Transcript Channels, Receptors, Neurotransmitters and the

Neuropathic Pain Assessment and Treatment
with a Review of Pathways, Channels, and
Receptors
Donna Bloodworth, MD
Baylor College of Medicine, Houston
October 3 2015, AAPMR, Boston, MA
Disclosures
• Disclosures: None
• Off label discussion of tricyclic
antidepressants, anti-epileptics and other
medications will occur and I have tried to
highlight any off label drug-mention in bold
and red
• ** is a must-read article
Goals
• Ascending nocioceptive pathways and sensitization of first
order neurons
• Descending pathways of nocioceptive: modulation
• Immune system and Inflammatory Cascade and how
inflammation sensitizes first order neurons
• Wind up(sensitization of second and higher nuerons in the
the CNS)
• Assessment of neuropathic pain
• FDA approved treatment for neuropathic pain
• Cochrane systematic reviews of off-label treatments for
neuropathic pain
Ascending Pathways of Nocioception,
Neospinothalamic tract and Paleospinothalamic tract
**Dafny, N Chapter 7: Pain tracts and Sources, Neuroscience on line @ nba.uth.tmc.edu
Thalamus
Hippocampus
A-delta
C-fibers
VPL discriminatory function
to
Sensory Cortex
3d order
neurons
Lateral spinothalamic
Tract (Anterolateral
Funiculus)
Neo: Dorsal horn, lamina 1 (marginal
zone )
Paleo: To DH lamina -2 (substantia
gelatinosa) 2nd order neurons from lam
2 to lam 4 to 8- wide dynamic range
neurons
Anterior Spinothalamic tract
to reticular formation, to
tectum and to thalamus
How Nocioception becomes Pain
•
Gudin JA. Expanding our understanding of
central sensitization. Medscape neurlopgy
2004;6(1)
• Nocioception without
tissue injury
• Stimulus transduced by
TRPV1, TRPA1, ATP/P2XP2Y, or ASIC
• Electrical impulses are
propagated through the
PNS to the CNS to the
primary sensory cortex
**TRPV1 Receptors , aka Vanilloid Receptors
Szallas A, Blumberg PM. Pain 68(1996): 195-208
• TRPV1 is activated by
capsaicin, other
resiniferatoxins , allylisothiocynate (wasabi) and
heat >42*C, and acidic
conditions (eg lactic acid in
heart attack)
• TRPV1 includes detecting
and regulating body
temperature
• Attempts to target TRPV1
pharmacologically result in
hyperthermia to the test
subject2
Marchand F et al. Role of the
Immune System in Chronic Pain.
Nature Reviews-Neuroscience.
2005; 6:521-532
Types of nerve channels and receptors
Wang W et al. Are Voltage-gated Na channels on the DRG involved in the development of neuropathic pain? Molecular Pain 2011
7:16-25
• Channels and receptors
have at least 3 functions:
• TRANSDUCTION-turn
stimuli into electric
impulses
• CONDUCTION –propagate
action potentials
• MODULATION
• TRP channels, ATP sensitive
receptors, voltage-gated Na+
channels, Acid-sensing
channels
• Sodium and potassium
channels
• Voltage-gated Ca++ channels
and glutamate receptors
Voltage Gated Sodium Channels Nav 1.1 -1.9
***LiuM Wood
JN Roles of Sodium channels in Nocioception: Implications for mechanisms in
Neuropathic pain. Pain Med 12(S3) 2011 S93-99
• Nav Subunits differ in
Two beta subunits
Four alpha subunits
– tissue expression,
• Nav1.3 neonatal and nerve
injury
• Nav1.4 skeletal muscle
• Nav1.5 Cardiac, GI
– activation kinetics,
• Nav 1.1 -1.7 rapidly inactivating
• Nav 1.8 slowly inactivating
• Nav 1.9 persistently active
– sensitivity to blockade by
puffer fish toxin, tetrodotoxin
Lipid
membrane
• Nav 1.8 and 1.9 are resistant
• Alpha subunits-ion passage
• The beta subunit: anchor and
localization
Sodium Pore
Drug inactivation
binding site
Voltage Gated Sodium Channels Nav 1.1 -1.9
LiuM Wood JN Roles of Sodium channels in Nocioception: Implications for mechanisms in
Neuropathic pain. Pain Med 12(S3) 2011 S93-99
• Subtypes Nav 1.7, 1.8, 1.9 are
associated with specific types of
pain
– Nav 1.7 acute mechanical and
inflammatory pain; links normal
sensation to pain
– Nav 1.8 visceral pain
– Nav 1.9 inflammatory pain
• Inflammatory mediators
depolarize cell membranes and
voltage gated Na channels are
activated
• Lidocaine, Carbamazepine and
also have Na channel blocking
function
• Nav 1.7 sympathetic, peripheral
sensory and olfactory epithelia
• Nav 1.8 small-diameter
peripheral sensory neurons;
expressed in 85 % of
nocioceptors; undetectable in the
CNS; can generate and transmit
nocioceptive information in cold
temperatures
• Nav 1.9 small diameter neurons;
highly co-localized with TRPV1
P2X3 and b2 bradykinin receptor
and show increased activity to
secondary messengers
Leukotriene
Nocioceptive
terminals
TRPV1 Channel
Prostaglandin receptor
Bradykinin Receptor
Marchand F et al. Role of the Immune System in
Chronic Pain. Nature Reviews-Neuroscience.
2005; 6:521-532
Histamine receptor
Interleukin-6 receptor
Bradykinin opens ion channels
Bradykinin sensitizes TRPV1 channels and results in
heat hyperalgesia
Interleukin 1B receptor
TNF Alpha receptor
Na
Prostaglandin activates CAMP which increases Na+
currents and sensitizes neurons
Na
NGF phosphorylates and sensitizes TRPV1 and results in
heat hyperalgesia
NGF modulates gene expression and long term sensitization of
TRPV1, P2X3, Substance p and Nav 1.8
Leukotriene opens DRG ( Dorsal root ganglion) TRPV1 channels
If we block TNF or are a mouse without IL receptors
We have less mechanical hyperalgesia
CAMP
NGF receptor
Immune system
https://en.wikipedia.org/wiki/Immune_system
Innate Immune System (IIS)
Adaptive Immune System (AIS)
•
• Pathogen and antigen
specific response
• Lag time between exposure
and maximal response
• T and B cells
• Exposure leads to
immunological memory
Response is non-specific
–
•
•
•
•
•
Surface barriers and forces: Wax, enzymes,
pH, secretions, competitive flora, sneeze
Exposure leads to immediate maximal
response
Cell-mediated and humoral
components
No immunological memory
Found in nearly all forms of life
Complement is the major humoral
component of the IIS
–
–
–
20 different protease proteins attacks the
carbohydrates on surfaces of foreign cells
It “complements” antibodies
Positive feedback catalytic cascade
Cellular Components of
IIS
Tissue
Eo
Phagocytes
•
• Neutrophils
–
–
–
•
Neutrophils (Leukotrienes)
Macropahges (NO, IL)
Dendritic cells
In connective tissues and mucous membranes
regulating the inflammatory response
– Eosinophils and basophils
•
–
Mast cells (Pg, His)
•
•
asthma
Allergy and anaphylaxis
Natural killer cells (IFN)
–
–
–
attack and destroy tumor cells
cells that have been infected by viruses
I.e. attack compromised self cells “missing
self” lacking Major Histocompatibility
Complex (MHC)
Blood vessel
Baso
Leukocytes
Phagocytes
Dendritic
PG
His
Mast
IL Pg
NO
Compl
Macro
– in the bloodstream
– migrate in response to
chemokines
• Macrophages
– reside in tissue
– make complement and IL
– Activate the AIS
• Dendritic cells
– reside in epithelial tissues and
linings
– Present Antigens to T-cells of
the AIS
Tissue Injury and Inflammatory
Cascade
• Rubror, calor, tumor,
dolor
• redness, heat, swelling,
and pain
• After injury or infection
• initiated by resident
immune cells present in
the involved tissue
• Requires constant
stimulation
– Bradykinin ½ life 17
seconds
•
•
•
Vasodilation then Heat then swelling: Bk,
His,Pg,NO
Increased pain; Bk, Pg, NO
Cytokines: attract other cells (IL, C omplement 3
and 5 IFN, Lk-4 )
TRPV
Na
PG NO
Hist Bk
NGF
BK
Mast
cell
•
Macro
phage
IL
C3,
IFN,
C5,
Lk-4
Meanwhile Bk opens TRPV ion channels
and Pg increases Na+ currents in
nocioceptors
Tissue Injury and peripheral (and central) sensitization
Evidence for a central component of post-injury pain hypersensitivity.
Woolf, Clifford J. Nature, Vol 306(5944), Dec 1983, 686-688
• Each dot is an action
potential
• A low threshold stimulus
was applied to the sural
nerve
• Characterization of
Peripheral Sensitization
• #1:Reduced threshold of
activation
• # 2 Amplification of outputs
)
(Latremoliere and Woolf
– Depolarization event: leaky
ion channels; increased
currents
Inflammatory Pain and the
Effect on Neurons
Marchand F et al. Role of the Immune System in
Chronic Pain. Nature Reviews-Neuroscience. 2005;
6:521-532
Khan N, Smith MT. Review Neurotrophins and
Neuropathic Pain: Role in Pathobiology Molecules2015,
20(6), 10657-10688
Gudin JA. Expanding our understanding of central
sensitization. Medscape neurlogy 2004;6(1)
•Opens ion channels; increase ion currents; increase
firing rate; depolarize:
•Leukotriene
•Bradykinin
•Prostaglandin
•TNF
•NGF
•Modulates gene expression, increase expression of
channels or receptors and long term sensitization
(TRPv1, P2X3, Nav1.8 and SubstanceP
•NGF (Nerve Growth Factor)
•TNF IL-1B
•Causes Schwann cells to produce NO Pg and NGF
•Cellular invasion: macrophages and T-cells invade
the SC in 3 to 14 days after L5 root transection
Dorsal Horn Wind Up: Central Sensitization
Latremoliere A Woolf CJ. Central Sensitization: A generator of pain hypersensitivity by central
neuronal plasticity J Pain 2009 10(9):95-926 Figure 6 from Latremoiere
•
•
Red
Neighboring
C fibers
usually OFF;
on in wind
up
C-fiber
ON
A-b fiber
usually OFF;
on in wind
up
Output: Pain Information
Phase 1: Depolarization and
phosphorylation
Phase 2: Later long lasting
transcription dependent phase gene
expression/ protein synthesis
– Spontaneous pain (ectopy)
– Pain from innocuous
stimuli and nonnocioceptive pathways are
co-opted (allodynia)
– Exaggerated and
prolonged pain to noxious
stimuli (hyperpathia)
– Pain spreads beyond the
site of injury (secondary
hyperalgesia)
Dorsal Horn Wind Up
Latremoliere A Woolf CJ. Central Sensitization: A generator of pain hypersensitivity by central neuronal plasticity J Pain
2009 10(9):95-926
**
• The stimulus must be intense repeated and
sustained (>10 secs)
• Muscle and joint stimuli produce more central
sensitization than skin stimuli
• Treatment is targeted at the CNS
• fMRi suggests evidence of cerebral central
sensitization
The c- and a-delta fibers enter the spinal cord in the dorsal horn
in laminas one, two, and five via Lissauer’s tract
**Carr DB, Goudas LC. Acute Pain. The Lancet 353: 2051-8,1999
FDA –approved treatments:
duloxetine (excellent efficacy)
Opioids (some efficacy)
Lamina 1-Marginal Layer
Lissauer’s Tract
Lamina 2- Substanstia Gelatinosa
Lamina 3 to 5; Nucleus Proprius
Not FDA approved :
Baclofen no information
Benzodiazepines –no
efficacy
Clonidine –limited efficacy
Ketamine –lack of evidence
Descending pathways of nocioceptive modulation,
Fields HL, Busbaum AI. Et al NUCLEUS RAPHE MAGNUS INHIBITION OF SPINAL CORD DORSAL
HORN NEURONS Brain Res., 126 (1977) 441–453
2 Xu M Et al. NMDA receptor-mediated activation of medullary pro-nocioceptive neurons is required for
secondary thermal hyperalgesia Pain 2007 127(3) : 253-262
3 S.V. Coutinho et al Role of glutamate receptors and nitric oxide in the rostral ventromedial
medulla in visceral hyperalgesia Pain 78 (1998) 59–69
PeriAqueductal Grey, opioid
receptor rich
FDA approved treatments in
include duloxetine and opioids
Amitriptyline: poor evidence
(Cochrane)
Rostro-ventral Medulla, 30 %
serotonergic receptors
Dorsolat. Pontine Tegmentum,
noradrenergic, A2 adrenergic
receptors
NMDA receptors exist in the
RVM and express Glutamate
and NO. NDMA agonists
increase hyperalgesia .2, 3
ASSESSMENT
Painful Peripheral Neuropathies
**Marchettini P, Lacerenza M Mauri E etal . Current Neuropharmacology 2006 4: 175-181
• Dysesthesia
– Large fiber stimtingling,
buzzing
– Small fiber stimburning, pins
and needles
• Allodynia (central)
• Hyperalgesia (peripheral)
• Small fiber neuropathy:
Systemic Autonomic
dysfunction (Hoitsma)
• complex regional pain
syndrome : Localized Sudo
(sweating) motor and
vasomotor instability
• Criteria
• There must be nerve injury
• Widespread pain not o/w
explained
• Burning pain
• Attacks of pain without
provocation
(dysesthesia/paresthesia)
–
Campbell JN Meyer RA Mechanisms of neuropathic
pain Neuron 2006 52 (1): 77-92
• Evidence of a sensory deficit
• Pain to light stroking
(allodynia)
Guidelines- Evaluation neuropathic pain
Cruccua G, Sommera C., Anandd P et al. EFNS guidelines on neuropathic pain assessment: revised 2009
European Journal of Neurology 2010, 17: 1010–1018
Haanpää M. Attal N, Backonja M et al. NeuPSIG guidelines on neuropathic pain assessment. Pain. 2011
Jan;152(1):14-27. doi: 10.1016/j.pain.2010.07.031. Epub 2010 Sep 19.
• DO a good H&P
• Screening tools
– lack of specificity of the MPQ for NP
– LANSS clinical diagnosis, its sensitivity and specificity
range 82–91% and 80–94%, respectively
– Neuropathic Pain Questionnaire (NPQ) 66% sensitivity
and 74% specificity compared to clinical diagnosis
– The Neuropathic Pain Scale (NPS) lacks several pain
qualities commonly seen in NP and is fully validated
only in multiple sclerosis
Leeds Assessment of Neuropathic
Signs and Symptoms
• Does your pain feel like strange, unpleasant sensations in your skin?
Words like pricking, tingling, pins and needles might describe these
sensations (yes-5 points)
• Does your pain make the skin in the painful area look different from
normal? Words like mottled or looking more red or pink might describe
the appearance. (yes-5 points)
• Does your pain make the affected skin abnormally sensitive to touch?
Getting unpleasant sensations when lightly stroking the skin, or getting
pain when wearing tight clothes might describe the abnormal sensitivity
• (yes-3 points)
• Does your pain come on suddenly and in bursts for no apparent reason
when you’re still? Words like electric shocks, jumping and bursting
describe these sensations. (yes-2 points)
• Does your pain feel as if the skin temperature in the painful area has
changed abnormally? Words like hot and burning describe these
sensations (yes-1 point)
LANSS
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B. SENSORY TESTING Skin sensitivity can be examined by comparing the painful area with a
contralateral or adjacent non-painful area for the presence of allodynia and an altered pinprick threshold (PPT).
1. Allodynia Examine the response to lightly stroking cotton wool across the non-painful area
and then the painful area. If normal sensations are experienced in the non-painful site, but
pain or unpleasant sensations (tingling, nausea) are experienced in the painful area when
stroking, allodynia is present.
a) NO – Normal sensations in both areas
................................................................................................................. (0)
b) YES – Allodynia in painful area only
...................................................................................................................... (5)
2. Altered pin-prick threshold Determine the pin-prick threshold by comparing the response
to a 23-gauge (blue) needle mounted inside a 2ml syringe barrel placed gently onto the skin
in a non-painful and then painful areas. If a sharp pin prick is felt in the non-painful area, but
a different sensation is experienced in the painful area, eg. none/ blunt only (raised PPT) or a
very painful sensation (lowered PPT), an altered PPT is present. If a pinprick is not felt in
either area, mount the syringe onto the needle to increase the weight and repeat.
a) NO – Equal sensation in both areas
..................................................................................................................... (0) b) YES – Altered
PPT in painful area
......................................................................................................................... (3) SCORING: Add
values in parentheses for sensory description and examination findings to obtain overall
score. TOTAL SCORE (maximum 24)
........................................................................................................................................ If score
< 12, neuropathic mechanisms are unlikely to be contributing to the patient’s pain. If score ≥
12, neuropathic mechanisms are likely to be contributing to the patient’s pain
(Evaluation) Guidelines-NeupSIG (neuropathic pain SIG of IASP)
Haanpää M. Attal N, Backonja M et al. NeuPSIG guidelines on neuropathic pain assessment. Pain. 2011
Jan;152(1):14-27. doi: 10.1016/j.pain.2010.07.031. Epub 2010 Sep 19.
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Sensory examination (i.e., pinprick, heat, cold and tactile stimuli);
Particularly discriminant
– hypoalgesia to pinprick,
– hypoesthesia to tactile stimuli,
– allodynia to brush and cold,
– temporal summation
– more sensitive than QST for Sm Fiber N.
•
Allodynia: to brush, cold and heat and temporal summation to tactile stimuli,
higher frequency in patients with neuropathic pain.
Allodynia to pressure is not specific
•
Guidelines-EFNS 2010
Lauria G1, Hsieh ST, Johansson O et al. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on the use of skin biopsy in the
diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society.
Eur J Neurol. 2010 Jul;17(7):903-12, e44-9. doi: 10.1111/j.1468-1331.2010.03023.x.
• Distal leg 3 mm skin biopsy with quantification of the linear density of
intraepidermal nerve fibers (IENF), using generally agreed upon
counting rules, is a reliable and efficient technique to assess the
diagnosis of SFN (Recommendation Level A).
• Reference values exist for bright-field immunohistochemistry
(Recommendation Level A) but not for other techniques.
• Skin biopsy samples should be matched for age.
• Training experience and quality control are tantamount.
• Procedures to quantify other subepidermal structures have yet to be
standardized
• In experienced centres, the sensitivity and specificity of IENFD are 88%
(higher than that of QST and LEPs for SFN)
• + skin biopsy doubles the responsiveness to neuropathic pain
medications vs persons negative bx
What’s covered
•
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11100 1st puncture code
11101 2d puncture code
356.9 neuropathy; 729.2 nerve pain
Insurance may pay for diagnostic EFND
Not for “therapeutic follow up” EFND
Insurance considers QST investigational
Skin Biopsy
• 1 Saperstein DS, Levine TD. (Proprietary interest) Diagnosing small fiber
neuropathy through the use of skin biopsy. Practical neurology 2009: 3740
• 2 Levine TD, Saperstein DS. (Proprietary interest) The most sensitive inoffice test for diagnosing early diabetic and pre-diabetic neuropathy.
Unpublished; www.corinthianreferencelab.com
• 3 Levine TD, Saperstein DS. (Proprietary interest) Diagnosis of RSD/CRPS
and Small fiber Neuropathy. Pain Medicine News March 2012
• 4 Hermann DN et al. Broadening the spectrum of controls for skin biopsy
in painful neuropathies . Muscle and Nerve 2010: 436-438.
• 5 Devigili G et al. doi:10.1093/brain/awn093 Brain (2008), 131, 1912-1925
• Cruccua G, Sommera C., Anandd P et al. EFNS guidelines on neuropathic
pain assessment: revised 2009 European Journal of Neurology 2010, 17:
1010–1018\
• Oaklander AL et al. Evidence of focal small fiber axonal degenaration in
CRPS, type 1. Ann Neurol 2009: 15 (3):202-7
Clinical course of SFN
Devigili G et al. doi:10.1093/brain/awn093 Brain (2008), 131, 1912^1925
• pinprick and thermal hypoesthesia in about 50% patients,
• peripheral vascular autonomic dysfunction in about 70%
• Spontaneous pain dominated the clinical picture in most SFN
patients.
• Neuropathic pain intensity: SFN >>>large or mixed fiber
neuropathy
• Pain intensity does not correlate with IENF density.
• Etiology of SFN is unknown in 41.8% of patients.
• At 2 yr follow up, 13% of SFN patients showed the
involvement of large nerve fibers
• Spontaneous remission 10.9% of SFN patients,
• worsened in 30.4% of SFN patients.
Small Fiber Neuropathy History Tools
Parambil JG et al Efficacy of IVIG fir SFN associated with Sarcoid Resp Med 2011 105:101-105
• Hoitsma criteria: “gold standard” temperature
threshold testing
• Tingling
• Can’t swallow
• Hands /feet feel cold
• Trouble urinating/constipation
• Dry eyes
• Dizziness/ orthostasis
• Palpitations
TREATMENT
Gabapentin in the management of reflex sympathetic dystrophy
(Off label use of gabapentin)
Mellick GA Mellicy L Mellick LB
Journal of Pain and Symptom Management 10(4) , May 1995, Pages 265–266
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Off label use of gabapentin
Letter to the editor
9 patients with RSD
4 UE, 4LE, 1 four limb
Failed SGB or LSB and other therapies
Onset 2 to 5 yrs
Doses 900 to 2400 mg/day
Results 8 excellent (VNS <3) and 1 good VNS < 5
FDA Labeled medications for Neuropathic pain
(daily med.gov CPI accessed July 22, 2015)
Smith HS Drugs for Pain 2002 Philadelphia Hanley and Belfus
Smith HS Pappagallo M. Essential Pain Pharmacology Cambridge Press, NYC NY
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Duloxetine
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selective serotonin and norepinephrine
reuptake inhibitor
potent inhibitor of neuronal serotonin and
norepinephrine reuptake and a less potent
inhibitor of dopamine reuptake
Onset for pain relief 2 to 4 weeks
Pregabalin
–
–
–
binds with high affinity to the alpha2-delta
site (an auxiliary subunit of voltage-gated
calcium channels) in central nervous system
tissues
reduce calcium-dependent release of pronociceptive neurotransmitters in the spinal
cord, possibly by disrupting alpha2-delta
containing-calcium channel trafficking and/or
reducing calcium currents; thereby reduces
release SubP, glutamate and norepinephrine
interactions with descending noradrenergic
and serotonergic pathways originating from
the brainstem that modulate pain
transmission in the spinal cord
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Diabetic Peripheral Neuropathy
Fibromyalgia
Chronic MSK pain
Anxiety disorder
Major Depression
•
neuropathic pain associated with diabetic
peripheral neuropathy
Management of postherpetic neuralgia
Management of fibromyalgia
Management of neuropathic pain associated
with spinal cord injury
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FDA Labeled medications for Neuropathic pain
(daily med.gov CPI accessed July 22, 2015)
Smith HS Drugs for Pain 2002 Philadelphia Hanley and Belfus
Smith HS Pappagallo M. Essential Pain Pharmacology Cambridge Press, NYC NY
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Gabapentin
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gabapentin prevents allodynia and hyperalgesia
decreases pain-related responses after peripheral
inflammation (carrageenan footpad test
Gabapentin did not alter immediate pain-related
behaviors (rat tail flick test
it does not modify GABAA or GABAB radioligand
binding, it is not converted metabolically into GABA or
a GABA agonist, and it is not an inhibitor of GABA
uptake or degradation
gabapentin binding site in areas of rat brain including
neocortex and hippocampus. A high-affinity binding
protein in animal brain tissue has been identified as
an auxiliary subunit of voltage-activated calcium
channels
Carbamazepine
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Na+ channel blockade (Smith) particularly
spontaneous firing in hyperexcited C/A-delta fibers
reducing polysynaptic responses and blocking the
post-tetanic potentiation
depresses thalamic potential and bulbar and
polysynaptic reflexes
control the pain of trigeminal neuralgia. The
mechanism of action remains unknown.
•
Postherpetic Neuralgia
•
Trigeminal Neuralgia; “Beneficial results have also
been reported in glossopharyngeal neuralgia”
FDA Labeled medications for Neuropathic pain
(daily med.gov CPI accessed July 22, 2015)
• Capsaicin 8%
(Qutenza@)
– agonist for the transient receptor
potential vanilloid 1 receptor
(TRPV1
– causes an initial enhanced
stimulation of the TRPV1expressing cutaneous nociceptors
that may be associated with painful
sensations. This is followed by pain
relief thought to be mediated by a
reduction in TRPV1-expressing
nociceptive nerve endings
– reduced epidermal nerve fiber
density and minor changes in
cutaneous nociceptive function
(heat detection and sharp
sensation) were noted one week
after exposure that are reversible
•
management of neuropathic pain
associated with postherpetic neuralgia
Drugs for neuropathic pain
Kalso E. AldingtonDJ, Moore RA. Drugs for neuropathic pain BMJ 2013 347:7339
• Small studies, short studies and
studies with high drop out
overestimate effect
• Duloxetine is probably the most
effective drug for diabetic
neuropathy
• Pregabalin is probably the most
effective drug for treating PHN
(post herpetic neuralgia)
• Most off label drugs including
TCAs show little or no good
evidence of efficacy –even in
combination
• NSAIDs and opioids have trivial
evidence of efficacy
(Woolf/Latremioliere disagree)
• Serious adr- carbamazepineStevens Johnson
• NNT (number needed to treat)
Best=lowest
• Implication is that only 15 to
25% of patients are helped
• Diabetic neuropathy
– 4 to 6 NNT
– duloxetine (60-120mg/d
– Gabapentin 1200 mg/d
• (off label for this dx)
– Pregabalin 600 mg /day
• PHN pregabalin
– 4 to 6 NNT
– 300 to 600 mg /day
Guidelines –AAN/AAPMR 2011
Evidence-based guideline: Treatment of painful diabetic neuropathy
Bril V, England L, Franklin GM et al [email protected]
doi: http:/​/​dx.​doi.​org/​10.​1212/​WNL.​0b013e3182166ebeNeurology May 17, 2011 vol. 76 no. 20 1758-1765
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Pregabalin is established as effective and should
be offered for relief of PDN (Level A).
Duloxetine probably effective and should be
considered for treatment of PDN (Level B)
Opioids(morphine sulfate, tramadol, and
oxycodone controlled-release), and capsaicin are
probably effective and should be considered for
treatment of PDN (Level B).
ALL OFF LABEL BELOW
Venlafaxine, amitriptyline, gabapentin, valproate
are probably effective and should be considered
for treatment of PDN (Level B).
Other treatments have less robust evidence or the
evidence is negative.
Effective treatments for PDN are available, but
many have side effects that limit their usefulness,
and few studies have sufficient information on
treatment effects on function and QOL.
• Pregabalin
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Four efficacy studies (3 Class
I and 1 Class II)
Class I studies : relieves pain,
but the effect size vs.
placebo, reducing pain by
11%–13% on the 11-point
Likert scale
Class II study: A large dosedependent effect (24%–50%
reduction in Likert pain
scores compared to placebo)
NNT is 4: for a 50%
reduction in pain , at 600
g/day.
Significant improvement (p
0.05 ) in the QOL measures
of social functioning, mental
health, bodily pain, and
vitality improved, and sleep
interference
Pregabalin: Its Pharmacology and Use in Pain
Management
Gajraj NM. Anest analg 105(6): (2007)1805-1815
• Lipophilic GABA analog
• Diffuses across the BBB
• Site of action is the presynaptic voltage-dependent
Calcium channel (N-type)
• Causes inhibitory modulation
of neuronal excitability
• Decreases ectopic activity
without changing normal
nerve function
• Decreases the release of Glu,
Sub P, dopamine , serotonin,
and Noradrenaline
• Starting dose 50mg TID to 300
mg /d over one week
• The dose of 600 mg /d confers
no additional benefit
• ADR Dizziness (29%) and
somnolence (22%)
Pregabalin: Its Pharmacology and Use in Pain
Management
Gajraj NM. Anest analg 105(6): (2007)1805-1815
DPN (diabetic peripheral
neuropathy)
PHN (post herpetic neuralgia)
•
•
Rosenstock N=146
–
–
–
•
•
–
–
–
–
–
Placebo 14% efficacy (50% pain relief)
Pregabalin 100 TID 40%
(NNT 3.9 )
Lesser N=337 onset relief 1 week
–
–
–
–
–
Placebo 18%
Pregabalin 300 mg 46%
(3.5 NNT)
Pregabalin 600 mg 48%
NNT 3.2
Richter N= 246
–
–
–
–
Placebo 15%
Pregabalin 50 mg TID 18%
Pregabalin 600 mg 39%
NNT 4.2
Sabatowski N=238
•
Dworkin N=173 onset relief first day
–
–
–
–
•
Placebo 10% efficacy
Pregabalin 50 mg TID 26%
NNT 6.3
Pregabalin 100 mg TID 28%
NNT 5.6
Placebo 20%
Pregabalin 100 mg TID
Pregabalin 200 mg TID 50%
NNT 3.4
Van Seventer N= 370
–
–
–
–
–
Placebo 7.5%
Pregabalin 75mg BID 26%
Pregabalin 150 mg BID 26%
NNT 5.2
Pregabalin 300 mg BID 37% (NNT 3.3)
Converting gabapentin to pregabalin
**Bockbrader Hn et al. gabapentin to pregabalin therapy transition: A pharmacokinetic simulation Am J
Therapeutics 20, 32-36 (2013)
• Pregabalin has a better
pharm-kinetic and pharmdynamic profile than
gabapentin
• Persons who do not repsond
adequately to gabapentin
may respond to pregabalin
• Neither significantly binds
proteins, requires
adjustment with food, and
has negligible metabolism
with renal clearance
•
•
•
•
Gabapentin 3600 mg/d to pregabalin 600
mg /d
Gabapentin 900 mg /d to pregabalin 150
mg/d
6:1
Two constructs
– Stop gabapentin and start
corresponding dose of pregabalin the
next day
– Give half the “old gabapentin” dose
and half of the corresponding
pregabalin dose for four days and the
stop all gabapentin and start the full
pregabalin dose on day 5
– Either strategy yielded stimulated
pregabalin equivalents comparable to
plasma pregabalin concentrations
Strategy 1: Simulated plasma
exposure to Pregab equivalents
was comparable to plasma
pregab concentration
Strategy 2: At no stage did simulated
pregab equivalents fall below those of
gabapentin alone or above those of
pregabalin alone
Substitution of gabapentin (off label) with pregabalin in
neuropathic pain due to peripheral neuropathy
Toth C. Pain Med 2010 11: 456-65
– Direct switch, overnight
– Indication Gabapentin failure.
Not ADR
•
•
•
•
Both GBP responders and GBP nonresponders had significant
improvements in VAS for NeP after
the substitution for both 6 and 12
months follow-up periods
GBP_resp GBP_non Gaba_control
Original
VNS 7.9
7.8
7.7
•
•
Gabapentin
VNS 4.9
•
•
Pregabalin
VNS 3.4
•
ADR end**
– Gabapentin (mg) to Pregabalin (mg)
•
•
– 0–900  150
– 901–1,500 225
– 1,501–2,100 300
– 2,101–2,700 450
– 2,700 or higher 600
no serious adverse effects in any
group. (#1 and 2 sedation dizziness)
After several months, GBP
nonresponder group patients (21% 6
of 29) discontinued their use of PGB,
while all patients in the GBP
responder group continued PGB (**
?ADR)
– 25%
6.6
4.9
76%
5.7
Gaba_control
5.8
30%
Duloxetine (60 mg/d) vs Pregabalin (300mg /d) vs Duloxetine
(60 mg /d) plus gabapentin (>= 900mg/d) (not FDA) in DNP
Tanenberg RJ et al Duloxetine , Pregabalin and Duloxetine plus Gabapentin for DNP in patients with inadequate
response to gabapentin: Open label randomized non-inferiority comparison Mayoo Clin Proc 2011 86(7): 615624
• 12 week study
• N=508 (138 Dulox;134 PreGab; 135 Combo)
• Noninferiority (as good as) would be declared if the
mean improvement for duloxetine was no worse than
the mean improvement for pregabalin by a margin of 0.8 unit
• Mean change in pain rating at end point:
• -2.6 duloxetine and -2.1 pregabalin
• Duloxetine was non-inferior to pregablin for the
treatment of DPN who had inadequate response to
gabapentin
Duloxetine (60 mg/d) vs Pregabalin (300mg /d) vs Duloxetine
(60 mg /d) plus gabapentin (>= 900mg/d) (not FDA) in DNP
Irving G et al Comparative safety and tolerability of Duloxetine vs Pregabalin vs Duloxetine plus gabapentin in DNP.
Int J clin Prac doi:10.1111/ijcp. 12452 2014
• Duloxetine
•Pregabalin
• Discontinuation
•10.4%
• 19.6%
•
• D + gabapentin
• 13.3%
Vs. Pregabalin, p 0.04
• More insomnia
•More edema
•
• Loss Wt 2.3 kg)
•Gained Wt (1kg)
• Lost Wt (1kg)
More nausea
insomnia
hyperhydrosis and
appetite loss
Other targets and off label trials in the
literature
Smith H. Drugs for pain ISBN-10: 1560535113
Smith H Pappagalo M Essential Pain Pharmacology ISBN-10: 0521759102
CLONIDINE
Alpha receptors-Spinal cord
TCA
Monoamine receptors-brain stem
SSRI / SNRI
5HT receptors brain stem spinal cord
Lidocaine
Neuronal sodium channels
Baclofen
Gaba-receptors spinal cord
Carbamazepine
Neuronal sodium channels
Valproic Acid
Neuronal sodium channels
NSAIDs
Inflammatory mediators c-fiber terminal
Ketamine
NMDA receptor dorsal horn
What does Cochrane say? No
evidence: Seizure meds
•
There was no indication that levetiracetam was effective in reducing neuropathic pain, but it
was associated with an increase in participants who experienced adverse events
–
Cochrane Database Syst Rev. 2014 Jul 7;7:CD010943. doi: 10.1002/14651858.CD010943.pub2. Levetiracetam
for neuropathic pain in adults. Wiffen PJ et al
•
lamotrigine's lack of efficacy in chronic pain Cochrane Database Syst Rev. 2011 Feb 16;(2):CD006044. doi:
•
10.1002/14651858.CD006044.pub3. Lamotrigine for acute and chronic pain. Wiffen PJ et al
Cochrane Database Syst Rev. 2013 Dec 3;12:CD006044. doi: 10.1002/14651858.CD006044.pub4. Lamotrigine for
chronic neuropathic pain and fibromyalgia in adults. Wiffen PJ et al
•
•
•
Three studies no more than hint that sodium valproate may reduce pain in diabetic neuropathy, and divalproex sodium in
post-herpetic neuralgia, but the use of 'completer' analysis may overestimate efficacy, and there were too few data for
pooled analysis of efficacy or harm, or to have confidence in the results of the individual studies. There is insufficient
evidence to support the use of valproic acid or sodium valproate as a first-line treatment for neuropathic pain.
Cochrane Database Syst Rev. 2011 Oct 5;(10):CD009183. doi: 10.1002/14651858.CD009183.pub2. Valproic acid and sodium
valproate for neuropathic pain and fibromyalgia in adults. Gill D et al
Phenytoin –no evidence Cochrane Database Syst Rev. 2012 May 16;5:CD009485. doi: 10.1002/14651858.CD009485.pub2.
Phenytoin for neuropathic pain and fibromyalgia in adults. Birse F et al
What does Cochrane Say? No
evidence-antidepressants/anxiolytics
•
Topiramate is without evidence of efficacy in diabetic neuropathic pain
Cochrane Database Syst Rev. 2013 Aug 30;8:CD008314. doi:
10.1002/14651858.CD008314.pub3. Topiramate for neuropathic pain and fibromyalgia in
adults. Wiffen PJ et al
•
Little evidence to support the use of desipramine to treat neuropathic pain. There was very
low quality evidence of benefit and harm, but this came from studies that were
methodologically flawed and potentially subject to major bias
–
•
little evidence to support the use of imipramine to treat neuropathic pain
–
•
Cochrane Database Syst Rev. 2014 Sep 23;9:CD011003. doi: 10.1002/14651858.CD011003.pub2. Desipramine
for neuropathic pain in adults. Hearn L et al
Cochrane Database Syst Rev. 2014 May 19;5:CD010769. doi: 10.1002/14651858.CD010769.pub2. Imipramine
for neuropathic pain in adults. Hearn L et al.
We found little evidence to support the use of nortriptyline to treat the neuropathic pain conditions
included in this review. There were no studies in the treatment of trigeminal neuralgia.
–
Cochrane Database Syst Rev. 2015 Jan 8;1:CD011209. doi: 10.1002/14651858.CD011209.pub2. Nortriptyline
for neuropathic pain in adults. Derry S et al.
What does Cochrane say? No evidence
•
little compelling evidence to support the use of venlafaxine in neuropathic pain.
–
Cochrane Database Syst Rev. 2015 Aug 23;8:CD011091. [Epub ahead of print] Venlafaxine for neuropathic pain in
adults. Gallagher HC et al
•
Clonazepam –no evidence Cochrane Database Syst Rev. 2012 May 16;5:CD009486. doi:
10.1002/14651858.CD009486.pub2. Clonazepam for neuropathic pain and fibromyalgia in
adults. Corrigan R etal
•
lack of evidence suggesting that zonisamide provides pain relief in any neuropathic pain condition
–
•
Cochrane Database Syst Rev. 2015 Jan 22;1:CD011241. doi: 10.1002/14651858.CD011241.pub2. Zonisamide
for neuropathic pain in adults. Moore RA
Milnacipran no evidence Cochrane Database Syst Rev. 2015 Jul 6;7:CD011789. [Epub ahead of print]
Milnacipran for neuropathic pain in adults. Derry S et al
What does Cochrane say? No
evidence: current standard of care
•
There remains a scarcity of published evidence to support the use of local anaesthetic
sympathetic blockade for CRPS. From the existing evidence it is not possible to draw firm
conclusions regarding the efficacy or safety of this intervention but the limited data available
do not suggest that LASB is effective for reducing pain in CRPS.
–
•
There is high quality evidence that oral aciclovir does not reduce the incidence of PHN
significantly. In addition, there is insufficient evidence to determine the effect of other
antiviral treatments; therefore, further well-designed RCTs are needed to investigate
famciclovir or other new antiviral agents in preventing PHN.
–
•
Cochrane Database Syst Rev. 2013 Aug 19;8:CD004598. doi: 10.1002/14651858.CD004598.pub3. Local anaesthetic
sympathetic blockade for complex regional pain syndrome. Stanton TR et al
Cochrane Database Syst Rev. 2014 Feb 6;2:CD006866. doi: 10.1002/14651858.CD006866.pub3. Antiviral treatment
for preventing postherpetic neuralgia. Chen N et al
There is moderate quality evidence that corticosteroids given acutely during zoster infection are
ineffective in preventing postherpetic neuralgia.
–
Cochrane Database Syst Rev. 2013 Mar 28;3:CD005582. doi: 10.1002/14651858.CD005582.pub4. Corticosteroids for
preventing postherpetic neuralgia. Han Y
What does Cochrane say? No
evidence: topicals
•
This review found no evidence from good quality randomised controlled studies to support
the use of topical lidocaine to treat neuropathic pain
–
•
Although there are reports that describe the benefits of topical amitriptyline for neuropathic pain, data
from evidence-based controlled clinical trials do not support efficacy in patients who use topical
amitriptyline for neuropathic pain control
–
•
Cochrane Database Syst Rev. 2014 Jul 24;7:CD010958. doi: 10.1002/14651858.CD010958.pub2. Topical lidocaine
for neuropathic pain in adults. Derry S et al.
J Clin Pharm Ther. 2015 Jun 7. doi: 10.1111/jcpt.12297. [Epub ahead of print] Systematic review of topical
amitriptyline for the treatment of neuropathic pain. Thompson DF1, Brooks KG1.
Low concentration capsaicin cream is no more effective than placebo Cochrane Database Syst Rev. 2012
Sep 12;9:CD010111. doi: 10.1002/14651858.CD010111. Topical capsaicin (low concentration) for
chronic neuropathic pain in adults. Derry S et al
NO evidence
He L et al Non-epileptic drugs for Trigeminal Neuralgia Cochrane Database 2006
• There is insufficient evidence from
randomized controlled trials to show
significant benefit from non-epileptic drugs in
TGN (Baclofen; tizanidine )
What does Cochrane say?
Some evidence-lots of qualifiers
LACOSAMIDE AND OXCARBAZEPINE OFF LABEL
•
Lacosamide has limited efficacy in the treatment of peripheral diabetic neuropathy. Higher doses did not
give consistently better efficacy, but were associated with significantly more adverse event withdrawals.
Withdrawals may overestimate efficacy, therefore, that lacosamide is without any useful benefit in
treating neuropathic pain; any positive interpretation of the evidence should be made with caution if at
all.
–
Cochrane Database Syst Rev. 2012 Feb 15;2:CD009318. doi: 10.1002/14651858.CD009318.pub2. Lacosamide
for neuropathic pain and fibromyalgia in adults. Hearn L et al
•
On the basis of moderate quality evidence from one trial in diabetic peripheral neuropathy, oxcarbazepine
is effective in reducing pain for this condition. However, this conclusion does not take into account
negative results from other trials in diabetic peripheral neuropathy that could not be included in our metaanalysis. Most adverse effects related to oxcarbazepine are rated as mild to moderate in severity
–
•
Cochrane Database Syst Rev. 2013 Mar 28;3:CD007963. doi: 10.1002/14651858.CD007963.pub2. Oxcarbazepine
for neuropathic pain. Zhou M et al
Short-term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the
intensity of neuropathic pain. Intermediate-term studies demonstrated significant efficacy of opioids over
placebo, but these results are likely to be subject to significant bias because of small size, short duration,
and potentially inadequate handling of dropouts. Analgesic efficacy of opioids in chronic neuropathic
pain is subject to considerable uncertainty
–
Cochrane Database Syst Rev. 2013 Aug 29;8:CD006146. doi: 10.1002/14651858.CD006146.pub2. Opioids
for neuropathic pain. McNicol ED et al
What does Cochrane say?
Some evidence-lots of qualifiers
BTX-A and Amitriptyline OFF LABEL
•
Perineural steroids may provide analgesic efficacy for one to three months in patients with
chronic peripheral NP of traumatic or compressive origin; however, the strength of this
recommendation is weak
–
•
Tests for significance, low overall risk of bias, and almost no statistical heterogeneity suggests
that there is a correlation between BTX-A and improvement of pain scores in PDN. Further
large-scale controlled trials are needed.
–
•
Can J Anaesth. 2015 Jun;62(6):650-62. doi: 10.1007/s12630-015-0356-5. Epub 2015 Mar 6. Perineural steroids for
trauma and compression-related peripheral neuropathic pain: a systematic review and meta-analysis. Bhatia A et al.
Pain Med. 2015 Mar 20. doi: 10.1111/pme.12728. [Epub ahead of print] Botulinum Toxin-A for Painful Diabetic
Neuropathy: A Meta-Analysis. Lakhan SE1, Velasco DN, Tepper D.
Amitriptyline has been a first-line treatment for neuropathic pain for many years. The fact
that there is no supportive unbiased evidence for a beneficial effect is disappointing, but has
to be balanced against decades of successful treatment in many people with neuropathic
pain. There is no good evidence of a lack of effect; rather our concern should be of
overestimation of treatment effect. Amitriptyline should continue to be used as part of the
treatment of neuropathic pain, but only a minority of people will achieve
satisfactory pain relief.
–
Cochrane Database Syst Rev. 2015 Jul 6;7:CD008242. [Epub ahead of print] Amitriptyline for neuropathic pain in
adults. Moore RA et al
What does Cochrane say?
Some evidence: Cardiac drugs
mexiletine and Topical clonidine OFF LABEL
•
Limited evidence from a small number of studies of moderate to low quality suggests that TC
may provide some benefit in peripheral diabetic neuropathy.
–
•
Lidocaine and mexiletine were superior to placebo [weighted mean difference (WMD) = -11;
95% CI: -15 to -7; P <0.00001], and limited data showed no difference in efficacy (WMD = 0.6; 95% CI: -7 to 6), or adverse effects versus carbamazepine, amantadine, gabapentin or
morphine.
–
•
Cochrane Database Syst Rev. 2015 Aug 31;8:CD010967. [Epub ahead of print] Topical clonidine for neuropathic pain.
Wrzosek A et al
Cochrane Database Syst Rev. 2005 Oct 19;(4):CD003345. Systemic administration of local anesthetic agents to
relieve neuropathic pain. Challapalli V et al
Mexilitine is a treatment for arhythmias . The CAST study of flecanide and ecanide showed
a 7.7 % cardiac arrest mortality rate compared to 3.3% for placebo. Mexilitine is associated
with DRESS syndrome (rash, hematopeotic and multi-organopathology)
What does Cochrane say? Helpful
•
Most placebo controlled studies indicated that carbamazepine was better than placebo. Five
studies with 298 participants provided dichotomous results; 70% improved with
carbamazepine and 12% with placebo. Carbamazepine at any dose, using any definition of
improvement was significantly better than placebo (70% versus 12% improved; 5 studies, 298
participants); relative benefit 6.1 (3.9 to 9.7), NNT 1.7 (1.5 to 2.0)
–
•
High-concentration topical capsaicin used to treat postherpetic neuralgia and HIVneuropathy generates more participants with high levels of pain relief than does control
treatment using a much lower concentration of capsaicin. The additional proportion who
benefit over control is not large, but for those who do obtain high levels of pain relief there
are additional improvements in sleep, fatigue, depression and an improved quality of life.
–
•
Cochrane Database Syst Rev. 2011 Jan 19;(1):CD005451. doi: 10.1002/14651858.CD005451.pub2. Carbamazepine for acute
and chronic pain in adults. Wiffen PJ et al and in 2014
Cochrane Database Syst Rev. 2013 Feb 28;2:CD007393. doi: 10.1002/14651858.CD007393.pub3. Topical capsaicin (high
concentration) for chronic neuropathic pain in adults. Derry S et al.
There is adequate amounts of moderate quality evidence from eight studies performed by the
manufacturers of duloxetine that doses of 60 mg and 120 mg daily are efficacious for
treating pain in diabetic peripheral neuropathy but lower daily doses are not. Further trials are not
required.
–
Cochrane Database Syst Rev. 2014 Jan 3;1:CD007115. doi: 10.1002/14651858.CD007115.pub3. Duloxetine for treating painful
neuropathy, chronic pain or fibromyalgia. Lunn MP et al
Basic Science- Baclofen off label
Activation of spinal GABAB receptors normalizes N-methyl-D-aspartate receptor in diabetic neuropathy Hui-Ping
Bai et al. J Neuro Sci 341(1–2),2014, Pp.68–72
•
•
•
N-methyl-D-aspartate receptor (NMDAR) activity is increased,
while GABAB receptor is downregulated in the spinal cord dorsal horn in diabetic
neuropathy.
Spinal NR2B, an NMDA receptor subunit, protein and mRNA expression levels were
significantly higher in STZ-treated rats than in vehicle-treated
rats. Intrathecal baclofen significantly reduced the NR2B protein and mRNA
expression levels in STZ-treated rats
These data suggest that stimulation of spinal GABAB receptors
reduces hyperalgesia in diabetic neuropathy.
Basic Science- NSAIDS
J Neurosci. 2001 Oct 15;21(20):8026-33. Nonsteroid anti-inflammatory drugs inhibit both the activity and the
inflammation-induced expression of acid-sensing ion channels in nociceptors. Voilley N et al
• The acid sensitivity of nociceptors is associated with
activation of H(+)-gated ion channels.
• With inflammation, ASIC1a appears in some larger A-beta
fibers
• NSAIDs prevent the large increase of ASIC expression in
sensory neurons induced by inflammation
• NSAIDs such as aspirin, diclofenac, and flurbiprofen directly
inhibit ASIC currents on sensory neurons
• Along with the capacity to block COXs and inhibit both
inflammation-induced expression and activity of ASICs
present in nociceptors is an important factor in the action
of NSAIDs against pain.
• Kalso doesn’t like NSAIDs; Woolf does
If you prescribe opioids
• Employ best practices like urine drug testing
and opioid agreements
• Be familiar with Federal law , the Controlled
Substance act of 1970 –download at
deadiversion.gov/ publications
• Be familiar with your specific State’s guidelines
or regulations for the treatment of pain and
the prescription of controlled substances.
FDA labeling for IVIG
http://dailymed.nlm.nih.gov/
• CIDP label is specific to Gamunex; Gamunex is indicated for 1.1, 1.2 & 1.3
• 1.1 Primary Humoral Immunodeficiency (PI)
– congenital agammaglobulinemia, common variable immunodeficiency, X-linked
agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined
immunodeficiencies. (Bivigam, Carimune, Flebogamma, Octagam)
• 1.2 Idiopathic Thrombocytopenic Purpura (ITP) (Bivigam and Privigen)
– to prevent bleeding or to allow a patient with ITP to undergo surgery.
• 1.3 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
– neuromuscular disability and impairment and for maintenance therapy to prevent
relapse.
• Gammagard S/D indicated for 1.1, 1.2, B-cell CLL, and Kawasaki syndrome
• supplies a broad spectrum of opsonic and neutralizing IgG antibodies
against bacteria, viral, parasitic, mycoplasma agents, and their toxins. The
mechanism of action in these disorders has not been fully elucidated.
Off label use of IVIG in neuropathy
•
J Clin Neurosci. 2010 Aug;17(8):1003-8. doi:
10.1016/j.jocn.2009.12.013. Differential
response to intravenous immunoglobulin
(IVIg) therapy among multifocal and
polyneuropathy types of painful diabetic
neuropathy. Kawagashira Y et al.
• N=6
• Three patients with
multifocal neuropathy
showed a marked
improvement in severe pain
with IVIG
• Three patients with
symmetric polyneuropathy
did not respond to IVIG
therapy.
•
•
•
•
•
•
Efficacy of intravenous immunoglobulin for
small fiber neuropathy associated with
sarcoidosis. Parambil JG et al. Respiratory
Medicine (2011) 105, 101e105
three patients with biopsy-proven sarcoidosis
who developed intractable neuropathic pain
and/or symptoms related to associated
autonomic dysfunction
Failed treatment with various
immunosuppressive medications and
narcotic analgesics.
QSART showed evidence of a postganglionic
sudomotor abnormality in one patient.
Skin biopsy findings were abnormal,
demonstrating a non-length-dependent
sensory SFN in all three patients.
Painful neuropathic symptoms, as well as
symptoms related to dysautonomia from SFN
responded significantly to treatment with
intravenous immunoglobulin (IVIG).
Summary: Why physical findings occur
• Dysesthesia
– Large fiber stimtingling, buzzing
– Small fiber stimburning, pins and needles, Hyperalgesia
(peripheral)
•
•
•
•
hypoalgesia to pinprick (sensory nerve injury)
hypoesthesia to tactile stimuli (sensory nerve injury)
Allodynia (central)
complex regional pain syndrome : Sudo (sweating) motor
and vasomotor instability
• Small fiber neuropathy: Autonomic dysfunction (Hoitsma)
• Cramps: motor neuropathy manifestation
Summary
• CNS Calcium channels: Pregabalin (PHN&DPN)
– Gabapentin (PHN)
• Descending pathways: Duloxetine (DPN), Opioids,
Amitriptyline (Depression)
• Dorsal horn 1st* 2nd* synapse Gaba (Baclofen), Alpha
(Tizanidine, Clonidine), Mu (opioids), 5HT receptors
(Duloxetine?); NMDA receptor (Ketamine)
• 1st* Order neuron Sodium Channel: Carbamazepine
(Trigeminal neuralgia)
• TRPV1: Capsaicin
• Anti-inflammatory: prostaglandin increases Na
currents: NSAIDs