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CHRONIC
PAINMANAGEMENT
By Dr. Khairy EhabMD of Anesthesia & ICU
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Pain
A physiochemical responses leadingto perception of:
An unpleasant sensory &emotional experience arising fromactual or potential tissue damage.
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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.
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II- TransmissionPropagation through first-order
neurons
III- Modulation Neuronal plasticity at the synapse bet1st & 2nd order neurons within the
spinal cord
IV- Perception
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Noxious
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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
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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.
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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
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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.
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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
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Chronic Pain
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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].
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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
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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.
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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.
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PrecipitationOf Chronic Pain
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Sensitization Of PeripheralField
Following release of a complex arrayof chemical mediators, nociceptors andtheir neurons display sensitization.
Sensitization manifested
by:
# Enhanced response to noxious
stimulation.
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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.
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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
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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
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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
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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
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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.
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How Dose PathophysiologyOf Chronic Pain
Affect Its treatment
M h i f C l
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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
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Facilitatory CentralModulationClick to edit Master text styles
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ac tatory entra
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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
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“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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Calcium Mediated SeriesOf Intracellular Events
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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
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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
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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
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II- Ca++ Activates phospholipase A2
osp aidyl
cholinePhospholipa
se A2
LipoxygenaseCycloxygenaseProstaglan
din
cascade
Leukotriene
s
Aracidonic acid
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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
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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
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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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Segmental Inhibitory
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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.
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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
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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
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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
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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
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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.
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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
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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
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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
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Pharmacology ofChronic Pain
D I hibit A ti
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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
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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
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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
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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
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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
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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
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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
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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 .
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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
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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
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# 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
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- Decreased respiratory rate, & peripheral
venous desaturation.
- Vomiting.
- Increased urine output.
- Transient hyperglycemia due to inhibition
of insulin secretion.
- Increases myometrial tone and pressure.
Uses:
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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
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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
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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
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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
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transporter
mechanismson primary afferent nerveterminals andglial cells ,blockingreuptake of excitatory aminoacids andincreasing theirsynaptic levels.
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glutamate
II- Postynaptic Causes
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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
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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
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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
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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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Thank You