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Pharmacology of Pain

Medications
From: Bonica, “The Management of pain” 1990
Nerve Fibers
Class Velocity Function
A-α Fast Motor
A-β Fast Touch,
pressure
A-γ Intermediate Muscle tone

A-δ Intermediate Pain,


temperature
B Small Motor
C Small Pain
Pain Fibers

•C
• A-δ
• Changes in A-β
From: Dickinson & Fleetwood-Walker, Trends in Pharm. Sci. 20: 324, 1999.
From: Yaksh, Trends in Pharm. Sci. 20: 329, 1999.
Temporomandibular Joint
dysfunctions
• Disorders of muscles of
mastication(myofascial pain
dysfunction)
• Internal joint derangement
• Degenerative joint disease
• Fractures, infections, tumors
Treatment of Myofascial
Pain Dysfunction
• Non-drug treatment
• Drug treatment
– NSAIDS, Opioids
– Tricyclic antidepressants
(amitriptyline)
– Centrally-acting muscle relaxants
– Glucocorticosteroids
Diagnosis Drug Treatment
Acute and chronic pain NSAIDS, Opioids,
acetaminophen
Myofascial pain Analgesics, tricyclics,
dysfunction centrally-acting muscle
relaxants, glucocorticoids

Neuropathic pain, Carbamazepine,


neuralgias phenytoin, baclofen,
tricyclics, gabapentin,
others?
Aspirin
• Analgesic • Irreversible inhibitor of
COX
• Antiinflammatory
• Nonselective inhibitor of
• Benefits in addition COX (adverse effects)
to analgesia • Analgesic ceiling
• Inhibits COX • Elimination kinetics
• Drug-drug interactions
• Reye’s syndrome
Phospholipids
Phospholipase A2

Arachidonic Acid

COX Lipoxygenase

Prostaglandins Leukotrienes
Thromboxanes
Prostacyclin
Aspirin
Usual dose Effect
80 – 160 mg Antiplatelet
325 – 1000 mg Analgesic, antipyretic
325 mg – 6 grams Antiinflammatory,
tinnitus
6 – 10 grams Respiratory alkalosis
10 – 20 grams Fever, dehydration,
acidosis
> 20 grams Shock, coma
Aspirin
(rapid)

Salicylate
(slower) *

Metabolites In urine

( * = http://www.hsc.wvu.edu/som/pcol_tox/pharm361/lectures/djs/nsaid.htm
Ibuprofen and other NSAIDS
• Analgesic • Nonselective
• Antiinflammatory inhibitor of COX
• Reversible (adverse effects)
inhibitors of COX • Analgesic ceiling
Acetaminophen
• Analgesic • Not
• Low effect on antiinflammatory
peripheral COX • Analgesic ceiling
• Few drug-drug • Liver toxicity
interactions
Acetaminophen
• May inhibit COX selectively in central
nervous system
• Only weak inhibitor of peripheral COX
(peroxide effects?)
• Inhibits effects of substance P in CNS?
• Inhibits effects of glutamate in CNS?
Acetaminophen – Mechanisms
of Action
• Central effect at level of spinal cord ( Little
effect on peripheral COX-1 or COX-2)
• Spinal antinociceptive effect is amplified by
acetaminophen in the brain.*
• The brain effect is mediated by an opioid
mechanism expressed at the level of spinal
cord.*
* Raffa et al., J. Pharm. Exp. Therap. 295: 291, 2000.
Acetaminophen

(conjugation) (oxidation)

Non-toxic Toxic
metabolites metabolites*

(* = http://www.hsc.wvu.edu/som/pcol_tox/pharm361/lectures/djs/nsaid.htm
Selectively For COX-1 and -2

• Most NSAIDS (COX-1 > COX-2)


• Nabumetone (Relafen) and Etodolac
(Lodine) (COX-1 = COX-2)
• Celecoxib (Celebrex) and Rofecoxib
(Vioxx) ( COX-2 > COX-1)
Selective COX-2 inhibitors
• Analgesic • Less experience
• Antiinflammatory • More expensive
• Fewer adverse
effects
• Blood
• GI tract
• Kidney
Celecoxib (Celebrex)
• Half life ~ 12 hours
• Metabolized in liver
• Has a sulfur atom – possible
problem in patients with allergies to
sulfonamides
Rofecoxib (Vioxx)
• Half life ~ 17 hours
• Metabolized in the liver
• Does not contain a sulfur atom
Opioids
• Much less ceiling • Adverse effects
effect • GI tract
• Work through • CNS
opioid receptor • Histamine
mechanisms release
∀↑ cranial
pressure
Sites of Opioid Action (*)
Midbrain
*

Medulla
*
Sensory
Ascending
Nerve
Tract

•* Spinal Cord
Some Opioid – Nonopioid
Combinations
• Codeine + Aspirin (Empirin)
• Codeine + Acetaminophen (Tylenol#?)
• Dihydrocodeinec+ Aspirin + caffeine (DHC Plus)
• Hydrocodone + Acetaminophen (Lortab ?/?)
• Oxycodone + Acetaminophen (Percocet)
• Pentazocine + Aspirin (Talwin compound)
• Propoxyphene + Acetaminophen (Wygesic)
Clinical Study (Diclofenac-100 mg
[D]; Acetaminophen-1000 mg [A];
codeine-60 mg [C])

50 ***
45 ***
40
35
**
30 * *
25
Total Pain Relief
20
15
10
5
0
D A A+C D+A D+A+C
Breivik et al. Clin.Pharmacol. Ther. 66: 625, 1999
NSAID +Acetaminophen
• Greater analgesic effect than either
alone
• Avoids adverse effects of opioids
• Similar half lives for many NSAIDS
and acetaminophen
• Over-the-counter
• Each has analgesic ceiling.
NSAID + Acetaminophen
• Ibuprofen
• 400-600 mg, q 4-6 hr
• max of 2400 mg q 24 hr
• Acetaminophen
• 600-1000 mg, q 4-6 hr
• max of 4000 mg q 24 hr
NSAID + Acetaminophen
• Ibuprofen (400 mg q 4 hr) +
acetaminophen (600 mg q 4 hr)

• Ibuprofen (600 mg q 6 hr) +


Acetaminophen (1000 mg q 6
hr)
Diagnosis Drug Treatment
Acute inflammatory pain NSAIDS, Opioids

Myofascial pain Analgesics, tricyclics,


dysfunction centrally-acting muscle
relaxants,
glucocorticoids
Neuropathic pain, Carbamazepine,
neuralgias phenytoin, baclofen,
tricyclics, gabapentin,
others?