Chronic Pain Ss

8/8/2019 Chronic Pain Ss

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CHRONIC

PAINMANAGEMENT

By Dr. Khairy EhabMD of Anesthesia & ICU



Pain

A physiochemical responses leadingto perception of:

An unpleasant sensory &emotional experience arising fromactual or potential tissue damage.



Classification Of

Pain

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Map Of Pain Battle

Nociception Processing a noxious stimulus

resulting in the perception of pain bythe brain.

I- TransductionConversion of a noxious stimulus into

electrical energy by a peripheralnociceptor.



II- TransmissionPropagation through first-order

neurons

III- Modulation Neuronal plasticity at the synapse bet1st & 2nd order neurons within the

spinal cord

IV- Perception



Noxious

StimulationsClick to edit Master text stylesSecond level

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Fifth level



Functional Classification Of Primary Afferent Nociceptors

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1st& 2nd-Order

NeuronsClick to edit Master text styles

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Projection Of SpinothalamicTract 1- Brain Stem Centers:

- Periaqueductal gray linking ascendingand descending inhibitory pathways of

pain.- Nucleus raphe magnus Form a link to

descending inhibitory serotoninergicfibers.

- Reticular activating system and thehypothalamus Responsible for the arousal

response to pain.- Para-brachial nucleus Thou ht to be



2- Thalamic Projection

Divided into a lateral and a medial tract.

Neospinothalamic, “lateral spinothalamic tract”

To Ventral Thalamic Nucleus

Carries Discriminative pain, such as[location, Intensity, and Duration of pain]

Paleospinothalamic, “medial spinothalamictract”

To Medial Thalamus Nucleus

Responsible for Autonomic andUnpleasant emotional perceptions of pain.



Alternate Pathways Of PainI- Crossing Tracts

1- Spinoreticular Tract Mediates arousaland autonomic responses to pain.

2- Spinomesencephalic Tract Activates antinociceptive, descending

pathways, because it has a projections toperiaqueductal gray area.

3- Spinohypothalamic And Spinotelencephalic Tracts Activate the

hypothalamus and evoke emotional behavior



II- Uncrossing Tract1- Spinocervical tract Ascends uncrossed tothe lateral cervical nucleus, which relays thefibers to the contralateral thalamus; this tractis likely a major alternative pathway for pain.

2- Fibers in the dorsal columns whichmainly carry light touch and proprioception arealso responsive to pain. They ascend mediallyand ipsilaterally.

It is well apparent that pain fibers ascend diffusely,ipsilaterally, and contralaterally hence, somepatients continue to perceive pain following ablationof the contralateral spinothalamic tract.



Third-Order NeuronsLocated in the thalamus.

Ventral Thalamic Nuclei Neurons Project to the primary

somatosensory cortex, whereperception and discrete localization of pain take place.

Medial Thalamic Nuclei Neurons Project to the anterior



Chronic Pain



Chronic Pain

Defined as Pain that persistsbeyond the usual course of an acutedisease or after a reasonable time forhealing ……………….. So

Although the pathologic process of chronic pain went on from the start,chronic pain can’t be announced before

healing time [1 to 6 months].



Features Of Chronic Pain1 Absent or attenuated neuro-endocrine stressresponse.2 Prominent Psychological, sleep and mooddisturbances.

3 Neuropathic pain is classically paroxysmal, has aburning quality, and is associated with hyperpathia.

• Deafferentation pain When associated with lossof sensory input into the central nervous system.

• Sympathetically maintained pain When thesympathetic system plays a major role



Categories Of ChronicPain1-Nociceptive Pain Associated with an

ongoing noxious stimulus

2- Inflammatory Pain Due to ongoing

tissue inflammation, e.g. musculoskeletaldisorders

3- Neuropathic Pain Resulting from alesion to P/ or CNS e.g.Diabetic neuropathy, Causalgia, Phantomlimb, post-herpetic neuralgia, Stroke, Spinalcord injury, and Multiple sclerosis.



4- Dysfunctional pain

Said to be in absence of:# Peripheral noxious stimulus,

# Peripheral pathology, or

# Identifiable nervous lesion.

It Is Due To

An abnormal functioning of the nervous

system.



PrecipitationOf Chronic Pain



Sensitization Of PeripheralField

Following release of a complex arrayof chemical mediators, nociceptors andtheir neurons display sensitization.

Sensitization manifested

by:

# Enhanced response to noxious

stimulation.



I- Primary Hyperalgesia

Sensitization of nociceptors results in:1- Decrease in pain threshold .

2- Increase in the frequency response to the

same stimulus intensity.

3- Decrease in response latency .

4- After-discharges : Spontaneous firing even

after cessation of the stimulus.



xpans on er p eraField

II- Secondary Hyperalgesia …Or

Neurogenic InflammationManifested by Triple Response

1- Flare red flush around the site of injury.2- Local tissue edema.

3- Sensitization to noxious stimuli.

Secondary hyperalgesia is due to antidromic

release of sP and CGRP from collateral axons of the primary afferent neuron.

I fl d l f hi



Inflammatory models of neuropathicpain

Recently it has been shown that neuropathic pain

is the end result of chronic inflammatory pain:Inflammatory mediators

Activate mast cells, recruit neutrophils,

macrophagesRelease of cytokines, tumour necrosis factor

(TNF),

Glial cells and Schwann cellsRelease of nerve growth factor (NGF)

Changes of endoneurial

microenvironment [ Wallerian degeneration ]

I fl M d l Of N hi



Inflammatory Models Of NeuropathicPain

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Central Modulation

Four neuronal components of thedorsal horn1. Central terminals of 1st order neurons .

2. Intrinsic neurons with cell bodies andterminations within the spinal cord.3. 2nd order neurons with its axons travel

in ascending columns to terminate in thebrain. 4. Axons of descending systems whosecell bodies reside in the brain.

l



I- Wind-up1- Decreased Threshold of the 2nd Order

Neuron

Prolonged depolarization of spinal neurons= Increase in the magnitude and duration of neuron firing Amplification of pain

response and, increase in the excitability of

spinal neuronsHyperalgesia = An excessive response to

a painful stimulus.

Allodynia = A painful response to a

Central Sensitization

2- Increased Frequency of WDN discharge with the same



2- Increased Frequency of WDN discharge with the samerepetitive stimuli, as a result of backward diffusion of NO

3- Decrease Response Latency of the 2nd order neuron.

4- Prolonged After Discharge of the 2nd Order neuron evenafter C fiber input has stopped.

II- Expansion Of Receptive Field

Dorsal horn neurons increase their receptive fields such thatadjacent neurons become responsive to stimuli (whether noxious or not) to which they were previously irresponsive.

III- long-Term Potentiation

Due to Changes in dorsal horn neural function as a result of damage or loss of segmental inhibitory neurons.



How Dose PathophysiologyOf Chronic Pain

Affect Its treatment

M h i f C l



Mechanism of CentralSensitization

Neurochemical Mediators

Receptor Major Ligand(s)

1- Excitatory Ionotropic

AMPA Glutamate

Kainate GlutamateNMDA Aspartate

2- Excitatory Metabotropic

Neurokinin NK1 Substance PProstaglandin PG E2, & PG F2



Facilitatory CentralModulationClick to edit Master text styles

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ac tatory entra



ac tatory entraModulation

Intense and/or chronic noxious input

Mainly C-Fibers

Unplug Mg++from

NMDA The Chief Receptors Of Pain

Exposing Them To There Activator -Aspartate

Allowing Ca++ to Surge into the 2nd order

neuron

“C l i ” Th C di l I



“Calcium” The Cardinal IonOf Pain

High concentration of Ca++ into dorsalhorn cells

Generated by

1- Membrane depolarization .

2- NMDA receptor activation.3- Released from the endoplasmic reticulum after

activation of metabotropic receptor .

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Fifth level

Calcium Mediated SeriesOf Intracellular Events



I- PhospholipaseC

Phosphatid yl inositol

Biphosphat e

Inositol triphosphat

e

Diacylglycerol

Activate

c a t a

l y z e s

Activated metabotropi

c receptor

Highintracellular

Ca++

Di l l l



DAG + high intracellular ca++increase production of Protein kinase Cwhich, has two actionsI- On Cell membrane of the 2nd order neuron

1- Sustains increased Ca++ permeability.2- Enhances NMDA receptor excitation.

3- Uncouples the G protein that activates thepotassium channel from the opioid receptor.This can lead to opioid tolerance.

Diacylglycerol



II- Protein Kinase C - AnIntracelluer 3rd Messenger

As, it Activates proto-oncogenes[c-fos and c-jun ], which control transcription of

genes encoding a variety of

neuropeptides that modulateresponses to noxious stimuli.Enkephalins Dynorphin , Tachykinins



II- Ca++ Activates phospholipase A2

osp aidyl

cholinePhospholipa

se A2

LipoxygenaseCycloxygenaseProstaglan

din

cascade

Leukotriene

s

Aracidonic acid



III- Ca++ Increases intracellular production of NO through

activation of NOS# In side the 2nd order neuron NOScatalyzes

1- Production of protein kinases PKC and,2- Alterations in gene expression . # Diffused NO enhances

1- Neurotransmitters release from theprimary afferent.

2- NMDA receptor response of the



Glial Cells ImmuneMechanisms Of Chronic Pain-

Phantom PainMicroglias initiate the immuneresponse,

when their toll-like receptors areactivated, they obtains an amoeboid form,and they release substances thatsubsequently activate Astrocytes andOligodendrocytes .

Both types of cells produce pro-inflammatorycytokines, including the interleukins IL-1β and



Effects Of Released

Cytokines1- Release of cyclooxygenase.2- Nitric oxide synthase.3- SP and activate NMDA receptors.

4- Activate chemokines in macrophagesand endothelial cells, which initiateextravasation of leukocytes from the blood

neuronal damage.

mainly segmental inhibitory interneuron

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● Fifth level



Segmental Inhibitory



Segmental InhibitoryNeurotransmitters

GABAB Increases K+ conductance across thecell membrane. Baclofen is an agonist.

GABAA Increases Cl– conductance across thecell membrane. Benzodiazepines potentiatethis action.

Glycine receptors Increases Cl– conductanceacross neuronal cell membranes but, also has afacilitatory effect on the NMDA receptor.

Adenosine A1 receptor inhibits adenylcyclase

but, A2 receptor has an opposite effect.



Ascending Noxious

Stimulation & MedullaryResponses1- “On” Facilitatory Response

Prolonged noxious stimulation activatedescending facilitatory pathways thatenhance dorsal horn nociceptiveconduction.

2- “Off” Inhibitory ResponseProvide inhibitory input to dorsal horn

nociceptive circuits but, they are inhibited

by noxious stimuli.

D di I hibi



Descending InhibitoryPathwaysDorsolateral funiculus originates from rostral

ventro-medial medulla.It conveys 3 inhibitory fibers.

1- Noradrenergic System Originate from the periaqueductal gray

area and the reticular formation.

It activates presynaptic andpostsynaptic α2- G proteins receptors openingK+ channels and inhibiting increases in

intracellular calcium concentration.

2- Serotonergic System



2- Serotonergic System

Originate from NRM. It provides both

inhibitory and facilitatory control of dorsal hornnociceptive function depending on the receptorsubtype(s) activated.

Presynaptic 5- HT Inhibition Mediated bymetabotropic 5-HT receptors, activation of whichdecreases transmitter release.

Postynaptic 5- HT Facilitation Mediated by

ionotropic receptors (5-HT3) that enhancetansmitter release from nociceptive primaryafferents.

That is why selective serotonin reuptake-

3- Endogenous Opiate System



3 Endogenous Opiate System

Originate from NRM and reticular formation,acts via methionine enkephalin, leucineenkephalin, and β-endorphin.

1- Hyperpolarization of 1st order neuron , by inhibition of voltage-gated Ca2+channels thus,inhibiting the release of sP. [ Unlike exogenous ]

2- Hyperpolarization of 2nd order neuron , as it enhances K+ efflux by activating G-protein– coupled inwardly rectifying K+ channels.

Mechanisms Of Nerve lesion



Mechanisms Of Nerve lesionPain

1- Neuroma Spontaneous self-sustainingneuronal activity in the primary afferentneuron.2- “Entrapment Syndrome” Chronic nerve

compression marked mechano-sensitivity.3-Ephaptic transmission: followingDemyelination , development of short-circuitsbetween pain fibers and other types of fibers,results in, activation of nociceptive fibers bynon-noxious stimuli at the site of injury.



4- Functional reorganization of receptive fieldsin dorsal horn neurons such that sensory input from

surrounding intact nerves aggravates any inputfrom the area of injury.5- Spontaneous electrical activity in dorsal horncells & / or thalamic nuclei.6- Release of segmental inhibition in the S.C.7- Loss of descending inhibitory influences that aredependent on normal sensory input.

8- Lesions of the thalamus or supraspinalstructures

Sympathetically



SympatheticallyMaintained PainFollowing trauma, surgery, and certain pain syndromes,

hyperalgesia, autonomic dysfunction, and dystrophy ,Complex regional pain syndrome (CRPS) explained by

I- Central dysregulation of

sympathetics autonomic functionUnder the effect of facilitatory ascending pathway of pain,

medullary sympathetic muscle vasoconstrictors take the upperhand, inhibiting hypothalamic skin vasoconstrictors.

I- Red Hot Limb Loss of hypothalamic V.C.

2- Motelled cold limb Medullary V.C.

3- Atrophic limb Diminished blood supply to

the muscles

II C t lk



II- Cross-talk

Ephaptic transmission between different fibertypes leading to depolarization of nociceptor

fibers by e fferent sympathetic fibers.

III- In certain post traumatic

states

Indirect sensitization of mechanoreceptors bys m athetic nerve terminals, lus disinhibition of

Ph l f



Pharmacology ofChronic Pain

D I hibit A ti



Drugs Inhibit ActionPotentialI- Old Anticonvulsants Drugs

Phenytoin, Valproic acid,Carbamazepine Inhibit Na+, influx across

the neuronal membrane

Nausea and ataxia are common side effects

Phenytoin causes vitamin D, K and folatedeficiencies, hirsutism, and gingival hyperplasia.

Valproic acid elevate hepatic enzyme ,up to fatal hepatic necrosis in children

Carbamazepine can significantly

2- New Anticonvulsant



2 New Anticonvulsant“Gabapentin”

Mechanism It inhibits voltage-gatedcalcium currents and posses anti-inflammatory properties

Uses It provides significant pain relief for patients with RSD, diabetic neuropathy,and postherpetic neuralgia.

Side effects It has fewer side effectsand drug interactions, howeversomnolence, dizziness, ataxia, andperipheral edema are occasional problems

Anticonvulsant & Pain



Anticonvulsant & PainManagementAnticonvulsan

tHalf-Life(h)

Daily Dose(mg)

TherapeuticLevel (g/mL)

Phenytoin 22 200–600 10–20

Valproic acid 6–16 750–1250 50–100

Carba-mazepine 10–20 200–1200 4–12

Gabapentin 5–7 900–1800 > 2

II S stemic Local



II- Systemic LocalAnestheticsLidocaine, Procaine, & Chloroprocaine

Used systemically in patients with neuropathic pain.Mechanism of action

Non selective Na+ blocker

They produce sedation and central analgesia thatoutlasts the pharmacokinetic profile of the drugs. It canbreak the cycle of pain.

Monitoring ECG, B.P., respiratory, & BIS

Full resuscitation equipment should beavailable.

Signs of toxicity



Signs of toxicity Tinnitus, nystagmus, slurring, or excessive

sedation, necessitate slowing or discontinuingthe infusion.

Infusion Rates

Lidocaine 1– 5 mg/kg over 5 – 30 min.Procaine 200 – 400 mg over 1 – 2 h.

Chloroprocaine Infused as 1% solution at arate of 1 mg/kg/min for a total of 10–20mg/kg.

III A i h h i



III- Antiarrhythmic

Patients who do not respond toanticonvulsants but respond to intravenouslocal anesthetics may benefit fromcontinuous oral antiarrhythmic therapy.

Mexiletine 150–300 mg every 6–8 h

is the most commonly used agent.It is generally well tolerated.

Antidepressants



AntidepressantsOlder Clomipramine , Amitriptyline , &

Desipramine More effective than selectiveserotonin reuptake inhibitors Fluoxetine , & Paroxeline …… Why?

Side effects1- Antimuscarinic

Xerostomia, impaired visualaccommodation, urinary retention, &constipation.

2- Antihistaminic effects (H1 andH2 Sedation and increased astric



TramadolDual mode of action Synergistic effect of Principally nonselective monoamine reuptakeinhibition and weak [10%] mu agonist,analgesia comparable to Meperidine.

Uses Acute and chronic pain syndromes,including neuropathic pain and allodynia.

Multimodal pain relieve NSAID’s, & mu

agonists enhances its efficacy.Drug interaction should not be used withTCAs, SSRIs, or MAO inhibitors Due to therisk of serotonin syndrome .



Alpha-2 agonistsSedative-hypnotic effects

Due to inhibition of norepinephrine releasefrom noradrenergic receptors Auto-receptors inthe venterolateral medulla of the brainstem.

I- Analgesic effects1- Principally Spinal throughBinding to non-noradrenergic Hetero-

receptors - 1- Pre-synaptically:

It Inhibits the release of neurotransmitters.- - -

2- Supraspinal



p pSuppression of norepinephrine release in the

venterolateral medulla in the brain stem Stimulate catecholaminergic nuclei in the pons, To increasenorepinephrine release from descending adrenergicinhibitory pathway Which , activates presynaptic andpostsynaptic heteroreceptors.

II- Sedative effectsWhile it’s Analgesic actions have a ceiling

effect, Sedative is d ose-dependent .i.e. further dosing only acts to lengthen the duration

of sedation and increase the risk of adverse effects.

Cardiovascular Side effects



# Initial hypertension (due to peripheral

postsynaptic adrenoreceptors causingvasoconstriction), which results in a baroreceptor-

mediated reflex bradycardia. As the peripheral

effects diminish, avoided in pediatric

# Central alpha-2 actions predominate,

leading to decreased blood pressure and cardiac

output.

# Short term A-V block (most often first or

Other Side Effects



- Decreased respiratory rate, & peripheral

venous desaturation.

- Vomiting.

- Increased urine output.

- Transient hyperglycemia due to inhibition

of insulin secretion.

- Increases myometrial tone and pressure.

Uses:



Uses:

Adjunct for epidural infusions inneuropathic pain management specially inpatients with opioid tolerance.

Dosage:Epidural clonidine is usually started at 30

µ g/h in a mixture with an opioid &/or localanesthetic.

Because it is highly lipid soluble



CorticosteroidsTheir antiinflammatory actions give analgesic effect.

Side effects: Result from large doses or prolongedadministration1- Glucocorticoid activity: can produceH Hyper tension, glycemia, acidity,

C C ataracts, Cushing's syndrome ,O steoporosis, myopathy , infection

2- Mineralocorticoid activity causes:

Sodium retention , Hypokalemia, C.H.F.

Corticosteroids



CorticosteroidsDrug Routs

Gluco-

corticoid Activity

Mineralo

corticoid Activity

Equivalent

Dose (mg)

Half-Life

(h)

Hydrocortison

e

O, I, T 1 1 20 8 - 20

Prednisone O 4 0.8 5 12 - 36

Prednisolone O, I 4 0.8 5 12 - 36

Methyl-

prednisolone O, I, T 5 0.5 4 12 - 36Betamethasone

&Dexamethason

e

O, I, T 25 0 0.75 36 - 72

Why Opioids Are Not So



y p

Effective

I- Presynaptic Causes1- Reduction of opioid receptors at thespinal level

- Nerve section loss of presynaptic opioidreceptor

- Inflammatory pains receptordysfunction.

2- Cholecystokinin (CCK)

# A neuro peptide released by depolarization of many brain areas in a calcium dependentmanner.

3- Direct interference with



transporter

mechanismson primary afferent nerveterminals andglial cells ,blockingreuptake of excitatory aminoacids andincreasing theirsynaptic levels.



● Fifth level

glutamate

II- Postynaptic Causes



y p

Prolonged occupation of opioids G receptorseceptors can translocate and activate PKC, which inurn is capable to

1- Uncouple opioids from G protein

2- Enhance calcium influx through the NMDAeceptor , producing sensitization of the cell.Thus, prolonged opioid administration can lead to

pinal sensitization, and prolonged EAA release, as

ccurs with neuropathic pain states, and can reduceesponsiveness to opioids.

NMDA Receptor



NMDA ReceptorAntagonists# Uses Adjuvant with other analgesics

drugs to reduce CNShyperresponsiveness and allow otheranalgesics to function more effective.

# NMDA receptor antagonists increaseopioid receptor sensitivity, reduce opioidtolerance and minimize rebound

hyperalgesia

I.V. or epidural ketamine micro-dose

Constant Rate Infusion For



I.V. & Epidural Ketamine

Loading dose 0.125 to 0.50 mg/kgMaintenance dose 2 to 20

ug/kg/minute Or 0.12 to 1.2 mg/kg/hr .

Other NMDA Receptor

Blockers

# Amantadine,

Intra operative Ketamine



pSeven French investigators report in the

journal Anesthesia and Analgesia in 2008 on a prospective,randomized, double-blind, controlled trial of 81 patientswith major abdominal surgery. They administeredketamine intra- and postoperatively for 48 hours in thefirst experimental group, only intra operatively in group 2,

and group 3 received placebo only. Cumulative morphineconsumption 24 hours after surgery in group 1 was cut tohalf of the control group and group 2 cut to 80%. Also,27% of the control group experienced nausea vs only 4%in the experimental ketamine group 1. No adverse effectswere noted.

The authors conclude that low-dose ketamineduring and after abdominal surgery improvesanalgesia decreases postoperative nausea and morphine consumption.



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Chronic Pain Ss

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