March 26, 2015
Anatomy of Pain
Pathways
 1 Order: Cell body in
st
DRG. Unmyelinated,
slow C fibers, & thinly
myelinated A fibers
 2nd Order: Cell body in
spinal cordspinothalamic tract
 3rd Order: Cell body in
thalamus (ex. Ventral
posteriolateral nucleus)
Pain occurs in the cortex

 Pain is a product of
higher brain
processing.
 Nociception
unmodulated by
descending pathways,
as with cord
transection, can lead to
autonomic
hyperreflexia.
Peripheral Receptors

Peripheral Receptors

 Membrane proteins transduce stimuli into electrical impulses. Ex.
TRPV1-heat, H+ (ischemia ), & capsaicin.
TRPM8-cold, menthol
 Injury releases inflammatory mediators: H+,K+, bradykinin
(activation & sensitization), 5-HT, ATP (purinoreceptors),
cytokines (which can act directly on receptors or indirectly by
stimulating prostaglandin release), prostaglandins (activation &
sensitization via cAMP or Na+ channel thresh hold), & NO, & can
activate nociceptors directly or can increase excitation state
(inflammatory cascade) at periphery with increased expression of
membrane proteins (vanilloid receptor proteins, tetrodotoxin + & Na= channels)
 Activation of voltage gated Ca+ channels will cause
neurotransmitter release.
 “Sleeping”/”Silent” nociceptors respond only at extreme intensity
with wake up in response to endogenous mediators such as
bradykinin from cell injury.
Peripheral Receptors

 All nociceptors can be sensitized so activation thresh
hold lowered leading to spontaneous firing &
hyperalgesia. In response to tissue injury, signals in
pain transmission circuits may be enhanced causing
hyperinflamatory pain, hyperalgesia & allodynia.
 Therefore, peri-op pain treatment should be directed
at interfering with development of hyperalgesia.
 1/3 of chronic pain patient cite surgery as initiating
cause.
2nd Order Nociception Neurons

 1st order fibers
innervate nociceptor in
lamina 1 & 2. Cells in 2
make connections with
in 5-7. Both give rise to
spinothalamic tracts.
 These can be
modulated by
descending fibers.
Presynaptic Modulation

Presynaptic Modulation

Pre-Synaptic Modulation

 Endogenous Opioids: Dynorphins acting on kappa
receptors, Enkephalins on delta, Endorphins on mu
& delta. (more or less). Inhibit Ca+ influx and open
K+ channels to hyperpolarize neurons.
 Nociceptin: opioid like, also acts on directly on
dopamine receptors or indirectly via inhibition of
GABA
 Alpha-2 agonists decrease sympathetic output via
negative feedback, modulates release of substance P
and epinephrine.
3rd Order Neurons

 2nd order synapse to
3rd order in thalamus
nuclei (Medial Dorsal,
VMP, VPL, etc.)
 3rd order synapse in
cingulate, primary
somatosensory, &
insular cortex
Problems with Pain

 Long standing nerve injury may show little change in descending
inhibition while huge increase in facilitation. May lead to chronic
pain & allodynia, with 1st order nociceptors releasing increased
neurotransmitters such as glutamate & substance P.
 Inflammatory pain can cause hypersensitivity, enhanced signaling
in pain transmission. “Central Sensitization” wherein sustained
activation of 1st order neurons produce long lasting changes in
spinal excitability
 Spinoparabrachial-amygdala pathway can affect emotive
component of pain, as well as thalamic-anterior cingulate
gyrus.(anxiety, chronic pain syndromes)
 Increasing sensitivity in surrounding cells (ex. Visceral injury
leading to muscle & skin pain. )
 Injury during neuronal maturation may lead to adult
hypersensitivity
Multimodal Treatment
of Pain

 Gateway Theory:
collaterals of sensory
fibers activate inhibitory
interneurons & inhibit
pain transmission
(rational for TENS)
 Stimulation produced
analgesia: stimulation of
periaqueductal grey area,
nucleus raphe magnus,
dorsal raphe, etc. Will
inhibit pain.
Opiates

 Obviously, work on endogenous opioid receptors.
 Especially good for inflammatory hyperalgesia.
 Presynaptic (& some post synaptic) inhibition of
neurotransmitter release by hyperpolarization and
opening of K+ channels & closing of Ca+ channels.
 Currently no opiates that bind to specific opioid
receptors, so, for example, can not target mu-1 for
analgesia while avoiding mu-2 respiratory depression.
 Increased intra-op dosing may decrease incidence of postop sensitization.
 Activation of NMDA may lessen sensitivity of opioid
receptor.
Local Anesthetics

 Selectively bind to inactivated-closed Na+ channels on inner (or H
gate) of channel. As gates open & close, further binding occurs, so
resting nerve less sensitive than stimulated nerve.
 Are weak bases with pKs of 7.6 to 8.9.
 Un-ionized form crosses membrane, then ionized in cytoplasm to
bind channel. (BiCarb added to increase % of un-ionized form. At
pH 7.4, only 5% of tetracaine un-ionized. In acidic infected area less
% un-ionized )
 Theorized need at least 2 cm of nerve blocked to block
transmission.
 Amides: lidocaine, bupivacaine, ropivacaine metabolized by
microsomal enzymes in liver
 Esters: procaine, chlorprocaine, tetracaine, coccaine undergo
hydrolysis by cholinesterases mostly in plasma and some in liver
Local Anesthetics

 Toxicity: Bupivacaine 3 mg/Kg
Lidocaine 5 mg/Kg without epinephrine
Lidocaine 7 mg/Kg with epinephrine
 BUT, toxicity dependent on:
1. method of injection: ICE-BS
2. Protein binding: Bupivacaine highly protein bound so increased toxicity in liver
failure, neonates, etc., but lidocaine much less bound.
 Lidocaine: neurologic effects manifest first
 Bupivacaine: cardiac effects manifest first.
 Ropivacaine: also has A-V conduction slowing but secondary to steroselective
inotropic effects much less cardiodepressive.
 Increasing fat solubilty slows induction. Increased mass effect speeds induction.
Increasing % of un-ionized speeds induction.
 By blocking nerve conduction, especially abnormal activity in peripheral nerves,
hypersensitivity may disappear. Rational for sympathetic nerve blocks
NSAIDs

 Inhibition of COX enzymes with reduction of prostaglandin
formation.
 Decreases inflammatory response to surgery
 Central inhibition of PGs may also decrease perception of pain.
 Ketorolac likely potentiates the antinociceptive actions of
opioids.
 Acetaminophen associated with both nephropathy & hepatic
necrosis
 COX-2 inhibitors associated with 40% increase in
cardiovascular events: thrombotic events & MI’s
 Current research with NO releasing derivatives (i.e. nitroaspirin) & direct EP receptor antagonists
Alpha-2 Agonists & NMDA blockers

 Dexmedetomidine: selective alpha-2 adrenergic agonist with
pre-synaptic modulation of release of substance P in dorsal
horn, decreases central sympathetic output (like clonidine),
increases firing of inhibitory neurons, and anxiolytic mainly in
locus ceruleus. Minor alpha -1 post synapse
 Glutamate receptors (n-methyl-d-aspartate=NMDA) are
essential to driving pain after inflammation, but are not
involved in pain after surgery.
 Ketamine inhibits NMDA system by blocking open channels,
decreasing frequency of channel opening, and decreasing open
time. Also regulates epinephrine release.
 Studies suggest that intrathecal ketamine may decrease pain at
48 hours and at 1 year post op.
Capsaicin & Cannabinoids

 Capsaicin receptor VR-1 ligand-gated, non-selective cation channel in same
family as vanilloid, mostly found in small diameter afferent neurons ( but
also in CNS ).
 Responds to moderate heat,~43 degrees, and to H+
 Topical applications may “exhaust” neurotransmitters (especially
substance P). Also may improve efficacy of local anesthetics by opening
channels (stimulation) to return to closed inactivated.
 Cannabinoids: Endocannabinoid receptors first found in 1988-G-protein
coupled affecting cAMP, with synergistic activity between periphery &
CNS.
 Suppress both pain & inflammatory processes. Especially active on
glutamatergic , also on GABA synapses. Interact with endorphin & TRPV
systems as well.
 In VPL nucleus of thalamus 10 X more potent than morphine in pain
mediating neurons, blocks capsaicin induced hyperalgesia, blocks PG
induced inflammation.
Gabapentin

 Similar in structure to GABA, but does not seem to
bind to GABA receptors.
 Main site of action is blockade of voltage gated Ca+
channels
 Appears to increase GABA synthesis & modulate
glutamate synthesis.
 Works well on diabetic & post herpetic neuralgias &
neuropathic pain in general
 Not as effective on inflammatory pain
Multimodal Analgesia

 Diverse opinion as to whether post operative outcome is
improved.
 Is there as benefit to pre-emptive local anesthesia?
 Benefit of decreased side effects: Decreased opioid use therefore
decreased risk of N/V, decreased GI problems with NSAIDs.
 Addition of gabapentin decreased opioid use, in arthroplasties
improved knee flexion & decreased pain at 6 months
 Addition of IV or IN ketamine decreased chronic pain at 6
months from 24% to 8%
 IV dexmedetomidine can increase duration of sensory nerve
block.
 Cannibinoids showing promise in decreasing chronic post op
pain.