Download PAIN FOX FINAL

ANALGESIC
PHARMACOLOGY
Bruce Onofrey, OD, RPh, FAAO
Professor, U. Houston
1
DISCLOSURE
• I’m a suffering CUBS fan
POSTER
FROM 1923
A CLINICAL MOMENT:
80 y/o with severe temporal
headache presents to ER
ER DX:Migraine
TX with Midrin
Classical Migraine Symptoms?
What IS the Differential?
NOT the Rear-end of An Automobile
• Do the facts support the
DX?
• What is the Differential
DX?
• Will this TX produce
harm?
• Any additional tests?
The Differential
• Cranial Arteritis
• Arteritic Ischemic Optic
Neuropathy
• Temporal Arteritis
• Carotid Artery Disease
• Hypertensive Crisis
• Impending CVA
The Tests
•
•
•
•
•
•
BP
ESR
CRP
CBC
ESR >47
CRP > 2.45
Pain is NOT a disease-It is a
sign of a disorder that must be
diagnosed in conjunction with
the management of the pain.
What is Pain?
• Any unpleasant sensory and emotional
experience associated with actual or
potential tissue damage.
• 75 million suffer from chronic pain
• 1/3- 1/2 require daily pain management
Pain Management
• Acute — injury,
inflammation (most
ocular pain)
• Chronic
• Neuropathic — from
diseases of the nerves
or from injury to nerves
• Cancer — pain related to
malignant disease or
tumors and their effects
on the body
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Neuropathic Pain:
Primary neuropathic
NO STIMULUS
DIABETES
H. ZOSTER
PAINFUL
SENSATION
Neuropathic pain: Allodynia
NONPAINFUL
STIMULUS
PAINFUL
SENSATION
Neuropathic Pain:
Hyperalgesia
PAINFUL
STIMULUS
FIBROMYALGIA?
HYPERALGESIA
Acute Pain
• ~ specific and obvious cause (e.g.
trauma, surgery)-ALWAYS FIND CAUSE
• ~ limited duration
• Resolves when the source of pain is
detected and treated
• ~ requires topical/local treatment
– Fewer side effects/complications
13
Physiologic Effects of Pain
•
•
•
•
Tachycardia
Systemic hypertension
Tachypnea
Can exacerbate pre-existing
cardiovascular disease
14
Psychological Effects of Pain
• Poor sleep patterns
• Anxiety
• Uncooperativeness
15
Need for Pain
• Short latency - warn the organism that it
is in danger so it will alter the situation
(e.g.,withdraw limb, take flight, respond
with defensive maneuver).
• Long latency - immobilize the organism
so that recovery from injury can occur.
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Pain Mediators
• Tissue injury causes
release of chemicals
• They sensitize or
activate receptors
• Neurons release
substance P, which
stimulates mast
cells and blood
vessels
• Histamine released
from mast cells and
bradykinin released
from blood vessels
add to pain stimulus
17
• Pain mechanisms are
Why??
complex
Why do I Have Pain?
• Peripheral VS Central
Pain
• Direct nerve
stimulation-Drop
hammer on toe
• Inflammatory painProstaglandins
• Tissue damage-Via
infection or trauma
Indications
• Abrasions
• Lacerations
• Thermal and
Chemical injury
• Dacryocystitis
• Bacterial corneal
ulcers
• Cryo therapy
• Micropuncture
Corneal Erosion
Infection Hurts
Watch Out for those Air Bags
• Blunt trauma to cornea
produces a concussive trauma
• Abrasive surface can denude
the epithelium completely
• Temporary to permanent
stromal edema and hazing-decompensation due to
endothelial shock
• Often an associated
uveitis/hyphema and other
forms of blunt ocular traumatic
injuries
Pain Management
The Drugs
• Peripheral agents: NSAID’s
• Acetaminophen?
• Central Agents: Opiates
23
Peripherally Acting Agents
• Prevent sensitization
and discharge of the
nociceptors
• NSAIDs (including
ASA)
– Block the formation of
inflammatory and pain
mediatory (e.g.
prostaglandins) at the
cyclooxygenase
pathway
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THE INFLAMMATORY CASCADE
Cellular phospholipid membrane
ARACHIDONIC ACID
CYCLOOXYGENASE
LIPOXYGENASE
PROSTAGLANDINS
LEUKOTRIENES
• COX:
• COX-1: constitutive enzyme: is involved
in tissue homeostasis.
• COX-2: inducible enzyme: is responsible
for the production of the prostanoid
mediators of inflammation.
Classification
selection
chemcial
constitution
Non-selective COX inhibitor
Selective COX inhibitor
Salicylates
Acetaminophen
Indomethacin
et al
NSAID’s: THE
CYCLOOXYGENASE BLOCKERS
Salicylates
• Block cyclooxygenase
• Analgesic vs Antiinflammatory dose
• Acetylated vs non-acetylated
Acetylated VS Non-acteylated
Salicylates
Non-acetylated developed to
reduce:
• GI bleeding
• GI Upset
Acetylated: ASA: Aspirin
• Irreversible block of platelets
• Best for use as an anti-coagulant
• None are safe in potential bleeders
THE SECOND GENERATION
NSAID’s
•
•
•
•
•
Less bleeding potential
Less GI Upset
Greater efficacy
Greater potency
All second generation drugs
have the same efficacy in
EQUIVALENT DOSAGES
AND THE SAME SIDEEFFECTS
EQUIVALENT DOSAGES
• 3200mg of ibuprofen = (800mg QID)
• 20mg of Feldene =
(20mg/D)
• 750mg of Naprosyn per day (375mg
BID)
• Only differ in 1/2 life = Dosing frequency
• Only differ in dosage = Potency
NSAID SIDE-EFFECTS
• Inhibit platelets: Only ASA is irreversible
• Allergic to one, allergic to all
• Avoid in asthmatics and those with nasal
polyps-Increased incidence of allergy
• Watch out for protein binding in Type II
diabetics@@@@
• Renal insufficiency: ALL DIABETICS
AT RISK
• CHF
NSAID SIDE-EFFECTS
• Kids with fever: Avoid ASA
• Avoid pregnant or nursing mothers
• Those with GI problems
New NSAIDS
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New COX-2 inhibitors for acute pain
Vioxx , hopefully not the patient, is dead
Celebrex 200mg/D max dose
Celebrex is a sulfonamide
Look close-they will soon be gone
Don’t prescribe them
GONE
Ibuprofen-The Best of the
NSAID’s
• Cheap
• Flexible dosage
Schedule
The Ophthalmic NSAID’s
Use of topical NSAID’s for acute pain
other than cataract surgery is:
OFF-LABEL
Diclofenac 0.1% (VoltarenCiba)
• Generic associated with corneal melting
(never able to prove association)
• Pain and inflammation associated with
cataract surgery
• Dosage: QID
Flubiprofen 0.03% (Ocufen-Allergan)
• ONLY INDICATION-Interoperative
miosis
• 1 drop Q 30min X 4 total 2 hours
prior to surgery
Ketorolac 0.5% and 0.4% (Acular,
Acular PF, Acular LS-Allergan)
•
•
•
•
Really know how to extend a patent
Only NSAID indicated for ocular allergy
Marked stinging
Dosage: QID
Brofenac 0.09%(Bromday – B and L)
• First “once daily” post-op cataract
treatment
Nepafenac 0.1% (NevanacAlcon)
• Only “Pro-drug” NSAID
• Not available as generic
• Dosage TID
Analgesic Pharmacology
• Tylenol/Acetaminophen/(N-Acetyl-Paminophenol)/APAP
• Unknown central mechanism
• Anti-pyretic: Hypothalmus
• No anti-inflammatory effect@@@@
• No inhibition of platelets@@@@
Acetaminophen is a Safe Drug?
Drug of Choice (DOC)
in:
• Children
• Viral induced fever
• Pregnancy@@@@
• Nursing mothers
• No GI distress
• No Increase in
Bleeding?@@@@
If They Like to Drink, Think Twice
About Acetaminophen
• Acetaminophen associated with liver
failure in alcoholics (>3 drinks/d)
• Liver failure = decreased drug
metabolism = overdose
• Reduced vitamin K clotting factors =
increased bleeding
• Max adult dose = 4gm/D = 8 extrastrength Tylenol per 24 hours (2.6gms?)
• 5% of metabolites hepatotoxic
APAP Liver Metabolism
1. Major pathway —Majority of drug is
metabolized to produce a non-toxic
metabolite
2. Minor pathway —Produces a highly reactive
intermediate (acetylimidoquinone) that
conjugates with glutathione and is inactivated.
• At toxic APAP levels, minor pathway metabolism
cannot keep up (liver’s supply of glutathione is
limited), causing an increase in the reactive
intermediate which leads to hepatic toxicity and
necrosis
Acetaminophen toxicity
Centrally Acting Agents
• React with receptors in the
CNS
• Interrupts both the pain
message and its emotional
response
• Opioids – e.g., morphine,
oxycodone, codeine –
mechanisms poorly
understood
• Endorphins
– naturally manufactured
by brain, they may block
peripheral transmitters or
hyperpolarize neurons
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OOOHHH, That’s GOT to
Hurt!!
Opioid receptor types
• MU
• Kappa
• Delta
Ventral
tegmental area
DOPAMINE
movement
Dopam
motivation
ine
addiction
Reward & well-being
Most
strongly
binds
morphine
Best bet
for a safe
analgesic
Receptor Location
type
Effects
μ
Brain,
spinal cord
Analgesia, Respiratory
depression, euphoria, addiction,
ALL pain messages blocked
κ
Brain,
spinal cord
Analgesia, sedation, all nonthermal pain messages blocked
δ
Brain
Analgesia, antidepression,
dependence
MU Opioid receptors
•
•
•
•
Classic morphine receptor
Located in brain and spinal cord
Stimulated by endogenous endorphins
Binding of drug to these receptors produces
analgesia/sedation/decreased
BP/itching/nausea/euphoria/decreased
respiration/
• Effects decline as drug tolerance develops
• Narcotic antagonists block these receptors
Why you feel “happy”
Kappa Opioid receptors
• Novel receptors
• Stimulation relieves pain, but produces
nausea and sweating (dysphoria)
• Endogenous transmitters are dynorphins
• Located in the periphery by pain neurons
• Not associated with euphoria response
Delta Opioid receptors
• Stimulated by endogenous enkephalins
• Produces “ischemic preconditioning”
• Stimulation induced protective increase
in blood flow to tissues surrounding an
ischemic area
• May have cardioprotective effect
Opiate Analgesics
• Block central pain receptors, reduce
perception of pain-They feel pain, but
don’t care
• Inhibits descending pain pathways
• Allergic to one opiate, allergic to all
opiates
• Know your schedules
• Schedule II, high abuse, V= low abuse
• Know your side-effects/autonomics
Side-effects
• Respiration-sleep apnea/COPD
• Urinary tract/the big
prostate/incontinance TX
• GI Tract: The food stops here
• Interaction with other anticholinergics/
• DRY/DROWSINESS/GLC
Is Constipation a Side-effect or
Indication-Depends on your point
of view
INDICATION
SIDE-EFFECT
Tolerance and Dependence
Tolerance
• Tolerance is a diminished responsiveness to the drug’s
action that is seen with many compounds
• Tolerance can be demonstrated by a decreased effect
from a constant dose of drug or by an increase in the
minimum drug dose required to produce a given level
of effect
• Physiological tolerance involves changes in the binding
of a drug to receptors or changes in receptor
transductional processes related to the drug of action
• This type of tolerance occurs in opioids
Dependence
• Physiological dependence occurs when the drug is
necessary for normal physiological functioning – this is
demonstrated by the withdrawl reactions
• Withdrawl reactions are usually the opposite of the
physiological effects produced by the drug
Withdrawl Reactions
Acute Action
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Analgesia
Respiratory Depression
Euphoria
Relaxation and sleep
Tranquilization
Decreased blood pressure
Constipation
Pupillary constriction
Hypothermia
Drying of secretions
Reduced sex drive
Flushed and warm skin
Withdrawl Sign
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Pain and irritability
Hyperventilation
Dysphoria and depression
Restlessness and insomnia
Fearfulness and hostility
Increased blood pressure
Diarrhea
Pupillary dilation
Hyperthermia
Lacrimation, runny nose
Spontaneous ejaculation
Chilliness and “gooseflesh”
COMBINATION OPIATE
ANALGESICS
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Propoxyphene +
Propoxyphene +
Codeine +
Hydrocodone +
Oxycodone +
Oxycodone +
•
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•
•
ASA = Darvon cmpd
APAP = Darvocett
Tylenol 1,2,3,4
APAP = Vicodin
ASA = Percodan
APAP = Percocett
PROPOXYPHENE = DARVON
•
•
•
•
Relatively poor analgesia
Lots of sedation
Neurological side-effects
Use if you want them to
sleep a lot
• Darvocett N 50 and 100
are the best of group =
propoxypene napsylate
with acetaminophen
Which Tylenol with Codeine Should
You Use?
All contain 5 grains of APAP (325mg)
WITH:
• Tylenol #4 = 1 grain (60mg) codeine
• Tylenol #3 = 1/2 grain (30mg)
codeine@@@@
• Tylenol #2 = 1/4 grain (15mg)
codeine
• Tylenol #1 = 1/8 grain 7.5mg)
codeine
A CLINICAL MOMENT
36 Y/O construction worker suffers an
orbital blow-out fracture, complains
about severe pain, requests pain
reliever
Write him a prescription for
acetaminophen with codeine-give him
the maximum pain relieving dosage of
the drug
John Doe
7/20/00
100 Low Life Ln.
Acetaminophen with Codeine #3
#20 (Twenty)
SIG: i-ii tabs q 4-6H prn pain
Refills: Zero
B. Onofrey MO 0182597
ALWAYS PRESCRIBE
FROM THE BIG BOTTLE
Oxycodone, The “BIG GUN”
• With ASA = Percodan
• With APAP = Percocett
• Schedule II drug = High
abuse
• Better alternative with a
schedule III drug
5MG/300MG
That all fine and good butttt:
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My Patients a drug abuser
My Patient’s allergic to opiates
I CAN’T prescribe Narcotic agents
I don’t want to prescribe narcotic agents
My patient doesn’t want to use dope
@@@@@@@@
+
Ibuprofen/acetaminophen
•
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Incredible synergism@@@@@@
Non-narcotic drugs
Non RX drugs
Inexpensive
Monitor for sensitivity to either drug
No motrin in pregnancy/with blood
thinners/GI problems/renal disease/CHF
Ibuprofen/Acetaminophen
Indication/dosage forms
•
•
•
•
Indications:
Mild to severe pain
Dosage forms
400-600mg motrin with 500-1000mg
acetaminophen (Do not exceed 4 gms
acetaminophen/day)
• No acetaminophen for persons that
regularly consume daily alcohol
A Potential Dis-zoster
Trigeminal N.-The 5th Cranial N
The three divisions of the trigeminal nerve come together in an area
called the Gasserion ganglion. From there, the trigeminal nerve root
continues back towards the side of the brain stem, and inserts into
the pons. Within the brain stem, the signals traveling through the
trigeminal nerve reach specialized clusters of neurons called the
trigeminal nerve nucleus. Information brought to the brain stem by
the trigeminal nerve is then processed before being sent up to the
brain and cerebral cortex, where a conscious perception of facial
sensation is generated.
Who gets Post-herpetic
Neuralgia
• Immunocompromised folk
• The elderly
• Best treatment is prophylactic TX
Prevention is Critical
• Acyclovir
• Famcyclovir
• Valcyclovir
Manage Potential Post-herpetic
Neuralgia
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•
•
•
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Oral acyclovir 800mg 5X daily
Valacyclovir 1000mg TID
Famcyclovir 500mg TID
Zostrix creme 3-4 times daily
Low dose tricyclic antidepressantamitryptyline 25mg/day
Anti-depressant for pain relief?
• Very good neural pain relief
• “GOOD” anticholinergic
side-effects
Neurontin: The New “Big Dog”
for chronic pain
• Huge dosage range: 100-5000mg/d
• Must start slow
• Must give enough
Seratonin (5HT Agonists)
• The “triptan drugs”
• Sulfonamides-beware of
allergy\Beware of heart
disease
• Prevent BV Spasm
(Vasoconstrictive effect)
• Inhibit trigeminal nerve
THE HEADACHE PILLSNEVER USE THEM
• HA is a DX of exclusion
• Don’t cover-up
undiagnosed pain
• We must exclude other
causes, but WE don’t
make the final DX
• Let PCP or neurologist
manage pain AFTER
final DX made