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A NEW STANDARD

IN THE MANAGEMENT OF
PAIN AND INFLAMMATION

The Gain of Pain


Pain is not a passive consequence of
the transfer of a defined peripheral
input to a pain center in the cortex,
but an active process generated
partly within the CNS by multiple
plastic changes that together
determine the gain of the system.
Woolf CJ et al. Science. 2000;288:1765-8.

Conditions Associated with


Chronic Pain
Osteoarthritis
Rheumatoid
arthritis
Low back pain
Headache

Musculoskeletal
pain
Malignancy
Chronic infection

Burden of Arthritis:

Escalating Prevalence
59.4

60

Arthritis prevalence

50

Million

40

Arthritis causing
activity limitation

37.9

30
20
10
0

11.6
7.0
1990

2020*
Year

*Projected
Lawrence et al. Arthritis Rheum. 1998;41:778799.

Barriers to Treatment of
Chronic Pain
Patient reluctance to report pain
Physician reluctance to prescribe opioid
therapy
Patient reluctance to take opioid analgesics
Ineffectiveness of simple analgesics in reducing
inflammation, swelling, and stiffness
Complications of NSAIDs and opioids
significant burden on health care resources
major factor in the hospitalization and premature
death of patients with arthritis

Mechanism of Action of
Anti-inflammatory Agents
Arachidonic
acid
COX-1

COX-2

NSAIDs
Prostaglandins/
thromboxane

Primarily support
platelet function

Primarily protect
gastroduodenal
mucosa

COXIBS

Prostaglandins

Primarily mediate
inflammation, pain,
and fever
C99000DT000- III.2

Role of COX-2 in Chronic Pain


Peripheral

Central

Inflammatory
stimulus

Pain and sensitization

COX-2

Prostaglandins

PGE2

COX-2
Adapted from Smith CJ et al. Proc Natl Acad Sci USA. 1998;95:13313-8.

Common Sequelae of OA and RA


Erosive joint
disease

Fatigue

Bone-on-bone
condition

Muscle
strength and
endurance

Chronic
inflammation

Activities of
daily living

Depression

Won A et al. J Am Geriatr Soc. 1999;47:936-42.

Multimodal Management
of OA and RA
Nonpharmacologic

Pharmacologic

Exercise/Weight loss
Physical therapy
Other

Analgesics
Anti-inflammatory agents
DMARDs/DMOADs

Surgical
Osteotomy
Arthroplasty

Nonpharmacologic
Therapy for Arthritis
Patient education
Weight loss (if overweight)
Aerobic and muscle-strengthening
exercise training
Physical/occupational therapy, rangeof-motion exercises
Joint protection, assistive devices
ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46:328-46.
ACR Subcommittee on OA Guidelines. Arthritis Rheum. 2000;43:1905-15.

Pharmacotherapy for Arthritis


OA

RA

Analgesics
NSAIDs

DMARDs

nonselective
COX-2 specific
inhibitors

Intra-articular
glucocorticoids
Intra-articular
hyaluronic acid

NSAIDs
nonselective
COX-2 specific
inhibitors

Local or low-dose
systemic steroids
ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46:328-46.
Creamer P et al. Lancet. 1997;350:503-8.
Hochberg MC et al. Arthritis Rheum. 1995;38:1535-40.
ACR Subcommittee on OA Guidelines. Arthritis Rheum. 2000;43:1905-

Goals of OA Treatment
No known cure for OA
Individualized treatment can
reduce pain
maintain and/or improve joint mobility
limit functional impairment

ACR Subcommittee on OA Guidelines. Arthritis Rheum. 2000;43:1905-15.

ACR 2000
Osteoarthritis Guidelines
Nonpharmacologic measures (ie, patient education, weight loss,
exercise, physical therapy [PT])
Pharmacologic therapy
mild-to-moderate joint pain
acetaminophen
topical agents (ie, methylsalicylate or capsaicin as adjunct or alone)
moderate-to-severe joint pain
joint aspiration in addition to other agents depending on upper
gastrointestinal (UGI) and renal risks
intra-articular injections (glucocorticoids or hyaluronic acid)
COX-2 specific inhibitors
nonselective NSAIDs
tramadol
opioids
ACR Subcommittee on OA Guidelines. Arthritis Rheum. 2000;43:1905-15.

ACR 2000
Osteoarthritis Guidelines
Nonpharmacologic measures
Acetaminophen
Mild-to-moderate joint pain
Topical agents
Methylsalicylate or
capsaicin
for those who do not want
systemic therapy

Joint aspiration plus


intra-articular injection or oral
NSAID Moderate-to-severe knee pain

Anti-inflammatory therapy

At risk for UGI event


COX-2 inhibitors or intra-articular injections
(glucocorticoids or hyaluronic acid)

Nonselective NSAID
(with misoprostol
or proton pump inhibitor in at-risk
patients)

Tramadol
Opioids
ACR Subcommittee on OA Guidelines. Arthritis Rheum. 2000;43:1905-15.

ACR 2000 OA Recommendations for


Patients at Risk for Upper GI Events
COX-2 specific agents
(celecoxib or rofecoxib)

Nonselective NSAID
plus misoprostol or PPI in high-risk patients
(even with low-dosage nonselective NSAID)
Nonacetylated salicylates

Pure analgesics
(tramadol or opioids)
ACR Subcommittee on OA Guidelines. Arthritis Rheum. 2000;43:1905-15.

American Pain Society 2002


Treatment of Chronic Pain in OA
Mild pain
Little or no inflammation
Acetaminophen
Continued pain?

Yes

Moderate-to-severe pain
Inflammation

Plus, as needed:

COX-2 specific inhibitor

Nonpharmacologic
interventions

Yes

Glucosamine

Continued pain?

Adjunctives

Conduct GI risk
factor analysis
High risk
Nonselective NSAID
+ PPI or misoprostol

American Pain Society, 2002.

Intra-articular
hyaluronic acid

Not high risk


Nonselective NSAID

Continued pain?

Tramadol

Yes

Surgical intervention

Hyaluronic acid injection for


knee pain
Glucocorticoid intra-articular
injection for other joint pain

American Pain Society 2002


Treatment of Chronic Pain in RA
DMARD therapy for all RA patients
For continued pain and inflammation,
algorithm follows that for OA
acetaminophen for less pain, inflammation
COX-2 specific inhibitor therapy for more pain
and inflammation
nonselective NSAIDs, with or without
protective agent, used only if patient is
unresponsive or cannot take COX-2 specific
inhibitors
GI risk factor analysis
Adapted from American Pain Society, 2002.

American Geriatrics Society 2002


Principles of Pharmacologic Management
of Pain in Older Persons

Individually tailored therapy


Dose titration while monitoring is provided for
subjective and objective measures of efficacy
and safety
Concurrent employment of nonpharmacologic
therapies to reduce pain and improve function
Use of multimodal therapy, when necessary
complementary mechanisms of action
potential for greater relief with less toxicity
American Geriatrics Society. J Am Geriatr Soc. 2002;50:S205-S224.

American Geriatrics Society 2002


Management of Mild-to-Moderate Musculoskeletal Pain
Acetaminophen
(up to 4,000 mg
daily)
No

Dose 50%75% in
patients with impaired
renal or hepatic
function or history of
EtOH abuse

Continued pain?
Monitor for
efficacy
and
adverse
events

Yes

COX-2 specific inhibitors


or nonacetylated salicylates

Avoid nonselective
NSAIDs for patients
requiring long-term,
daily analgesia

No

Continued pain?
Yes

Fixed-dose APAP/opioid
or NSAID/opioid
combinations
American Geriatrics Society. J Am Geriatr Soc. 2002;50:S205-S224.

American Geriatrics Society 2002

Rationale for COX-2 Specific Inhibitors


in Older Persons

Safety advantage with COX-2 specific


versus nonselective COX inhibitors
reduced gastrointestinal morbidity
unacceptable rate of life-threatening GI bleeding
with persistent use of nonselective NSAIDs in frail
patients with multiple-system disease

lack of antiplatelet effects

Avoid nonselective NSAIDs for patients


requiring long-term, daily analgesia
American Geriatrics Society. J Am Geriatr Soc. 2002;50:S205-S224.

Optimizing Treatment
Medical Concerns

Consideration of comorbidities and


concomitant therapies
Evaluation of risk factors for UGI
complications
Evaluation of risk factors for
reversible renal failure in patients
with intrinsic renal disease
(SCr > 2.0 mg/dL)
ACR Subcommittee on OA Guidelines. Arthritis Rheum. 2000;43:1905-15.

Optimizing Treatment
Practical Concerns

Cost of therapy
Compliance (dosing frequency)
Convenience of dosage form (oral vs
topical vs injectable)
Patient preference

ACR Subcommittee on OA Guidelines. Arthritis Rheum. 2000;43:1905-15.

ACR 2002
Rheumatoid Arthritis Guidelines
Establish diagnosis of rheumatoid arthritis early
Document baseline disease activity and damage
Estimate prognosis
Initiate therapy
Provide patient education
Start DMARD(s) within 3 months
Consider NSAID
Consider local or low-dose systemic steroids
Provide physical therapy/occupational therapy
Periodically assess disease activity
ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46:328-46.

Pharmacotherapy for OA/RA


NSAIDs
Salicylates, nonselective NSAIDs,
COX-2 specific inhibitors
Choice of agent is dependent on
efficacy
safety (risk for GI complications, renal
toxicity)
convenience (dosing regimen)
cost
ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46:328-46.

NSAIDs

very efficacious class of drugs


associated with a broad spectrum of untoward
reactions in the liver, kidney, skin and gut
Gastrointestinal (GI) side effects are the most
common adverse event
70,000 hospitalizations & 7000 deaths annually
1.3-1.6% / year chance of hospitalization or death
due to a GI event
incidence further increases to 4-5% / year among
high risk patients
Henry DA Ballieres Clin Rheumatol 1988
Fries JF J Rheumatol 1991

NSAIDs AND COX-1 / COX-2 SELECTIVITIES

Most inhibitors affect both COX isoenzymes with near equal potency
flurbiprofen, ibuprofen, mefenamic acid, docosahexaenoic
acid,diclofenac
More potent COX-1 inhibitors
piroxicam, indomethacin, sulindac sulfide
COX-2 selective
nabumetone, meloxicam, etodolac, nimesulide
COX-2 specific
celecoxib, rofecoxib

Scarpignato C et al. 1999

COMPARISON OF GASTRIC DAMAGE AND


COX-SELECTIVITY OF NSAIDs
GI Toxicity

COX-1 Selectivity

Diclofenac

Diclofenac

Ibuprofen

Ibuprofen

Sulindac
Indomethacin

Indomethacin

Piroxicam

Piroxicam
10

Garcia Rodriguez LA & Jick H Lancet 1994

Sulindac
0

10

100

1000

NSAID-Induced
Upper GI Bleeds and Perforations
3.1

Nabumetone
Ibuprofen

4.3

Indomethacin

4.4
5.6

Mefenamic Acid

6.5

Ketoprofen

6.7

Naproxen

7.8

Diclofenac

15.9

Piroxicam

10

15

20

Rate of GI Bleeds and Perforations (per 1000 patient years)


McDonald TM, et al. BMJ 1997; 315: 1333-7.

Definition of COX-2 Selective Inhibition


Based solely on in-vitro assays
COX-2 selective inhibitors have a lower IC50 for
COX-2 compared to COX-1
Different assay methods produce different results
Correlation to clinical effects in humans can only be
presumed

Criteria for COX-2 Specific Inhibition

Anti-inflammatory and analgesic in humans


Selective inhibition of COX-2 in vitro and in
vivo
Objective evidence of selectivity (GI,
platelet) at full therapeutic dose in humans
Dubois RN, et al. FASEB J 1998; 12: 1063-73
Lipsky PE, et al. J Rheum 1998; 25: 2298-303

Selective vs Specific COX-2 Inhibitor


Selectivity
an in vitro measure
of relative amounts
of drug required to
inhibit each
enzyme
tells little about
clinical relevance

Specificity
an in vivo concept
clinically relevant
inhibition of COX-2
without inhibition
of COX-1

RISK FACTORS: NSAID-RELATED GI TOXICITY


ESTABLISHED
Age > 65 years
Previous PU disease or complication
High dose of NSAID
Multiple NSAID intake
Concomitant corticosteroid use
Concomitant anticoagulant therapy or ASA
LIKELY
Sex (female)
Arthritis-related disability
Cardiovascular disease
CONTROVERSIAL
Helicobacter pylori
Smoking
Alcohol consumption
Use of antacids or H2blockers

Combined studies 1991-1998

NSAID-INDUCED GI COMPLICATIONS
Incidence by number of risk factors
Mean incidence Rate over 6 months

Incidence Rate

10

9.24%

4.32%

5
1.95%
0.38%
0

0.87%

1
2
3
4
Number of Risk Factors
Risk Factors: age > 65, history of PUD, history of
GI bleed, cardiovascular disease
Silverstein FE et al. Ann Intern Med 1995

Available Analgesic Therapy for


Chronic Musculoskeletal Pain
Nonselective NSAIDs
naproxen, ibuprofen, diclofenac

COX-2 specific inhibitors


celecoxib, rofecoxib, valdecoxib

Opioid analgesics
oxycodone, codeine, morphine

Pharmacotherapy for RA
DMARDs
Hydroxychloroquine Injectable gold
Sulfasalazine

Cyclosporine

Methotrexate

Azathioprine

Leflunomide
Etanercept
Infliximab
ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46:328-46.

Overview of DMARDs
Agent

Potential Adverse Effects*

Hydroxychloroquine Retinopathy, GI, cutaneous

Patients Who
Discontinue Owing
to Toxicity (%)
38

Sulfasalazine

GI, mucocutaneous, CNS


disturbance (such as headache,
irritability, and dizziness),
cytopenia, elevated LFTs

2030

Methotrexate

GI, mucocutaneous, cytopenias,


elevated LFTs, cirrhosis,
pneumonitis

1035

*Overview; information is not all-inclusive.


LFTs = liver function tests.

Jain R et al. Med Clin North Am. 1997;81:57-

Overview of DMARDs
Agent

Potential Adverse Effects*

Patients Who
Discontinue Owing
to Toxicity (%)

Injectable gold

Dermatitis, stomatitis,
thrombocytopenia, proteinuria/
nephrotic syndrome,
pneumonitis

Cyclosporine

Nephrotoxicity (acute and/or


chronic), hypertension, GI,
neurotoxicity, gingival
hyperplasia, hypertrichosis

1530

Azathioprine

GI, stomatitis, cytopenia,


drug fever, hepatitis, pancreatitis,
oncogenicity

1530

*Overview; information is not


all-inclusive.

30

ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46:328-46.


Jain R et al. Med Clin North Am. 1997;81:57-84.

Overview of DMARDs
Agent

Potential Adverse Effects*

Infliximab

Serious infections (eg, tuberculosis


and sepsis), infusion reactions,
demyelination

Leflunomide

Hepatotoxicity, GI, weight loss,


allergic reactions, skin rash, alopecia

Etanercept

Serious infections (eg, tuberculosis


and sepsis), injection site reactions,
demyelination, anemia

*Overview; information is not all-inclusive.

REMICADE [US package insert]. Malvern, PA: Centocor; 2002.


ARAVA [US package insert]. Kansas City, MO: Aventis; 2000.
ENBREL [US package insert]. Seattle, WA: Immunex; 2002.

Pharmacotherapy in RA
Glucocorticoids

Advantages
treat flares
minimize/control
disease activity

Disadvantages
greater toxicity
with higher doses,
longer duration
discontinuation
difficult

ACR Subcommittee on RA Guidelines. Arthritis Rheum. 2002;46:328-46.


ACR Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum. 1996;39:723-31.

Progress in Treatment of
Arthritis:
Optimal Drugs = Effectiveness

Efficacy

Safety

Tolerability

Is it SAFE and TOLERABLE ?


Is it EFFICACIOUS ?

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