Rheumatic pain management

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

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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

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0.5

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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