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CHRONIC PAIN MANAGEMENT
Efficacy & risk evaluation for long term therapy
Rheumatic pain
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Symptoms
Joint pain Joint swelling Morning stiffness Fatigue Weight loss Flu-like symptoms
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Symptomatic Treatments
Education/support Rest/relaxation Joint protection Physiotherapy Analgesics Anti-inflammatory drugs Steroids Joint injections Pain Management Clinics
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Symptomatic Treatments
Education/support Rest/relaxation Joint protection Physiotherapy Analgesics Anti-inflammatory drugs Steroids Joint injections Pain Management Clinics
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Key questions regarding NSAIDs* What are the benefits and risks from
NSAIDs? How do I reduce the GI risks? How do I reduce the CV risks? Are there specific safety concerns with
etoricoxib▼? What does the prescribing data Iook like?
*Note by NSAIDs we mean traditional NSAIDs (e.g. diclofenac, naproxen, ibuprofen); etodolac, meloxicam, or coxibs (e.g. celecoxib, etoricoxib)
WHAT ARE THE BENEFITS AND RISKS OF NSAIDS?
NICE Full Clinical Guideline 59: Osteoarthritis. Feb 2008
Benefits and risks of NSAIDs
Estimate of hospital-related admissions due to NSAID adverse reactionsBandolier 2000;79:6–8
Event due to NSAID Estimated number of cases per year per primary care group (PCG)
Upper GI bleed 18
Acute renal failure 10
Congestive heart failure 22
Information based on an average PCG of 100,000 patients where 3,800 patients aged over 65 years take NSAIDs
NSAIDs: Renal risksMHRA DSU. May 2009
Renal risk
HOW DO I REDUCE THE GI RISKS OF NSAIDS?
No strong evidence to suggest NSAIDs have a consistent benefit over paracetamol, although some patients obtain greater symptom relief from NSAIDs
Clinicians should consider offering paracetamol for pain relief in addition to core treatment; regular dosing may be required
Paracetamol (and/or topical NSAIDs) should be considered ahead of oral NSAIDs, COX-2 inhibitors or opioids
Paracetamol>< NSAIDs ?
NICE Full Guideline 59: Osteoarthritis, Feb 2008
NICE Full Clinical Guideline 59: Osteoarthritis. Feb 2008
Using Paracetamol ?Pincus T, et al. J Rheumatol 2000;27:1020–1027Wolfe F, et al. Arthritis Rheumatol 2000;43:378–385
Risk of upper GI ulcer bleedingLanas A, et al. Gut 2006;55:1731–38
Hospital-based, case-control study in Spain
2777 consecutive patients with endoscopy-proved major upper GI bleeding (peptic lesions) and 5532 matched controls
Use of NSAIDs increased risk
(RR 5.3;95%CI 4.5 to 6.2)
No increased risk for NSAIDs + PPI (RR 0.9, 95%CI 0.7 to 1.3)
Rofecoxib increased the risk
(RR 2.1; 95%CI 1.1 to 4.0)
No increased risk with celecoxib
(RR 1.0; 95%CI 0.4 to 1.6)
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NSAIDs: GI risks Ibuprofen offers the lowest GI risk; Coxibs are
associated with reduced GI risk relative to most NSAIDs at equivalent doses
MeReC Extra 30. November 2007
When offering treatment with an oral NSAID/coxib inhibitor, the first choice should be either a standard NSAID or a coxib (other than etoricoxib▼ 60mg). In either case, these should be co-prescribed with a proton pump inhibitor (PPI), choosing the one with the lowest acquisition cost.
NICE. Osteoarthritis Guideline CG59. February 2008
HOW DO I REDUCE THE CV RISKS OF NSAIDS?
Coxibs and cardiovascular risk MHRA. Safety of selective and non-selective NSAIDsOctober 2006
Coxibs are associated with an increased thrombotic risk.
Risk varies according to underlying patient risk factors
Population risk is about 3 additional events (mainly MI) per 1000 patients per year compared with placebo.
Dose-related adverse effects may manifest early and the risk may persist throughout treatment
Traditional NSAIDs and CV riskMHRA. Safety of selective and non-selective NSAIDs. October 2006
Diclofenac 150mg daily has a similar excess thrombotic risk to that of etoricoxib▼ and possibly other coxibs
Naproxen 1000mg daily may be associated with a lower risk of thrombotic events than coxibs. Although some risk with naproxen cannot be entirely ruled out, epidemiological evidence suggests that naproxen is not associated with an excess risk of MI
Ibuprofen may be associated with a small thrombotic risk at high doses (e.g. 2400mg daily), whereas at low doses (e.g. 1200mg daily) evidence does not suggest an increased thrombotic risk in the short term
CV Issues With COX-2 Selectiveand Traditional NSAIDs In placebo-controlled randomized trials, COX-2
selective NSAIDs ↑’ed the risk of thrombotic CV events Observational studies suggest ↑ CV risk for some
traditional NSAIDs CV risk of high-dose naproxen may be different:
Meta-analysis of randomized trials: CV risk of high-dose naproxen appears lower than COX-2 inhibitors
2005-6 FDA and European regulatory agencies added a warning of an increased thrombotic CV risk for all NSAIDs (both COX-2 selective and traditional)
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Kearney et al. BMJ. 2006;332:1302; Solomon et al. NEJM. 2005;352:1071; Bresalier et al. NEJM 2005;352:1092; FDA. At: http://www.fda.gov/bbs/topics/news/2005/NEW01171.html. Accessed October 2006; CHMP. At: http://www.emea.eu.int/pdfs/human/opiniongen/nsaids.pdf. Accessed October 2006.
Questions arising with COX-2 selective and traditional NSAID therapies
These studies raise many questions:
1. Does greater COX-2 selectivity increase CV risk vs. traditional NSAID?
2. Is high-dose naproxen, with its sustained antiplatelet effect, different?
3. Would use of aspirin attenuate the increased risk seen with NSAIDs?
Need large randomized trials comparing CV outcomes between different NSAID agents
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Primary Endpoint: Cumulative Incidence of Thrombotic CV Events
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Etoricoxib (320 events)
Diclofenac (323 events)
MonthsNo. of patients at risk*
EtoricoxibDiclofenac
16,81916,483
13,359 10,733 8277 6427 4024 80581538326213790110,14212,800
7.0
6.0
5.0
4.0
3.0
2.0
1.0
06 12 18 24 30 36 420
Cu
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(%
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95%
CI
Etoricoxib vs diclofenacHR = 0.95 95% CI = (0.81-1.11)
*Per protocol population.
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Cumulative Incidence of Confirmed Upper GI Events (Perforations, Ulcers, and Bleeds)*
POBs†
MonthsNo. of patients at risk
EtoricoxibDiclofenac
1741217289
13704 10972 8400 6509 4063 8218203867630680271039613190
3.0
2.5
2.0
1.5
1.0
0.5
06 12 18 24 30 36 420
Cu
mu
lati
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cid
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(%
) w
ith
95%
CI
Etoricoxib vs diclofenacHR = 0.69 95% CI = (0.57-0.83)
*ITT (14 days) population. 50.6% of patients were on gastroprotective agents.
Etoricoxib (176 events)
Diclofenac (246 events)
†No significant difference in perforations, obstructions, or major bleeds.
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“Our results show that patients with arthritis treated with the COX-2 selective NSAID etoricoxib and those given the traditional NSAID diclofenac have nearly identical rates of thrombotic cardiovascular events.”
Cannon CP, Curtis S, FitzGerald GA, et al. Lancet. 2006:368 (published online) www.thelancet.com
Dr. Loren Laine is presenting preliminary GI subgroup data at Am. Coll. Rheumatology in Wash DC todayFor the lower risk upper GI clinical events with etoricoxib: Generally consistent benefit in ASA and PPI subgroups
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ARTHRITIC PATIENTS WITH HYPERTENSION
Etoricoxib▼ and blood pressure MHRA. DSU July 2008
EMA review of etoricoxib Patients whose BP is persistently above 140/90 mmHg
and inadequately controlled must not receive etoricoxib High BP should be controlled before starting treatment,
and should be monitored for 2 weeks after the start of treatment and regularly thereafter
Key messages All NSAIDS (both coxibs and traditional NSAIDs)
are associated with CV, renal and GI side effects
Where NSAIDs are required, base prescribing on the safety profiles of individual NSAIDs taking into account individual patient risk factors
Generally, prescribe NSAIDS at the lowest effective dose and for the shortest period of time necessary to control symptoms. Review prescribing regularly.
Key messages
The risks of CV side effects with diclofenac and coxibs are similar
Low-dose ibuprofen and naproxen are associated with the lowest CV risk
Consider co-prescribing a PPI with an NSAID, especially to those at high risk of GI side effects, and when used for long-periods of time
THANK YOUHave an enjoyable learning
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