Module developed for primary care physicians to provide updates on management of osteoarthritis.

1. TREATMENT DECISIONS
in Osteoarthritis Management
Sidney Erwin T. Manahan, MD FPCP FPRA
Internal Medicine – Rheumatology

2. OBJECTIVES
• Discuss new recommendations in
diagnosing knee osteoarthritis
• Discuss principles in managing
osteoarthritis
• Discuss factors to be considered in
selecting appropriate medications to treat
osteoarthritis
• Discuss relevant data on CV and GI adverse
events associated with NSAID-use

3. 56/F with KNEE PAINS
• Progressive knee pains over the last 2 years – worse with
weight bearing/ activity, improves with rest – alleviated with
intake of paracetamol
• Morning stiffness 20min duration
• Difficulty in ambulation prompted consult
• Occasional pains and morning stiffness of hands
• Reports discomfort of the back with prolonged activity
• Known hypertensive on Losartan HCTZ
• Treated for PUD 6 months ago

4. Physical Exam • Bony enlargement of both knees
• Coarse crepitations of both knees
• Cannot fully extend the left knee
• No swelling/ warmth/ effusion
• (+) Heberden’s / Bouchard’s nodes –
both hands
• Normal examination of the back

5. IS THIS OSTEOARTHRITIS?

6. RISK FACTORS
• Age
• Gender
• BMI
• Occupation
• Family history
• Prior trauma
SYMPTOMS
• Knee pain
• Morning stiffness
• Fxn limitation
SIGNS
• Crepitation
• Limitation of motion
• Bony enlargement
RADIOGRAPHS
• Osteophytes
• Narrowing
• Subchondral
sclerosis
• Subchondral
cysts
Major Components in the Diagnosis
of KNEE OSTEOARTHRITISMILD
MODERATE
SEVERE
Zhang W, Doherty M, Peat G, et al. EULAR evidence-based recommendations for the diagnosis of knee
osteoarthritis. Ann Rheum Dis. 2010;69(3):483-489.

7. Other Features of Osteoarthritis
VARIABILITY
• Compartments affected
• Inflammation
• Crystal deposition
• Osteoarthritis in other sites
• Outcome
RED FLAGS
• Severe local inflammation
• Erythema
• Progressive pain unrelated
to use
Zhang W, Doherty M, Peat G, et al. EULAR evidence-based recommendations for the diagnosis of knee
osteoarthritis. Ann Rheum Dis. 2010;69(3):483-489.

8. 2010 EULAR Criteria for
Diagnosing Knee OA
SYMPTOMS
• Persistent knee pains
• Limited morning stiffness
• Reduced function
SIGNS
• Crepitus
• Restricted movement
• Bony enlargement
Zhang W, Doherty M, Peat G, et al. EULAR evidence-based
recommendations for the diagnosis of knee osteoarthritis. Ann
Rheum Dis. 2010;69(3):483-489.

9. Zhang W et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI
evidence-based, expert consensus guidelines. Osteoarthritis Cartilage. 2008;16(2):137-162.
OARSI
Management
Goals
Maintain,
improve
mobility
Reduce
physical
disability
Improve
HRQoL
Limit
damage
progress
Reduce
pain &
stiffness
Educate
patients

10. • Education
• Exercise
• Weight loss
• Rehab referral
• Aids and orthoses
• Thermal modalities
• TENS
• Acupuncture
• Paracetamol
• NSAIDs/ COXIBs
• Topical agents
• Tramadol
• Opioids
• IA Steroids
• IA Hyaluronate
• Duloxetine
• Joint replacement
• Osteotomy and other
joint preserving
surgeries
• Lavage/ debridement
NON-PHARMA PHARMA SURGICAL
Zhang W, et al. Osteoarth & Cart 2008; 16: 137-62. Hochberg MC, et al. Arth Care & Res 2012; 64: 465-74.

11. Treatment Differs for Joints Involved
Drug Intervention Knees Hips Hands
Paracetamol  
NSAIDs (Oral)   
COXIBs   
NSAIDs (Topical)  
Capsaicin (Topical) 
Intra-articular Steroids  
Intra-articular Hyaluronate 
Tramadol   
Opioids Analgesics  
Zhang W, et al. Osteoarth & Cart 2008; 16: 137-62. Hochberg MC, et al. Arth Care & Res 2012; 64: 465-74.

12. Specific Indications for Medications
Treatment Indications
Paracetamol Preferred long term therapy
NSAIDs
Evidence of inflammation or presence of effusion
COXIBs
Topicals Age >75 or unable to tolerate systemic therapies
IA Steroids Flares of arthritis, symptomatic effusion
IA HA Age >75, (-) systemic therapy
Tramadol Unable to tolerate NSAID/ COXIB
Opioids Unwilling candidates for surgery
Duloxetine Unwilling candidates for surgery
Zhang W, et al. Osteoarth & Cart 2008; 16: 137-62. Hochberg MC, et al. Arth Care & Res 2012; 64: 465-74.

13. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI Guidelines for the non-surgical management
of knee osteoarthritis. Osteoarth & Cartilage 2014; 22: 363-88.
Knee
Only
Multi-
Joint
(-) Co-Morbids (+) Co-Morbids
2014 OARSI Guidelines for the
Non-Surgical Management of Knee OA
APPROPRIATE
UNCERTAIN
NOT APPROPRIATE

14. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI Guidelines for the non-surgical management
of knee osteoarthritis. Osteoarth & Cartilage 2014; 22: 363-88.
Knee
Only
Multi-
Joint
(-) Co-Morbids (+) Co-Morbids
Exercise
Weight Management
Strength Training
Self Management
Education
Biomechanical Interventions
OARSI Appropriate Interventions

15. Oral and Topical nsNSAIDs
Oral COXIBs
Intra-articular steroids
Topical Capsaicin
Duloxetine
Paracetamol
Walking Cane
Intra-articular steroids
Topical NSAIDs
Walking Cane
Oral nsNSAIDs
Oral COXIBs
Intra-articular steroids
Duloxetine
Paracetamol
Oral COXIBs
Intra-articular steroids
Duloxetine
Balneotherapy
McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI Guidelines for the non-surgical management
of knee osteoarthritis. Osteoarth & Cartilage 2014; 22: 363-88.
Knee
Only
Multi-
Joint
(-) Co-Morbids (+) Co-Morbids
OARSI Appropriate Interventions

16. Co-Morbids Risk Stratification
MODERATE RISKS
• Advanced age
• Hypertension
• Diabetes Mellitus
• CV disease
• Kidney disease
• PUD/ Dyspepsia
• Depression
• Physical impairment
limiting activity
HIGH RISKS
• GI Bleed
• GI Complications
• Myocardial Infarction
• Chronic renal failure
McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI Guidelines for the non-surgical management
of knee osteoarthritis. Osteoarth & Cartilage 2014; 22: 363-88.

17. Specific Recommendations
McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI Guidelines for the non-surgical management
of knee osteoarthritis. Osteoarth & Cartilage 2014; 22: 363-88.
Appropriate
WITHOUT COMORBIDS
Uncertain
MODERATE COMORBID
RISK
Not Appropriate
HIGH COMORBID RISK
Appropriate
WITHOUT COMORBIDS
MULTI-JOINT + MODERATE
COMORBID RISK
Uncertain
KNEE + MODERATE
COMORBID RISK
Not Appropriate
HIGH COMORBID RISK
nsNSAIDS COXIBs

18. Contrasting Recommendations
Intervention Uncertain Not Appropriate
IA Hyaluronic Acid Knee OA Multi-joint OA
TENS Knee OA Multi-joint OA
Ultrasound Knee OA Multi-joint OA
Chondroitin Symptom relief Disease modification
Glucosamine Symptom relief Disease modification
McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI Guidelines for the non-surgical management
of knee osteoarthritis. Osteoarth & Cartilage 2014; 22: 363-88.

19. Other Interventions (OARSI 2014)
Not Appropriate
• Electrotherapy /
Neuromuscular electrical
stimulation
• Risedronate
Uncertain
• Acupuncture
• Crutches
• Avocado Soybean
Unsaponifiables (ASU)
• Diacerin
• Opioids (transdermal or
systemic)
McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI Guidelines for the non-surgical management
of knee osteoarthritis. Osteoarth & Cartilage 2014; 22: 363-88.

20. Duration of NSAID Use
Altman RD, et al. Arth Rheum 2000; Zhang W, et al. Osteoarth & Cart 2008; 16: 137-62. Hochberg MC, et al. Arth Care &
Res 2012; 64: 465-74. Penserga EG, et al. Unpublished.
Start NSAID / COXIB/ Paracetamol
For 2 Weeks Duration
Are symptoms well-controlled*?
Reduce NSAID/ COXIB/ Paracetamol Dose
Shift to PRN
Consider Paracetamol

21. Comparative Analgesia
in Osteoarthritis
Diclofenac 150 mg/day
Ibuprofen 2400 mg/day
Naproxen 1000 mg/day
CELECOXIB 200 MG/DAY
McKenna F et al., Scand J Rheumatol 2001;30:11-8. Bensen et al. Mayo Clin Proc. 1999;74:1095-1105.
Simon et al. JAMA. 1999;282:1921-1928. Ekman EF et al. Am J Orthop. 2002;31:445-451. Chou R, et al.
http://effectivehealthcare.ahrq.com/repFiles/AnalgesicsFinal.pdf

22. SUMMARY
• Osteoarthritis can be diagnosed based on risk factors,
symptoms and physical exam findings.
• In deciding what drugs to give in OA, consider:
– Joint involvement
– Disease features
– Co-morbid conditions
• Standard doses of NSAIDS produce comparable levels of
analgesia in osteoarthritis

23. FOCUS ON
SAFETY
It’s Not Just
The Class
Sidney Erwin T. Manahan, MD FPCP FPRA
Internal Medicine – Rheumatology
06 February 2015

24. ER consults for Analgesic Associated
Adverse Events, USA 2006
Data from Drug Abuse Warning Network. Visits in which a patient was exposed to more than one agent had
been counted as more than one visit. Woodcock J. A difficult balance – pain management, drug safety and
the FDA. NEJM 2009; 361:2105-7.
0
50000
100000
150000
200000
250000
300000
Opioids NSAIDs Paracetamol-containing
products
EstimatedNoofEDVisits
Tramadol NSAIDs Paracetamol

25. FDA BLACK BOX WARNING
[NSAID] may cause an increased risk of
serious cardiovascular thrombotic
events, myocardial infarction, and
stroke, which can be fatal. This risk may
increase with duration of use. Patients
with cardiovascular disease or risk
factors for cardiovascular disease may
be at greater risk

26. Stepped Care Approach for Musculoskeletal
Symptoms in Patients with Known
Cardiovascular Disease or Risk Factors for
Ischemic Heart Disease
Paracetamol, ASA, tramadol, narcotic analgesics
Non-acetylated salicylates
Non COX-2 Selective NSAIDs
NSAIDs with some
COX-2 Activity
COX-2 Selective
NSAIDs
Patients at low risk for
thrombotic events
Prescribed lowest dose to
control symptoms
Consider adding ASA + PPI in
patient at increased risk of
thrombosis
Regular monitoring for
sustained hypertension (or
worsening BP control), edema,
worsening renal function. If
these occur, consider reduction
or stopping offending drug
Taken from Antman EM, et al. Use of NSAIDs: A Scientific Statement from the American Heart Association.
Circulation 2007; 115: 1634-1632

27. The Dichotomy of COX Inhibition
Taken from Antman EM, et al. Use of NSAIDs: A Scientific Statement from the American Heart Association. Circulation 2007; 115:
1634-1632

28. Coxib and traditional NSAID Trialists’
(CNT) Meta-analysis
• Analyses of randomized
controlled trials (RCTs)
looking into individual
patient data
• 280 NSAIDs vs placebo
(124,513 participants)
• 474 NSAIDs vs NSAIDs
(229,296 particpants)
• Assessed both CV and GI
risks
Coxib and traditional NSAID Trialists' (CNT) Collaboration. Vascular and upper GI adverse effects of non-steroidal anti-
inflammatory drugs: meta-analyses of individual patient data from randomized trials. Lancet 2013; 382: 769-79.
Coxib vs
placebo ,
184
tNSAID
vs
placebo,
158coxib vs
tNSAID,
103
tNSAID
vs
tNSAID,
335
coxib vs
coxib, 35

29. Outcomes explored in the CNT MA
Coxib and traditional NSAID Trialists' (CNT) Collaboration. Vascular and upper GI adverse effects of non-steroidal anti-
inflammatory drugs: meta-analyses of individual patient data from randomized trials. Lancet 2013; 382: 769-79.
Non-fatal MI
Coronary
Death
Non-fatal
Stroke
Stroke
Death
Heart
Failure
Upper GI
Events
Major Vascular Events
Major Coronary Events
Stroke

30. Major Vascular Events were HIGHER
among coxibs & diclofenac
1 20.5 40.25
Coxibs 1.37
(1.14-1.66)
Ibuprofen 1.44*
(0.89-2.33)
Diclofenac 1.41*
(1.12-1.78)
Naproxen 0.93*
(0.69-1.27)
Favors PlaceboFavors NSAIDs
RR*Indirect Evidence
Coxib and traditional NSAID Trialists' (CNT) Collaboration. Vascular and upper GI adverse effects of non-steroidal
anti-inflammatory drugs: meta-analyses of individual patient data from randomized trials. Lancet 2013; 382: 769-79.

31. Major Vascular Events were HIGHER with
rofecoxib & diclofenac
1 20.5 40.25
Ibuprofen 1.44*
(0.89-2.33)
Diclofenac 1.41*
(1.12-1.78)
Naproxen 0.93*
(0.69-1.27)
Favors PlaceboFavors NSAIDs
RR
*Indirect Evidence
** Few placebo trials
Coxib and traditional NSAID Trialists' (CNT) Collaboration. Vascular and upper GI adverse effects of non-steroidal anti-
inflammatory drugs: meta-analyses of individual patient data from randomized trials. Lancet 2013; 382: 769-79.
Celecoxib 1.36
(0.91-2.02)
Rofecoxib 1.38
(1.07-1.80)
Etoricoxib 0.83**
(0.18-3.77)
Lumiracoxib 1.02
(0.37-2.83)

32. Annual Excess CV Risk
(per 1000 patients)
-2
0
2
4
6
8
10
Coxib Ibuprofen Diclofenac Naproxen
-2
0
2
4
6
8
10
Coxib Ibuprofen Diclofenac Naproxen
Non-Fatal Fatal
HIGH RISK
(2%/annum)
LOW RISK
(0.5%/annum)

33. Why NO labelling change for naproxen?

34. 1
Estimates do NOT show a clear advantage
over other NSAIDs
1 20.5 40.25
Ibuprofen 1.44*
(0.89-2.33)
Diclofenac 1.41*
(1.12-1.78)
Naproxen 0.93*
(0.69-1.27)
Favors PlaceboFavors NSAIDs
RR
*Indirect Evidence
** Few placebo trials
Coxib and traditional NSAID Trialists' (CNT) Collaboration. Vascular and upper GI adverse effects of non-steroidal anti-
inflammatory drugs: meta-analyses of individual patient data from randomized trials. Lancet 2013; 382: 769-79.
Celecoxib 1.36
(0.91-2.02)
Rofecoxib 1.38
(1.07-1.80)
Etoricoxib 0.83**
(0.18-3.77)
Lumiracoxib 1.02
(0.37-2.83)
2

35. Risk of Re-MI and death is
INCREASED on starting NSAIDs
Schjerning Olsen AM, Fosbol EL, Lindhardsen J, et al. Duration of Treatment with non-steroidal anti-inflammatory drugs and
impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: A nationwide cohort study.
Circulation 2011; 123: 2226-2235.
1 20.5 40.25
Day 0-7 1.34
(1.29-1.53)
Day 7-14 1.82
(1.61-2.05)
Day 14-30 1.58
(1.44-1.74)
Day 30-90 1.84
(1.74-1.99)
Day >90 1.56
(1.47-1.65)
Favors PlaceboFavors NSAIDs
RR

36. The risk with Diclofenac is
INCREASED on the 1st week
Schjerning Olsen AM, Fosbol EL, Lindhardsen J, et al. Duration of Treatment with non-steroidal anti-inflammatory drugs and
impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: A nationwide cohort study.
Circulation 2011; 123: 2226-2235.
1 20.5 40.25
Rofecoxib 1.04
(0.68-1.58)
Celecoxib 1.10
(0.71-1.68)
Ibuprofen 0.92
(0.71-1.20)
Diclofenac 3.52
(2.93-4.30)
Naproxen 1.63
(0.88-3.03)
Favors PlaceboFavors NSAIDs
RR

37. The risks with other NSAIDs
INCREASED during the 2nd week
Schjerning Olsen AM, Fosbol EL, Lindhardsen J, et al. Duration of Treatment with non-steroidal anti-inflammatory drugs and
impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: A nationwide cohort study.
Circulation 2011; 123: 2226-2235.
1 20.5 40.25
Rofecoxib 2.57
(1.91-3.46)
Celecoxib 1.39
(0.90-2.13)
Ibuprofen 1.57
(1.27-1.94)
Diclofenac 2.57
(2.03-3.24)
Naproxen 1.60
(0.83-3.08)
Favors PlaceboFavors NSAIDs
RR

38. Variables Affecting CV Risks w/ NSAIDs
• COX – 2 selectivity
• Dose responsivity
• Plasma half-life
• Interaction with aspirin
• Blood pressure
Farkouh ME, Greenberg BP. Am J Cardio May 2009; 103(9): 1227-1237

39. CV Profile based on 5 Variables
DRUG
COX-2
selectivity
Dose
Responseto
CVEvents
PlasmaHalf
Life
IncreaseinBP
Interactionw/
ASA
Nonselective NSAID
Naproxen - - ++ - +/-
Ibuprofen - ++ - +++ +++
Diclofenac + ++ - +++ -
COX-2 Inhibitors
Celecoxib + +++ ++ - -
Etoricoxib +++ +++ ++ +++ -
Farkouh ME, Greenberg BP. Am J Cardio May 2009; 103(9): 1227-1237
Legend: - not significant, +/- unknown, + mildly significant, ++ moderately significant, +++ highly significant

40. Interactions with ASA
• There is NO REDUCTION in cardio-protection when
diclofenac and celecoxib are used with low dose
asiprin
• The co-administration of ibuprofen and naproxen
has been shown to interfere with the anti-platelet
effect of aspirin.
– Naproxen – 2 hours before or after ASA
– Ibuprofen – 30 mins prior or 8 hours after ASA
Farkouh ME, Greenberg BP. An Evidence-based review on the CV risk of NSAIDs. Am J Cardio May
2009; 103(9): 1227-1237 Catella Lawson F, Reilly MP, et al. COX inhibitors and the antiplatelet
effects of aspirin. NEJM 2001; 345: 1809-17

41. Risk for Serious Upper GI Bleeding/
Perforation among NSAIDs
Celecoxib (4)
Ibuprofen (14)
Diclofenac (17)
Meloxicam (4)
Naproxen (18)
Ketoprofen (11)
Ketorolac (2)
RR
1 5 10
Masso Gonzales EL et al. Arthritis Rheum 2010; 62: 1592
1.42 (0.85, 237)
2.69 (2.17, 3.33)
3.98 (3.36, 4.72)
4.15 (2.59, 6.64)
5.63 (3.83, 8.28)
5.57 (3.94, 7.87)
14.54
(5.87, 36.04)
Favors Placebo4

42. GI Risk Mitigation Strategies
RISK FACTORS
• >65 years
• PUD/ UGIB
• Concomitant use of
steroids/
anticoagulants
• Co-morbids
• Smoking
• Alcohol
No Risk Factors
• Any NSAID
With Risk Factors or
PUD/Bleeding >1year ago
• NSAID+PPI
• COXIB
PUD/Bleeding <1year
• COXIB+PPI
Hochberg MC, et al. Arth Care & Res 2012; 64: 465-74.
Altman RD, et al. Arth Rheum 2000; Burmester G, et al. Ann Rheum Dis 2010; doi: 11.1136

43. On GI Risk Mitigation
Strategies
… the risk of distal GI toxicity
of NSAIDs appear to increase
with formulations that are
designed to release in the
intestines (e.g. enteric coated
and sustained release…
Harirforoosh S, Asghar W, Jamili F. Adverse effects of
NSAIDs: An Update of Gastrointestinal, Cardiovascular
and Renal Complications. `J Pharm Pharma Scie 2013;
16 (5): 821-47

44. Upper and Lower GI Events in NSAID Trials
3 3 2 3
17
78
52
95
0
20
40
60
80
100
120
Celecoxib NSAID+PPI Celecoxib NSAID+PPI
CONDOR GI-REASONS
Lower GI Events Upper GI Events
Chan FKL, et al. Celecoxb versus Omeprazole and Diclofenac in patients with osteoarthritis and rheumatoid arthritis
(CONDOR): a randomized trial. Lancet 2010; 376: 173-79. Cryer B, et al. GI REASONS: A Novel 6-month Prospective
Randomized Open-Label Blind Endpoint (PROBE) Trial. Am J Gastroenterol 2013; 108: 392-400.

45. Risk for Lower GI Clinical Events
(Etoricoxib 60-90mg OD vs Diclofenac 150mg/d)
1
HR
1.50.750.5
Bleeding, Perforation and
Obstruction
Bleeding, Perforation,
Obstruction, Diverticulitis
and Ulcer
Favors DiclofenacFavors Etoricoxib
0.84 (0.63–1.13)
0.85 (0.64–1.12)
Laine L, Curtis SP, Langman M, et al. Lower GI events in a Double Blind Trial of the COX-2 Selective Inhibitor and the
traditional NSAID Diclofenac. Gastroenterol 2008; 135: 1517-25.

46. Would you prescribe an
NSAID for this patient?
• Is an NSAID necessary?
• Is the NSAID safe given this
patient’s cardiovascular risk?
• Does the NSAID have the
lowest GI risk for the patient?
(Do I need to prescribe a PPI?)
• When should treatment and
dose next be reviewed?

47. Safety Summary
• There is NO CLASS
EFFECT in terms of
adverse CV and GI events
among NSAIDs and COXIBs
• Patients’ risk profile should
be considered before
writing a prescription