Pharmacology for the Athletic Trainer
Non-Steroidial Anti-inflammatory Drugs
NSAIDS
David S. Knitter, MD, FCCP
HTH 376
Fall 2001
In 1997, the Nonprescription Drug Manufacturers Association
(NDMA) published the report of a study conducted by Kline
& Co. and subtitled "Economic Benefits of Self-Medication."
“The economic analysis resulted in an estimate that OTC availability for
the categories studied resulted in savings to the consumer of $20.6 billion
annually when compared with the costs of treating the ailments using
physicians and prescription medications. The researchers estimated that
nearly two-thirds of the calculated savings could be traced to Rx-to-OTC
switched products.”
Rise In OTC Sales
Category
1996 ($ in
millions)
2001 ($ in
millions)
Analgesics
935.1
1,262.6
% average
annual growth
rate
7.5
Antifungal
(vaginal)
233.0
253.7
14.7
Smoking
cessation
53.0
410.0
51.0
Product
Percent of sales dollars of top
21 OTC products
Advil
9.0%
Aleve
4.0
Motrin IB
3.0
NSAID Classes
Acetylated Salicylic
acid
Non-Acetylated
Salicylic acid
Acetic acid
derivatives
Aspirin
Difunisal
Choline salicylate
Choline-magnesium
trisalicylate
Sodium salicylate
Salsalate
Magnesium salicylate
Indomethacin
Sulindac
Toletin
Etodolac
Diclofenac
Propionic Acids
Fenamic acids
Enolic acids
Fenoprofen
Flurbiprofen
Ibuprofen
Ketoprofen
Naproxen
Oxaprozin
Meclofenamate
Piroxicam
Phenylbutazone
Current OTC NSAIDs
•
Aspirin
 325mg not to exceed 4 grams in 24 hours
•
Ibuprofen
 200mg not to exceed 1200 mg in 24 hours
•
– Advil
– Nuprin
– Mortin AB
Naprosyn
 200mg not to exceed 600mg in 24 hours
•
– Aleve
Ketoprofen
 12.5mg not to exceed 75mg in 24 hours
– Orudis KT
Prostaglandin (PG) Synthesis
• Prostaglandins have been implicated in pathogenesis of
inflammation and fever
• Aspirin-like drugs inhibit the biosynthesis and release of
PGs
• Inhibition of the synthesizing enzyme (cyclo-oxygenase) is
fairly well correlated with anti-inflammatory action
 Inhibition of COX2 (inducible) may be responsible for therapeutic
effects of NSAIDs
 Inhibition of COX1 (constituitive) may be responsible for many
adverse effects of NSAIDs
Prostaglandin (PG) Synthesis
Pain
• Direct administration of PGs causes local pain
evidence suggests that PGs (PGE2?)sensitizes
pain receptors to bradykinin, a local mediator of
pain released during inflammation
• Aspirin is less effective against sharp pain (direct
stimulation of nerve endings - no PGs, opioids
more effective) than against the dull, throbbing
pain of inflammation (involves PGs)
Prostaglandin (PG) Synthesis
Fever
• Infection bacterial endotoxins cause release of endogenous
pyrogens from neutrophils
• Tissue damage or inflammation interleukin 1 released by
macrophages (principal role is to activate lymphocytes)
affects hypothalamus
• Aspirin-like drugs work by increasing heat loss
(vasodilatation of peripheral blood vessels) not by
reducing heat production
Adverse Effects
• Gastrointestinal Effects
 nausea and vomiting stimulation of CTZ in medulla
 gastric bleeding 3-8 ml/day blood loss with 4-5 g aspirin/day
vs 0.6 ml in untreated subjects
• Blood Clotting
 aspirin irreversibly inhibits platelet synthesis of thromboxane
A2 (TXA2) which is required for aggregation
 other NSAIDs - reversible effect on clotting
 non-acetylated salicylates - no effect on clotting
 terminate chronic use of aspirin 1 week prior to elective
surgery (most other NSAIDs 24-48 hr)
Adverse Effects
• Salicylism
 characterized by tinnitus (may be related to increased
labyrinthine pressure or effect on cochlear hair cells, pehaps
secondary to vasoconstriction of auditory microvasculature),
headache, nausea and vomiting, dizziness and dimness of
vision
• Aspirin Hypersensitivity or ”Aspirin Intolerance"
 1/4 million in USA
 symptoms include rhinitis, profuse watery secretions,
bronchial asthma, bronchconstriction, hypotension,
vasomotor collapse, coma
 non-acetylated salicylates may be used cautiously
Adverse Effects
• Reye's syndrome
 rare but often fatal consequence of infection
with varicella and various other viruses
 salicylates are contraindicated in children and
adolescents with chicken pox or influenza
Acetaminophen
• Little or no anti-inflammatory activity
• Mechanism of action is unknown
 Very weak inhibitor of cyclo-oxygenase
 Greater effect in the CNS ??
• Minimal gastrointestinal irritation
• No effect on bleeding time
Acetaminophen Toxicity
• Hepatic necrosis (acute 10-15 g; >25 g usually
fatal)
• Increased incidence of
hepatotoxicity in the
presence of ethanol and/or
fasting (with as little as 4
g/day)
• Ethanol induces hepatic
MFO metabolism (pathway
3) shifting reaction toward
toxic metabolite (limited
glutathione available)
Renal Tubular Necrosis
• Increased risk with lifetime intake
• Associated greater than 1000
tablets of acetaminophen
• Associated greater than 5000
tablets of NSAIDs
• ? effect of aspirin
• Gastrointestinal toxicity from NSAIDs is an important
cause of morbidity and mortality in the United States.
Severe complications primarily include
gastrointestinal hemorrhage, ulcer perforation, and
bowel obstruction. Among long-term users of
NSAIDs, the mortality rate from gastrointestinal
complications is 0.22% per year (1). However, with
such a large population of regular users, NSAIDrelated gastrointestinal complications rank 15th
among the most common causes of death in the
United States (table 1: not shown).
• Do the new drugs celecoxib (Celebrex) and rofecoxib (Vioxx)
reduce risk for clinically relevant gastrointestinal toxicity
compared with the older NSAIDs? Theoretically, there are
reasons to suggest that celecoxib and rofecoxib might be safer.
Both celecoxib and rofecoxib selectively inhibit cyclooxygenase2 (COX-2) and spare cyclooxygenase-1 (COX-1). In human
physiology research (23), COX-2 suppression decreased joint
inflammation, pain, and fever. By sparing inhibition of COX-1,
selective COX-2 inhibitors permit COX-1-mediated generation of
prostaglandin E2 and thromboxane A2. Prostaglandin E2 has a
physiologic role to protect the gastrointestinal mucosa from
ulceration. Thromboxane A2 in platelets is important in
hemostasis (23). The physiology of COX metabolism gives a
theoretical rationale for development of drugs that selectively
inhibit COX-2. In theory, selective COX-2 inhibitors should retain
the analgesic and anti-inflammatory efficacy of older NSAIDs
while demonstrating improvement in gastrointestinal toxicity
Table 5a. Comparison of annualized event rates for symptomatic
ulcers plus ulcer complications (perforation, obstruction, bleeding)
with NSAID use
Dose
Event rate NNT (95% CI)
Patients not taking aspirin
Celecoxib 400 mg bid
1.4%
67 (36 to 468)
NSAID
Ibuprofen 800 mg tid;
diclofenac 75 mg bid
Patients taking aspirin*
Celecoxib Same as above
2.9%
NSAID
6.0%
Same as above
4.7%
Not significant
Table 5b. Comparison of event rates for gastrointestinal adverse
effects** with NSAID use
Dose
Event rate NNT (95% CI)
Patients not taking aspirin
Celecoxib 400 mg bid
8.0%
47 (28 to 144)
NSAID
Ibuprofen 800 mg tid;
10.1%
diclofenac 75 mg bid
Patients taking aspirin*
Celecoxib Same as above
11.2%
Not significant
NSAID
Same as above
13.1%
Table 6. Comparison of event rates for rofecoxib and naproxen
Dose
Event rate NNT or NNH (95% CI)
Complicated confirmed upper gastrointestinal events (annualized)*
Rofecoxib 50 mg daily 0.6%
125 (80 to 293)
Naproxen
500 mg bid
1.4%
Other gastrointestinal side effects (total events during trial)**
Rofecoxib 50 mg daily 3.5%
72 (44 to 200)
Naproxen
500 mg bid
4.9%
Myocardial infarction (total events during trial)
Rofecoxib 50 mg daily 0.4%
338 (186 to 1,822)
Naproxen
500 mg bid
0.1%
• In one cost-utility estimate (26) published before CLASS or
VIGOR, the cost to treat with celecoxib or rofecoxib was
$400,000 per year to prevent one complicated ulcer in
rheumatoid arthritis patients at low risk of gastrointestinal
complications. When one is treating patients at high risk, the
costs to use these drugs may be more reasonable. The annual
cost estimate was $30,000 to treat high-risk patients with
celecoxib or rofecoxib to prevent one complicated ulcer. In light
of the CLASS and VIGOR results, formal pharmacoeconomic
analyses are needed. Because COX-2 inhibitors do not reduce
gastrointestinal risks in aspirin users, future decision analyses
should address the competing hazards of myocardial infarction
and stroke in patients who forego aspirin prophylaxis to take a
COX-2 inhibitor. The small risk of myocardial infarction is a real
risk to be considered, as demonstrated by the VIGOR study