth noting
that there are numerous other forms of neuropathy
as well, such as infection, trauma, ischaemia and
degeneration.
Symptomatology
Neuropathic pain is a highly complex clinical
condition. Much controversy surrounds the
pathophysiology, diagnosis and treatment of
neuropathic pain. One of the difficulties facing
clinicians and patients is that the pain experience
in neuropathic pain conditions is usually very
different from common, everyday experience. As a
result of this unique symptomatology, clinicians and
patients alike have been frequently frustrated by the
paucity of medical terms to describe accurately the
experiences of neuropathic pain. However, a huge
number of terms has evolved over the years which
are used almost exclusively in the field of pain
medicine, especially in the study and treatment
of neuropathic pain [52]. A clear understanding
of these terms is essential before discussing
neuropathic pain further. An alphabetical list of the
terms is presented below.
Allodynia
Pain due to a stimulus which does not normally
provoke pain. It is derived from the Greek word
“allo” meaning “other” and “odune’ or “odyne”
which means pain, as used in “coccydynia”. is
new 1994 definition of allodynia has omitted the
words “to normal skin”, which is present in the
previous definition. By this omission, allodynia can
now be applied to both normal skin and damaged
skin, e.g. over an ulcer. In this definition, it is
recommended to justify a stimulus as one which
“does not normally provoke pain” by testing the
stimulus elsewhere in the patient’s body, usually in
a corresponding part.
Anaesthesia dolorosa
Pain in an area or region which has no, or reduced,
sensation.
Causalgia
A syndrome of sustained burning pain, allodynia
and hyperpathia after a traumatic nerve lesion,
often combined with vasomotor and sudomotor
dysfunction and later trophic changes.
Dysaesthesia
An unpleasant abnormal sensation, whether
spontaneous or evoked. Both allodynia and
hyperalgesia are forms of dysaesthesia.
Hyperalgesia
An increased response to a stimulus which is
normally painful.
Hyperaesthesia
Increased sensitivity to stimulation, excluding
the special senses. Hyperaesthesia, similar
to dysaesthesia, includes both allodynia and
hyperalgesia.
Hyperpathia
A painful syndrome characterised by an abnormally
painful reaction to a stimulus, especially a repetitive
stimulus, as well as an increased threshold.
Neuralgia
Pain in the distribution of a nerve or nerves.
Pain threshold
e least experience of pain which a subject can
recognise. It should be noted the definition does
not refer to the least stimulus intensity at which
a subject perceives pain. e difference here is
the present definition centres around the subject’s
experience, rather than the stimulus, which is an
external event.
Pain tolerance level
e greatest level of pain which a subject is prepared
to tolerate. As with pain threshold, this is a subjective
experience rather than a stimulus level.
https://t.me/medicina_free
Neuropathic Pain 237
Paraesthesia
An abnormal sensation, whether spontaneous or
evoked.
Allodynia, hyperalgesia and hyperpathia are three
closely related yet different terms that tend to cause
a lot of confusion. Table 15.01 summarises the
differences in the three conditions.
Neuropathic and nociceptive
pain
In the traditional concept of pain, pain is initiated
by thermal, mechanical or chemical stimulation
of nociceptors. e pain that results is thus called
nociceptive pain. However, neuropathic pain
may occur without any stimulation. Spontaneous
pain is frequently experienced by patients with
neuropathic pain. Whether spontaneous or evoked,
neuropathic pain may occur without activation
of the nociceptors. e various mechanisms that
may initiate pain without nociceptor activation
are detailed in the pathophysiology section below.
Due to these unique mechanisms of pain initiation,
the character and quality of the pain sensation
in patients with neuropathic pain is often quite
different from that of those with nociceptive pain.
How patients with neuropathic pain respond to
drugs is also quite different.
e word “neuropathic” defines the presence of
neurological dysfunction or pathology, whereas
nociceptive pain occurs with an intact nervous
system functioning normally. So, although pain is
the common presentation in both neuropathic and
nociceptive pain, these two conditions are really
quite different diseases.
e former term for neuropathic pain was
neurogenic pain, and was originally introduced
to differentiate neuropathic pain from nociceptive
pain. e newer term, neuropathic pain, still serves
this purpose. It must be pointed out, however, that
these two mechanisms are not mutually exclusive
and frequently co-exist in a chronic pain patient.
Epidemiology
Neuropathic pain is a very common chronic pain
condition. A recent survey in the UK found an
8% prevalence of chronic neuropathic pain in
the general population [82]. In another survey of
primary care physicians in the UK, postherpetic
neuralgia, trigeminal neuralgia and diabetic
neuropathy were the top three neuropathic pain
conditions managed by primary care physicians.
e incidence of these conditions is 40, 27 and
15 per 100,000 person years respectively [30]. In
patients with chronic low back pain, it has been
found that more than 50% have a predominantly
neuropathic pain [38].
In hospitalised patients, neuropathic pain is
frequently found in patients with cancer pain and
in diabetic patients. More than one-third of cancer
patients suffer from neuropathic pain or chronic
pain with a neuropathic component [17, 40].
Neuropathic pain in cancer patients may result
from destruction or invasion of nerves by tumour,
or as a complication of chemotherapy, irradiation
or surgery. In diabetics, more than one-quarter
of patients with type 2 diabetes has neuropathic
pain resulting from diabetic peripheral neuropathy
[15].
Table 15.01 Comparison of allodynia, hyperalgesia and hyperpathia
Allodynia Hyperalgesia Hyperpathia
Mode of stimulus Not painful Painful Painful or not painful,
characteristically repetitive
Mode of response Pain Pain Pain
Threshold Decreased Normal Increased
Response Not increased Increased Increased
Dysaesthesia is a subset of paraesthesia. Whereas paraesthesia includes all abnormal sensations,
dysaesthesia refers to those which are unpleasant.
https://t.me/medicina_free
238 Kwok Fu Jacobus NG
Pathophysiology
Neuropathic pain is not a homogenous clinical
entity; there are many varied aetiologies. e
pathophysiology of neuropathic pain is equally
diverse and complex. For ease of understanding,
the pathophysiological mechanisms can be
conceptualised as consisting of peripheral
disturbances resulting in abnormal signal initiation
and/or transmission; and central disturbances
resulting in abnormal signal processing, or
abnormal excitability [59]. Peripheral and central
disturbances frequently contribute in varying
extents to the neuropathic pain syndrome seen in a
particular patient.
Peripheral disturbances
Ectopic nerve impulse generation
Normally, impulses originate from receptors and
are transmitted along axons. In dysfunctional nerve
fibres, impulses may originate from places other than
the receptors, e.g. from axons themselves. ese are
ectopic impulses [29, 60, 91]. e proximal stump
of an injured axon (neuroma) is one common
area where such ectopic impulses originate [87].
Myelinated sensory fibres are most susceptible
to this phenomenon and, therefore, conditions
involving ectopic impulse generation frequently
show paraesthesia [10]. ese ectopic foci may also
multiply nerve impulses normally triggered by the
gentle stimulation of the normal terminals of these
myelinated sensory fibres, giving rise the symptom
of allodynia [20]. ese foci are also susceptible to
increased discharge with direct pressure over the
dysfunctional axon, which is the basis for clinical
signs such as Tinel’s. Injury to peripheral axons
may also cause ectopic impulse generation from
the dorsal root ganglion cells directly [37, 56, 86].
Lastly, ectopic impulses can also be generated from
damaged neurons in the central nervous system.
is is one of the underlying mechanisms for
“central pain” and is described below.
Increased expression of voltage-gated sodium
channels is the most important mechanism
underlying ectopic impulse generation. Both an
increased number of these sodium channels as well
as increased expression of the mRNA encoding
these channels [21, 42] have been demonstrated.
ese are particularly abundant at a neuroma
formed by C-fibre sprouts after nerve injury.
Cross excitation
A pain producing mechanism which is closely
related to ectopic impulse generation is cross
excitation between neurons. ere are at least two
forms of cross excitation. First, as neurons start
to regenerate after injury, new connections can
develop between adjacent neurons which were
previously unconnected. is development of new
connections between neurons which were physically
close to each other is referred to as “ephapses” or
“ephaptic cross talk” [91]. Second, even physically
distant neurons can develop novel connections after
nerve injury, as the central connection at spinal
cord level may be altered. For instance, myelinated
axons which normally terminate in laminae III
and IV have been shown to sprout into lamina II,
thereby creating abnormal connections and cross
excitation of nociceptive afferents [91].
e loss of myelination following nerve injury or
in demyelinating diseases such as multiple sclerosis
contributes importantly to the development of
cross excitation. Demyelination disrupts the
“insulation” between adjacent nerves, which is
normally provided by the intact myelin sheath.
Frequently, new nerves that sprout after injury are
also myelin deficient, favouring the development
of cross talk. As with many other processes in the
body involving tissue remodelling, nerve sprouting
following injury and the subsequent development
of new connections and ephapses is dependent
on matrix metalloproteinase (MMP) activity.
Remodelling following nerve injury is dependent
on membrane-type 5 MMP (or MMP-24) and
both sprouting and allodynia have been shown to
be absent in MMP-24 knockout mice [43].
Nociceptor sensitisation
Nociceptors become sensitised after injury and
respond with increased magnitude to adequate
stimuli. Cooling usually reverses at least partially
this sensitisation. A particular form of sensitisation
is sensitisation of nociceptors to circulating and
locally released catecholamines. It has been found
that there are increased numbers of adrenergic
receptors on some previously injured neurons,
and this may be the basis for the phenomenon
of sympathetically maintained pain [13, 65,
73]. Immune and inflammatory mediators
are also important in nociceptor sensitisation.
Prostaglandins, histamine, bradykinin, adenosine,
adenosine triphospahte, serotonin, the cytokines
https://t.me/medicina_free
Neuropathic Pain 239
IL-1 and tumour necrosis factor have all been
implicated in nociceptor sensitisation.
Although such a large number of mediators may
be involved in the development of nociceptor
sensitisation, all these mechanisms suggest that
peripheral senisitisation is closely related to the
tissue inflammatory response. e vanilloid
receptor-1 (TRP-V1) is a key player in nociceptor
sensitisation, as inflammatory thermal hyperalgesia
has been shown to be absent in TRP-V1 deficient
mice [16]. In addition to initiating ectopic impulses,
up-regulation of voltage-gated sodium channels
may also contribute to peripheral nociceptor
sensitisation [76].
Release of nociceptor input
e “gate” theory established the inhibitory role of
large calibre myelinated nerve fibres in the afferent
nociceptive pathway [51]. Damage to these large
calibre fibres should therefore release this inhibition
and be responsible for some neuropathic pain. is
mechanism may be contributing to phenomena
such as hyperalgesia, but it is unlikely to be the
mechanism behind spontaneous pain as there is no
evidence that primary nociceptive afferents have
basal ongoing inputs [58].
e major neurotransmitters involved in the
“gating” mechanism are gamma aminobutyric acid
(GABA) and glycine. Both the secretion of GABA
and the number or function of GABA receptors
may be decreased after nerve injury [34, 54] and
contribute to the release of inhibitory modulation
of peripheral nociceptive input.
Central disturbances
Central sensitisation
Besides sensitisation of primary nociceptors,
sensitisation can also occur in the dorsal horn of the
spinal cord [14]. is is called central sensitisation
and is the basis for secondary hyperalgesia — the
widening of the hyperalgesic area around the
site of the injury. e mechanism of central
sensitisation is now fairly well established [92].
Brief afferent inputs from nociceptors activate
N-methyl-D-aspartate (NMDA) receptors via
release of glutamate and other neuropeptides.
Activated NMDA receptors cause calcium influx
[92], which then activate protein kinase [4, 47]
and produce changes in the neurons affected.
Calcium influx also occurs through the voltage-
gated calcium channels as a consequence of the
more prolonged depolarisation of the dorsal
horn neuron subsequent to NMDA activation
as well as continuous afferent nociceptive input.
Raised intracellular calcium concentration may
induce phosphorylation of ion channels and
altered gene expression [11], causing changes
in the excitability of these dorsal horn neurons.
N-methyl-D-aspartate receptor activation
may also result in selective death of inhibitory
neurons, compounding the hyperexcitability
phenomenon.
A close relationship has again been found between
the inflammatory response and central sensitisation.
Glial cells secrete mediators such as interleukins,
tumour necrosis factor, neurotrophins and free
radicals. ese have all been shown to contribute
to sensitisation of spinal neurons [53]. Intrathecal
injection of the IL-1-beta receptor antagonist has
been shown to reduce central sensitisation in rats
[72]. Central up-regulation of cyclo-oxygenase
(COX) receptors, particularly COX-2 and COX-3,
also plays an important role in central sensitisation
[2]. Adenosine triphosphate and its receptor,
the purinergic P2X3 receptor, also add to the
development of central sensitisation [5].
Because of the many varied mediators, receptors
and mechanisms involved in central sensitisation,
it is highly unlikely that therapeutic interventions
targeting a single receptor or mechanism will
prevent or abolish central sensitisation totally.
Central sensitisation is responsible for accentuating
the pain initialised from ectopic foci or sensitised
nociceptors as described above. Natural input from
large calibre myelinated fibres may also produce
pain due to central sensitisation.
Clinical Presentation and
Management
Patients with neuropathic pain classically use
descriptors such as shooting, burning, tingling,
electrical or lancinating to describe their pain. e
pain may be constant or paroxysmal. Paroxysmal
pain may be spontaneous or triggered. Other points
in the clinical history supporting the diagnosis of
neuropathic pain may include a history of nervous
https://t.me/medicina_free
Соседние файлы в папке Библиотека им академика М.И. Перельмана