Neuropathic Pain

Pain Pathophysiology
• Nociceptive pain
• Neuropathic pain
 Nociceptive Pain
• Sensitization and activation of “healthy”
nociceptor endings and recruitment of
“silent” nociceptors
• “Soup” of inflammatory algogenic agents,
such as protons, prostaglandins,
bradykinin, serotonin, adenosine,
histamine, cytokines
Mechanisms of Neuropathic Pain
• Noninflammatory states
• Inflammatory states
Pathophysiology of Neuropathic Pain
• Ectopic activity in the peripheral pathways,
including axons and DRG
• CNS mechanisms
Neuropathic Pain: Central Mechanisms
Peripheral neuropathic events can be
complicated by temporary or long-term
CNS changes, such as central sensitization
and then reorganization of the pain
pathways at the dorsal horn level
 Neuropathic Pain and SMP
• Some neuropathic pains are sustained, at least in
part, by sympathetic efferent activity
– SMP
• Expression of alpha-adrenergic receptors on
injured C-fibers may be a relevant mechanism of
SMP, but others are possible
• Clinical findings consistent with CRPS signal an
increased likelihood of SMP
 Nociceptive
Nociceptive Pain
Pain Neuropathic
Neuropathic Pain
Pain
PNS
peripheral
nervous Peripheral
Peripheral PNS
system sensitization
sensitization
“Healthy”
“Healthy” Abnormal
Abnormal
nociceptors
nociceptors nociceptors
nociceptors
CNS Normal C
Central
entral CNS
central Normal
nervous transmission
transmission
system sensitization
sensitization
Central
Central
reorganization
reorganization
Physiologic Pathologic
state Pathologic
state
state
Pappagallo M. 2001.
 Neuropathic Pain
• Diverse syndromes with uncertain
classification
• Mononeuropathies and polyneuropathies
• CRPS
• Deafferentation syndromes, including
central pain
 Painful Mononeuropathies and
Polyneuropathies
• Diabetic neuropathies
• Entrapment neuropathies
• Shingles and postherpetic neuralgia
• Trigeminal and other CNS neuralgias
• HIV-related neuropathy
• Neuropathy due to malignant disease
• Neuropathy due to rheumatoid arthritis, systemic
lupus erythematosus, Sjögren’s syndrome
• Idiopathic distal small-fiber neuropathy
 Painful Mononeuropathies and
Polyneuropathies
• Neuropathies due to toxins: arsenic, thallium,
alcohol, vincristine, cisplatinum,
didioxynucleosides
• Amyloid polyneuropathy: primary and familial
• Neuropathies with monoclonal proteins
• Vasculitic neuropathy
• Neuropathy associated with Guillain-Barré
syndrome
• Neuropathy associated with Fabry’s disease
Neuropathic Pain: Clinical Assessment
• A comprehensive diagnostic approach to
patients affected by neuropathic pain
– Medical history
– Examinations: general, neurologic, regional
– Diagnostic workup: imaging studies,
laboratory tests, nerve/skin biopsies,
electromyography/nerve-conduction velocity
(EMG-NCV) studies, selected nerve blocks
 Medical History
Ask patient about complaints suggestive of
• Neurologic deficits: persistent numbness
in a body area or limb-weakness, for
example, tripping episodes, inability to
open jars
• Neurologic sensory dysfunction: touch-
evoked pain, intermittent abnormal
sensations, spontaneous burning and
shooting pains
Neurologic and Regional Examinations
In patients with neuropathic pain,
examination should focus on the anatomic
pattern and localization of the abnormal
sensory symptoms and neurologic deficits
Neuropathic Pain: Clinical Characteristics

• Burning, shooting, electrical-quality pain

• May be aching, throbbing, sharp
• Neuropathic sensations: dysesthesias,
paresthesias
 Neuropathic Sensations
• Paresthesias: abnormal; spontaneous,
intermittent, painless
• Dysesthesias: abnormal; spontaneous or
touch-evoked, unpleasant
Neuropathic Pain: Evoked Dysesthesias
• Allodynia: pain elicited by a nonnoxious stimulus
(clothing, air movement, touch)
– Mechanical (induced by light pressure)
– Thermal (induced by a nonpainful cold or warm
stimulus)
• Hyperalgesia: exaggerated pain response to a
mildly noxious (mechanical or thermal) stimulus
• Hyperpathia: delayed and explosive pain
response to a noxious stimulus
 Primary Hyperalgesia
• Present in the primary zone, at the location
of injury
• Characterized by pinprick hyperalgesia +
warm and heat hyperalgesia + static
mechanical allodynia (tenderness)
• Indicative of PNS sensitization
 Secondary Hyperalgesia
• Present in the zone surrounding an injury
• Characterized by dynamic mechanical
allodynia + cold hyperalgesia
• Indicative of CNS sensitization
 Diagnostic Workup: Lab Tests
• Complete blood cell count with differential,
erythrocyte sedimentation rate, chemistry profile
• Thyroid-function tests, vitamin B12 and folate, fasting
blood sugar, and glycosylated hemoglobin
• Serum protein electrophoresis with immunofixation
• Lyme titers, hepatitis B and C, HIV screening
• Antinuclear antibodies, rheumatoid factor, Sjögren’s
titers (SS-A, SS-B), antineutrophil cytoplasmic
antibody
 Diagnostic Workup: Lab Tests
• Cryoglobulins
• Antisulfatide antibody titers, anti-HU titers
• Heavy metals serum and urine screens
• Cerebrospinal fluid study for demyelinating
diseases and meningeal carcinomatosis
Diagnostic Workup: Electrophysiologic
Studies

EMG-NCV and QST

• To localize pain-generator/nerve or root
lesion
• To rule out
– Axonal vs focal segmental demyelination
– Underlying small-fiber or mixed
polyneuropathy
 Biopsies
• Nerve (eg, sural nerve): to diagnose
vasculitis, amyloidosis, sarcoidosis, etc.
• Skin: to evaluate density of unmyelinated
fibers within dermis and epidermis
 Neuropathic Pain: Management
• Pharmacotherapy
– Nonopioid
– Opioid
– Adjuvant analgesics
• Interventional
– Neural blockade (eg, sympathetic nerve blocks)
– Neurostimulatory techniques (eg, spinal cord
stimulation)
– Intraspinal infusion
 Neuropathic Pain:
Pharmacologic Therapies

• Gabapentin, carbamazepine, lamotrigine,

and newer AEDs
• Antidepressants
• Opioid analgesics
• Lidocaine (transdermal, intravenous [IV]),
mexiletine
• Alpha-2 adrenergic agonists
 Neuropathic Pain: Management
• Rehabilitative approaches
• Psychologic interventions
 Conclusions
• More effective medical therapies for
neuropathic pain are becoming available
and physicians should use them to limit
unnecessary suffering, with the ultimate
goal of significantly improving patients’
quality of life