Transcript Use of Analgesics

Use of Analgesics
• Most commonly used medications in the US by survey
data
– #1: acetaminophen
– #2: ibuprofen
– #3: aspirin – 50% of users on for cardiovascular prophylaxis
• Among most frequently prescribed meds to those over 65
• OTC analgesic use underreported to healthcare providers
and 10-40% of those prescribed NSAIDs concomitantly
use OTC NSAIDs
Kaufman, JAMA 2002; 287: 337-344
Hensrud, Mayo Clin Proc 1999; 74: 443-447
Eliason, J Am Board FP 1996; 9: 249-253
Use of Analgesics
• Each year in the US:
– Over 30 billion OTC NSAID tablets sold (~$2 billion)
– Over 70 million NSAID prescriptions written
– NSAIDs have been potentially implicated in ~16,500 deaths and
~100,000 hospitalizations for adverse events; most are due to GI bleeds
or renal impairment
– These admits cost the healthcare system ~$2 billion.
• Treatment of NSAID-related gastrointestinal side effects accounts for one third of
the cost of arthritis therapy
• Even though advanced age is well-known factor for adverse GI and renal events,
over half of patients over 65 have been prescribed NSAIDs.
Wolfe, NEJM 1999; 340: 1888-1899
Curhan, Arch Intern Med 2002; 162: 2204-2208
Tamblyn, Ann Intern Med 1997; 127: 429-438
Possible Adverse Interactions between NSAIDs and ASA:
Physician’s Health Study
• Use of non-aspirin NSAIDs in conjunction with aspirin for
primary prophylaxis may increase the risk of first MI
– 22,000 male physicians on aspirin 325 mg QOD or placebo
– Aspirin use was associated with a 44% relative risk
reduction of first MI
– Concomitant NSAID use for  60 days/yr associated with
increased risk of first MI (RR 2.86; 95% CI 1.25-6.56)
Kurth, Circulation 2003; 108: 1191-1195
Possible Adverse Interactions between NSAIDs and ASA
• Use of NSAIDS in conjunction with ASA in patients after 1st CV
admission (angina, MI, CVA, TIA, PVD)
– 7,107 patients
– Administration of ibuprofen with aspirin was associated
with an increased risk of all-cause mortality (adjusted
HR 1.93, 95% CI 1.30-2.87, p=0.001) and CV mortality
(1.73, 1.05-2.84, p=0.031) compared to administration
of ASA alone
– Similar risks were found among patients in ASA alone,
ASA plus diclofenac, and ASA plus other (nonIbuprofen) NSAIDS.
Lancet 2003; 361: 573-4
Platelets in Hemostasis
•Vascular injury
•Platelet adhesion
–
Binding to exposed vWF/collagen
•Platelet activation
–
–
ADP, 5HT, PF4, etc are released
Signals cause COX conversion of
arachidonic acid to thromboxane
in platelets
•Platelet aggregation
–
–
Mediated by thromboxane
Dense network of plateletfibrinogen bridges form occlusive
thrombus
Braunwald, Heart Disease 2001
Antiplatelet Action of Aspirin
Aspirin irreversibly inactivates COX, inhibiting thromboxane production.
Braunwald, Heart Disease 2001
The Balance of COX-1 and COX-2
•COX-1 is expressed constituitively in many tissues.
– In the GI tract, COX-1 results in cytoprotective prostacyclin
production
– In platelets, COX-1 activation results in Thromboxane Synthesis
• Platelet aggregation
• Vasoconstriction
• Smooth muscle proliferation
•COX-2 is induced at sites of inflammation.
– In the endothelium, COX-2 production of prostacyclin inhibits the
actions of thromboxane
• Inhibits platelet aggregation
• Vasodilator
The Balance of COX-1 and COX-2: A Simplified Model
• In vivo, there is a balance of COX-1 and COX-2 activity resulting in
maintenance of vascular hemostasis.
• Non-selective NSAIDS act by suppressing both COX-1 and COX-2
activity, with generally no net effect on hemostasis.
• Selective COX-2 Inhibitors, by inhibiting COX-2 and allowing COX-1
activation (COX-1 is unopposed), have the potential for potentiating
thrombosis and vasoconstriction.
–
? Increased CV risks in retrospective non-randomized analyses
Selective COX-2 Inhibitors and Cardiovascular Outcomes
VIGOR: The Vioxx Gastrointestinal Outcomes Research Study
• Rofecoxib (Vioxx) (50 mg qd) vs. naproxen (500 mg bid)
• 8,076 patients with rheumatoid arthritis
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–
–
–
–
–
–
Excluded patients on ASA or with CV events requiring ASA
1o endpoint: GI events reduced in rofecoxib group
Higher CV event rates among patients treated with rofecoxib
MI rate of 0.4% vs. 0.1% (95% CI 0.1% to 0.6% for rofecoxib)
38% of events occurred in the 3.9% of patients who qualified as aspirin
candidates (for secondary prophylaxis)
Among pts without indication for ASA prophylaxis, MI rates did not differ
between rofecoxib and naproxen
? Untoward effect of rofecoxib among pts not treated with ASA or
beneficial effect of naproxen
NEJM 2000; 343:1520-8
Selective COX-2 Inhibitors and Cardiovascular Outcomes
CLASS: Celecoxib Long-term Arthritis Safety Study
• Celecoxib (400 mg bid) vs. ibuprofen (800 mg tid) or
diclofenac (75 mg bid). Naproxen not evaluated.
• 8,059 patients, majority with osteoarthritis
–
–
–
–
Patients were permitted to take ASA (22%) unlike VIGOR
No difference in MI rates among groups
Similar rates of CV and cerebrovascular events
No differences in non-ASA subgroup (underpowered
though)
– Reduced bleeding rates in celecoxib arm vs. NSAID alone
(6.0% vs 3.1%)
– The two comparator arms (diclofenac and ibuprofen) have
relatively weak antiplatelet effects
JAMA 2000; 284:1247-55
Pooled Analyses of COX-2 Selective Agents
• Mukherjee et al (JAMA 2001)
– Compared MI rates from RCT’s (including VIGOR and
CLASS) with 23,407 patients in placebo arms of primary
prevention trials of ASA, and found higher MI rates among
patients taking refecoxib and celecoxib
– Annualized MI rates: 0.52% for placebo; rofecoxib 0.74%
(p=0.04); celecoxib 0.80% (p=0.02)
– ? confounded by comparisons of different groups of
patients: txd pts with inflammation compared to placebo pts
from primary prevention
*Reicin et al, AJC 2002
White et al, AJC 2002
Mamdani et al, Arch Int Med 2003
Pooled Analyses of COX-2 Selective Agents
• Konstam et al (Circulation 2001)
– 28,000 patients from rofecoxib clinical trials
– No difference in CV events between rofecoxib vs. NSAIDS
other than naproxen
– Higher risk of thrombotic events with rofecoxib vs. naproxen
(RR 1.69 with 95% CI 1.07-2.69).
• Other studies have demonstrated no differences between
COX-2 selective agents vs. non-Naproxen NSAIDS*
*Reicin et al, AJC 2002
White et al, AJC 2002
Mamdani et al, Arch Int Med 2003
NSAIDS and COX-1 Suppression
• Aspirin: Irreversibly acetylates cyclooxygenase in platelets
• Inhibits COX-1 166 times more than COX-2
• 95% suppression of COX-1 activity is necessary to inhibit
Thromboxane-dependent platelet aggregation
– This degree of COX-1 suppression is achieved with
low-dose ASA (92% inhibition of aggregation with 81
mg)
– Other NSAIDS produce variable reversible COX-1
suppression with time-dependency (relative to the
dosing cycle), which may explain beneficial effects of
aspirin relative to these agents.
Aspirin
• Secondary prevention
– >20% reduction in vascular events
• Primary prevention: consistent reduction in CV events
may be offset by an increase in hemorrhagic stroke and
other bleeding events (especially in low-risk patients)
From 3rd US Preventive Task Force; Ann Int Med 2002; 136(2): 157-60
Naproxen
• Naproxen: non-selective NSAID with greater COX-1
activity*
– 95% inhibition of thromboxane synthesis
– 88% inhibition of platelet aggregation
• Observational case-control studies have suggested
possible cardioprotective effect not seen with other nonselective NSAIDS, and benefits in comparison to other
agents (e.g. ibuprofen).**
*J Clin Pharm 2000; 40:1109-20
**Lancet 2002; 359:118-23
Arch Int Med 2002, Vol 162
Antagonism of COX-1 Inhibition by Aspirin
Prior
occupancy
of the
catalytic
site by
ibuprofen
may
prevent
aspirin
from
gaining
access to
its target
serine.
Catella-Lawson, NEJM 2001; 345: 1809-1817
Effects of NSAIDs on Inhibition of COX-1
Activity by Aspirin
• Crossover Study (Single Doses of Each Medication)
– Aspirin 2 hours prior to ibuprofen, then reversed
– Aspirin 2 hours prior to acetaminophen, then reversed
– Aspirin 2 hours prior to rofecoxib, then reversed
• Parallel-Group Study with Multiple Daily Doses of NSAIDs
– Aspirin, then ibuprofen tid starting 2 hours later
– Aspirin, then diclofenac bid starting 2 hours later
Catella-Lawson, NEJM 2001; 345: 1809-1817
Effects of NSAIDs on Inhibition of COX-1
Activity by Aspirin
Catella-Lawson, NEJM 2001; 345: 1809-1817
Effects of NSAIDs on Inhibition of COX-1
Activity by Aspirin (Single Dose Crossover)
Mean inhibition of cyclooxygenase-1 activity as assessed by measurement of serum
thromboxane B2 and inhibition of platelet aggregation after six days of therapy.
Catella-Lawson, NEJM 2001; 345: 1809-1817
Effects of NSAIDs on Inhibition of COX-1
Activity by Aspirin (Single Dose Crossover)
• Despite initial inhibition of COX-1 activity by Ibuprofen,
Ibuprofen prior to ASA inhibited anti-COX-1 effects of ASA
– Not seen when ASA was administered prior to ibuprofen
• Acetaminophen had no significant intrinsic or antagonistic
effects on anti-COX-1 activity
• Similar results were seen with rofecoxib (COX-2 selective
agent)
Catella-Lawson, NEJM 2001; 345: 1809-1817
Effects of NSAIDs on Inhibition of COX-2
• No intrinsic anti-COX 2 effects of ASA were seen
– All effects on Prostaglandin production were seen
after administration of the other agents
– Consistent with the known half-lives of these
agents.
• Ibuprofen: up to 80% inhibition that was transient
• Acetaminophen: up to 50% inhibition that was
transient
• Rofecoxib: > 80% inhibition that was sustained
Catella-Lawson, NEJM 2001; 345: 1809-1817
Effects of NSAIDs on Inhibition of COX-1 by
Aspirin (Multiple Doses)
Mean inhibition of cyclooxygenase-1 activity as assessed
by measurement of serum thromboxane B2 and
inhibition of platelet aggregation after six days of therapy.
Catella-Lawson, NEJM 2001; 345: 1809-1817
Effects of NSAIDs on Inhibition of COX-1 by Aspirin
(Multiple Doses)
• Multiple Daily Doses of ibuprofen antagonized the
anti-COX-1 effects of ASA
– Allowed recovery of thromboxane synthesis and
platelet aggregation
– These findings persisted even though ASA was
administered 2 hours prior to the daily dose of
ibuprofen
• This effect was not seen with diclofenac
Catella-Lawson, NEJM 2001; 345: 1809-1817
Conclusions
• Commonly used OTC doses of NSAIDs may inhibit the
antiplatelet effects of aspirin via competitive binding to
COX-1.
• Patients who use aspirin for cardiovascular prophylaxis
and self medicate with the OTC analgesic ibuprophen may
risk reducing aspirin’s antiplatelet effect.
• Acetaminophen and naproxen do not appear to share this
property and may be taken with aspirin without affecting its
antiplatelet effects.