Pain 2.

See the course schedule for readings.

H. Schaefer, MN 1
 Pain treatment: ‘Analgesia’

1) At CNS level:
• non-opioid centrally acting agents
• acetaminophen (Tylenol)

• Opioid analgesics
• E.g. morphine

2) At peripheral level:
• NSAIDS
• E.g. Ibuprofen

Tx: if inflammation - high efficacy

H. Schaefer MN
routes of administration, common e.g.

• IV
• PCA
• PO
• Extended release options

• intranasal

• PR

• Other, classified under

anesthesia (discussed in year 2):
• epidural, spinal, nerve block

H. Schaefer, MN 3
Acetaminophen (Tylenol)

• centrally acting analgesic

• not anti-inflammatory
• administration: PO; q4h
• antipyretic
• highest efficacy

• Overdose tx:

H. Schaefer MN
Review: Tylenol metabolite metabolism

Phase I N-acetyl-p-
acetaminophen benzoquinoneimine
Hepatotoxic

Phase II
Glutathione
Conjugate

Acetaminophen overdose depletes stores of

glutathione, resulting in build-up of toxic intermediate
metabolite
H. Schaefer MN
 ADME
• Absorption
• PO excellent bioavailabity
• Cmax 30-60 min
• Well distributed
• low (20%) PPB
• Active metabolites
• Hepatic metabolism CYP 3A4 & 1A2
• Hepatotoxic metabolite N-acetyl benzo
• phase II metabolized (glutathione)
• Renal excretion
• t1/2 : 2-3 hrs

H. Schaefer MN
Opioid drugs

• Opioid:
• Any drug that is derived from the opium formula
• Opium: contains morphine and codeine substances

• Narcotic: describes CNS depressing substances

• Terminology is associate with illegal use
• Terminology is used in clinical settings to imply the drug is monitored
E.g. ‘narcotic count’ at start and end of shift

• Controlled dispensing and prescribing

• Most are Schedule 1 (some are schedule 2)
• Prescribing monitored

H. Schaefer, MN 7
Opioids (‘opium-like’)

• Centrally acting analgesics

• agonists for receptors mu, kappa, delta
• efficacious
• binding inhibits release of Substance P

H. Schaefer MN
 Opioids
• used for moderate-severe pain

•High efficacy e.g.

•Fentanyl
•hydromorphone (Dilaudid) – 5x stronger than morphine
• meperidine (Demerol)
• Morphine
• methadone (Metadol)
• Moderate efficacy
• hydrocodone, oxycodone (OxyNeo), oxycontin, tramadol
(Ultram)
• combo drugs: Percocet, Percodan, Vicodin, Tramacet

• Codeine; combo drugs: Tylenol #1-#4

H. Schaefer MN
Combination drugs:
• Synergy effect

• E.g.
• Percocet (oxycodone + acetaminophen)
• Percodan (oxycodone + ASA)
• Vicodin (hydrocodone + acetaminophen)
• Tramacet (Tramadol + acetaminophen)

• Tylenol #1, 2, 3, 4 (acetaminophen + codeine + caffeine)

H. Schaefer MN
ADME: general
• Intermediated PPB (30%)
• Varying affinity
• Lipophillic
• Quickly distribute via bloodstream into tissues
• Accumulation in fatty tissue!!!

• Metabolism:
• Hepatic
• Codeine metabolized into Morphine (CYP 2D6 & 3A4)
• NO CODEINE FOR KIDS

• Excretion:
• Renal
• Bile – biliary recirculation?
• Extremely small

H. Schaefer MN
FYI: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704133/
 Effects & side effects
Opioid receptor effects other

Mu1 Analgesia Histamine release

Euphoria
Confusion Dopamine release
Dizziness
Nausea
Sedation

mu2 Resp depression

Cardiovascular effects
(hypotension)
GI effects (slow motiolity)
Urinary retention
Miosis

delta Analgesia
Cardiovascular effects
Respiratory depression

kappa Analgesia
Psychomimetic effects
(nightmares) H. Schaefer, MN 12
Clinical application: Adverse Effects!!!!
• Common side effects:
• CNS depression
• CNS effects
• N&V
• Pruritus
• Constipation
• Urinary retention

H. Schaefer MN
Brainstorm

• Using your health assessment, what would you assess with opioid
administration?

• Head-toe approach:

H. Schaefer, MN 14
Opioid OD treatment:
Opioid receptor Antagonist
• Naloxone (Narcan)
• onset – 2-4 minutes
• Duration of action = 45 min

• Treatment of opioid dependence: methadone protocol

BRAINSTORM:
What would the effects of administering Narcan to a patient receiving
opioids for therapeutic reasons be?

What could decrease the effectiveness of Narcan? (think dynamics)

H. Schaefer MN
Euphoria: 4 C’s of Addiction:

• Loss of Control over use

• Use despite harmful Consequences
• Compulsion to use
• Craving

• https://www.youtube.com/watch?v=K3gfzfqEre0

H. Schaefer MN
Pain rating = treatment options

• < 4/10
• => non-opioid medications
• less invasive route, e.g. PO
• NSAIDs, Tylenol

• 4-6/10
• => opioids
• less invasive route, e.g. PO
• combination drugs, Morphine

• >6/10
• => higher potency opioids
• Consider IV route
• Consider PCA

H. Schaefer MN
Efficacy is important
• Tx of inflammation
• Allergy?
• Antihistamines (in allergy)

• Tissue injury?
• NSAIDS; biologics per disease dx

• Glucocorticoids
• Beta 2 adrenergic agonists (bronchoconstriction)
• Tx of pain
• Acetaminophen
• NSAIDS
• Opioids
• TX of fever
• Acetaminophen
• NSAIDS

H. Schaefer MN
Other Efficacy, e.g.:
• MI pain
• Med: Morphine
• Opioid
• Vasodilation (decreased BP & CO)

• Headache
• Ibuprofen

• ASA
• Low-dose antithrombotic (cardiac treatment)

• GI pain
• Med: dicyclomine (Bentyl)
• Muscarinic Antagonist
• GI smooth muscle relaxant
H. Schaefer MN
Noxious stimulus & relationship with fever

H. Schaefer MN
FEVER
• Fever:
• Stimulated body response to pyrogens & pro-inflammatory
mediators (e.g. cytokines
• CNS: Hypothalamus triggered
• Non-specific
• Aim: destruction of pathogen by high temperature

• High fever – increases metabolism, decreases cellular

function

H. Schaefer MN
Fever tx: Antipyretics

Acetaminophen (Tylenol)
• Hypothalamus Dilation of peripheral vasculature = heat loss
• 1st choice; best efficacy
• no Rye’s syndrome
• PO, q4h administration

• 2nd choice:
• NSAIDS (Ibuprofen, ASA)
• Antiinflammatory action reduces fever
• no ASA in pediatrics

H. Schaefer MN
 Clinical application
• Cause of fever?

• Tx associated symptoms:
• Hydration
• Nutrition
• rest
• isolation precautions

• Tylenol Pregnancy category B

H. Schaefer MN