Topic#3-Osteoarthritis_2017_finalize.ppt

Pharmacology topic

1. 1
Osteoarthritis (OA)
Spring 2016

2. References
NICE Clinical Guideline: Osteoarthritis
Care and management in adults Issued:
February 2014
DiPiro Ch. 95: Osteoarthritis
Koda-Kimble K et al. Applied Therapeutics,
10th edition, (2013); Ch. 43
American College of Rheumatology 2012
Recommendations for the Use of
Nonpharmacologic and Pharmacologic
Therapies in Osteoarthritis of the Hand,
Hip, and Knee.
http://www.rheumatology.org
American Academy of Orthopaedic
Surgeons 2013 guidelines for the
treatment of knee osteoarithritis.
2

3. Introduction
Osteoarthritis is a disease characterized by degeneration
of cartilage and its underlying bone within a joint as well as
bony overgrowth.
The breakdown of these tissues eventually leads to pain
and joint stiffness. The joints most commonly affected are
the knees, hips, and those in the hands and spine.
The specific causes of osteoarthritis are unknown, but are
believed to be a result of both mechanical and molecular
events in the affected joint.
3

4. Introduction (cont’d)
Disease onset is gradual and usually begins
after the age of 40.
There is currently no cure for OA.
Treatment for OA focuses on relieving
symptoms and improving function, and
can include a combination of:
patient education,
physical therapy,
weight control,
and use of medications.
4

5. Before we start!
5

6. DEFINITION
Osteoarthritis (OA), which is also known as
osteoarthrosis or degenerative joint disease
(DJD), is a progressive disorder of the joints
caused by gradual loss of cartilage and resulting
in the development of bony spurs and cysts at
the margins of the joints. The name
osteoarthritis comes from three Greek words
meaning bone, joint, and inflammation.
6

7. EPIDEMIOLOGY
OA is the most prevalent (3-6%) of the rheumatic diseases & is
responsible for enormous disability & loss of productivity
The prevalence of OA is > in older age groups

In those < age 45 yrs, ~1/5 have OA of the hands, while of those ages
75-79 yrs, 85% have OA of the hands
OA of the knee occurs in less than 0.1% of those aged 25 to 34 years,
but in 10% to 20% of those aged 65 to 74 years.
OA severity also ↑ with age
Women are > often affected by OA,

older women being twice as likely as men
to have OA of the knee & hands

Women are also more likely to have
inflammatory OA of the proximal & distal
interphalangeal joints of the hands.
OA of the hip occurs more frequently in men.
8

8. ETIOLOGY
Multifactorial
Many patients have >1 risk factor
The most common risk factors:
obesity
number one preventable risk factor for OA, and a predictor for eventual
prosthetic joint replacement

previous occupation,
participation in certain sports,

history of joint trauma,

genetic predisposition to OA (e.g., genes for IL-1, calmodulin)
Patients with OA are < likely to have osteoporosis because
heavy individuals have > bone density as a result of weight-
bearing, but ↑ risk of OA as a consequence of excessive joint
loading
10

9. PATHOPHYSIOLOGY
OA falls into 2 etiologic classes:
Primary (idiopathic) OA - the most common type, has no
identifiable cause. Subclasses:

localized OA, involving 1 or 2 sites

generalized OA, affecting 3 or > sites

Erosive osteoarthritis: erosion & marked proliferation in the
proximal & distal interphalangeal joints of the hands
Secondary OA - associated with a known cause such as
rheumatoid or another inflammatory arthritis, trauma,
metabolic or endocrine disorders, & congenital factors
Some changes in the OA joint may reflect compensatory
processes to maintain function in the face of ongoing joint
destruction
11

10. PATHOPHYSIOLOGY
OA is a multifactorial disease typified by:
progressive destruction of joint cartilage,
erratic new bone formation,
thickening of subchondral bone and the
joint capsule,
bony remodeling,
development of osteophytes,
variable degrees of mild synovitis, and
other changes.
12

11. Cartilage in OA
OA most commonly begins with damage to
articular cartilage, through trauma, joint
loading from obesity, etc.
damage to cartilage →↑ metabolic activity of
chondrocytes →↑ synthesis of matrix
constituents, with swelling of cartilage
this hypertrophic response does not restore
the cartilage to normal
→↑ turnover (↑ collagen synthesis &
destruction), but with destruction outpacing
formation →loss of cartilage.
13

12. Characteristics of osteoarthritis in the
diarthrodial joint.
14

13. Cartilage in OA (cont’d)
Key players in cartilage destruction are the
matrix metalloproteinases (MMPs)
In normal cartilage, activities of these enzymes
are blocked by tissue inhibitors of
metalloproteinases
In OA cartilage: ↑ expression & synthesis of
MMPs by chondrocytes in response to
inflammatory mediators present in OA (IL-1 &
TNF-α)
Chondrocytes in OA cartilage undergo apoptosis,
likely as a result of induction of nitric oxide
synthase & production of toxic metabolites
15

14. Cartilage in OA (cont’d)
Subchondral bone undergoes pathologic changes that may
precede, coincide with, or follow damage to the articular cartilage
In OA, subchondral bone releases vasoactive peptides & MMPs
Neovascularization & subsequent ↑ permeability → further
cartilage loss
→ joint space narrowing & painful, deformed joint
the remaining cartilage softens & develops fibrillations (vertical
clefts into the cartilage), with splitting & exposure of underlying
bone
→ cartilage is eroded completely → subchondral bone becomes
dense, smooth (eburnation) →
↓ weight-bearing ability & microfractures →
new bone formations, or osteophytes
16

15. 17

16. Cartilage in OA (cont’d)
There is evidence that osteophytes can help stabilize
osteoarthritic joints
local inflammatory changes & pathologic changes can occur
in the joint capsule & synovium: infiltration with T-helper type 1
phenotype occurs + immune complexes
Inflammation is due to crystals or cartilage shards in synovial
fluid + inflammatory mediators (IL-1, PG E2, TNF-α, & NO)
effusions & synovial thickening occur
pain of OA is not related to destruction of cartilage, but due to
activation of nociceptive nerve endings within the joint by
mechanical & chemical irritants: distension of the synovial
capsule by ↑ joint fluid, microfracture, or damage to ligaments
or synovium
18

17. Clinical presentation of OA
General
mild symptoms for months to years prior to seeking
medical care; self-treatment is common for mild
symptoms
typical age at presentation is usually >50 years.
Symptoms
nearly all pts. have pain in the affected joints, with
the hands, knees, & hips being the most common
locations
pain is most commonly associated with motion, but
in late disease can occur with rest
joint stiffness resolves with motion; recurs with rest
19

18. Clinical presentation of OA
(cont’d)
Signs
joint stiffness with or without joint enlargement
crepitus, a crackling or grating sound heard with joint
movement caused by irregularity of joint surfaces may be
present
limited range of motion that may be accompanied by
joint instability
late-stage disease: joint deformity
Diagnostic Tests

no specific laboratory tests useful in the dx

Plain Radiographic Films:
joint space narrowing, appearance of osteophytes in moderate
disease
abnormal alignment of joints & joint effusion in late disease20

19. 21
b. Plain x-ray films of
the knee demonstrating
joint space narrowing
a. Physical findings of
joint enlargement &
genu varum (bandiness)
of the knees

20. 22

21. 23
Manifestations of inflammatory OA:
Heberden nodes (distal interphalangeal joint) noted on all fingers
Bouchard nodes (proximal interphalangeal joint) noted on most
fingers.

22. Heberden's nodes
(osteophytes)

23. Clinical manifestations of osteoarthritis
Age of onset Usually after age 40
Commonly affected
joints
Cervical and lumbar spine, first carpometacarpal
joint, proximal interphalangeal joint, distal
interphalangeal joint, hip, knee, subtalar joint, first
metarsophalangeal joint
Uncommonly affected
joints
Shoulder, wrist, elbow, metacarpophalangeal joint
Symptoms Pain, stiffness, gelling
Findings on physical
examination
Crepitus, bony enlargement, decreased range of
motion, malalignment, tenderness to palpation
Synovial fluid analysisClear fluid, WBC <2000/mm3, normal viscosity
Radiographic featuresJoint space narrowing, subchondral sclerosis,
marginal osteophytes, subchondral cysts
Patterns of
presentation
Monoarticular in young adult; pauciarticular, large-
joint in middle age; polyarticular generalized; rapidly
progressive; secondary to trauma, congenital
abnormality, or systemic disease
Prognosis Variable, generally slowly progressive 25

24. 26

25. DIAGNOSIS
Diagnosis depends on:
history
physical examination
characteristic radiographic findings
laboratory testing
The major diagnostic goals:
to discriminate between primary & secondary
OA
to clarify the joints involved, severity of joint
involvement, & response to prior therapies 27

26. NICE 2014 guideline
28

27. Distinction between rheumatoid arthritis
and osteoarthritis
Feature Rheumatoid arthritis Osteoarthritis
Primary joints affectedMetacarpophalangeal Distal interphalangeal
Proximal interphalangealCarpometacarpal
Heberden's nodes Absent Frequently present
Joint characteristics Soft, warm, and tenderHard and bony
Stiffness Worse after resting (eg,
morning stiffness)
If present, worse after
effort, may be described
as evening stiffness
Laboratory findings Positive rheumatoid factorRheumatoid factor
negative
Positive anti-CCP
antibody
Anti-CCP antibody
negative
Elevated ESR and C
reactive protein
Normal ESR and C
reactive protein
29
CCP: cyclic citrullinated peptide

28. 30

29. PROGNOSIS
Depends on the joint involved
If a weight-bearing joint or the spine is
involved, considerable morbidity &
disability are possible
Treatment may relieve pain or improve
function, but does not reverse
preexisting damage to the articular
cartilage
31

30. TREATMENT
Desired outcome
to educate the patient, caregivers, &
relatives
to relieve pain & stiffness
to maintain or improve joint mobility
to limit functional impairment
to maintain or improve quality of life
32

31. General approach to treatment
depends on:
the distribution & severity of joint involvement,
comorbid disease states,
concomitant medications,
allergies
management for all individuals with OA
should begin with:
patient education,
physical &/or occupational therapy,
weight loss or assistive devices if appropriate
33

32. General approach to treatment
(cont’d)
The primary objective of medication is to alleviate pain
scheduled acetaminophen, up to 4 g/day initially →
NSAIDs COX-2 selective inhibitor (celecoxib)
capsaicin or methylsalicylate topical creams over
specific joints as adjuncts
glucosamine & chondroitin in combination for
moderate to severe arthritis
joint aspiration followed by glucocorticoid or
hyaluronate injection to relieve pain concomitantly with
oral analgesics or after their lack of efficacy
opioid analgesics if other therapies are unsuccessful
when symptoms are intractable or there is significant
loss of function → joint replacement
34

33. 35
Homework:
Summary of Recommendations for
Osteoarthritis (table 95-1 in DiPiro)
(by Third Canadian Consensus Conference
Group. An evidence-based approach to
prescribing nonsteroidal antiinflammatory
drugs. Third Canadian Consensus
Conference. J Rheumatol 2006;33:140–157)

34. Treatment algorithm for OA
36

35. 37

36. 38

37. ACR Recommendations 2012
39

38. 40

39. 41

40. 42
A: lateral wedge insole (conventional)
B: lateral wedge insole with the strapping (strapping
insole)

41. Fig.
 3 Biomechanical effect of both insoles to correct lower leg alignment. (A) Barefoot; (B) wearing conventional insole; (C) wearing
strapping insole. Conventional insoles move the weight bearing axis and reduce knee joint load in the medial compartment,...
Y. Kuroyanagi , T. Nagura , H. Matsumoto , T. Otani , Y. Suda , T. Nakamura , Y. Toyama
The lateral wedged insole with subtalar strapping significantly reduces dynamic knee load in the medial compartment :
Gait analysis on patients with medial knee osteoarthritis
Osteoarthritis and Cartilage, Volume 15, Issue 8, 2007, 932 - 936
http://dx.doi.org/10.1016/j.joca.2007.02.004

42. 44

43. AAOS 2013-symptomatic
knee OA
A 2013 clinical practice guideline from the American Academy of
Orthopaedic Surgeons (AAOS) recommends the following
Oral NSAIDs
Topical NSAIDs
Tramadol
The AAOS was unable to recommend for or against the use of the
following:
Acetaminophen

Opioids
Pain patches

Intra-articular corticosteroid injections
Growth factor injections and/or platelet rich plasma
The recommendation on acetaminophen is a downgrade from the
previous AAOS guideline, and reflects the selection of only one study,
which found no statistical significance or minimum clinically important
improvement with acetaminophen compared with placebo.
45

44. Paracetamol ineffective in treating
osteoarthritis, meta-analysis finds!!
17-3-2016:
da Costa BR, Reichenbach S, Keller N
 
et al. Effectiveness of non-
steroidal anti-inflammatory drugs for the treatment of pain in knee
and hip osteoarthritis: a network meta-analysis. The Lancet 
2016. 
The researchers pooled data from 74 randomised trials published
between 1980 and 2015, which involved 58,556 patients with
osteoarthritis and compared the effects of 22 treatments and placebo
on pain intensity and physical activity.
 
All 22 preparations of medications, irrespective of dose, improved
symptoms of pain compared with placebo, but paracetamol did not
achieve the minimum clinically important difference. Its effect size
was -0·17 and to be deemed clinically important a difference of -0.37 is
required, the researchers say, meaning that paracetamol had “nearly
a null effect on pain symptoms at various doses”.
 
46

45. Paracetamol ineffective in treating
osteoarthritis, meta-analysis finds!!
The maximum daily dose of diclofenac (150mg
per day) was found to have the greatest impact
on pain, with an effect size of -0.57. This was
superior to the effects produced with the
maximum doses of frequently used NSAIDs,
including ibuprofen, naproxen and celecoxib.
47

46. AAOS 2013-symptomatic
knee OA
The AAOS does not recommend
treatment with any of the following:
Intra-articular hyaluronic acid
Glucosamine and/or chondroitin sulfate
or hydrochloride
48

47. 49

48. 50

49. Nonpharmacologic therapy for
patients with osteoarthritis
Patient education
Self-management programs
Personalized social support through telephone contact
Weight loss (if overweight)
Aerobic exercise programs
Physical therapy
Range-of-motion exercises
Muscle-strengthening exercises (as quadriceps strengthening
exercise)
Assistive devices for ambulation (as canes, crutches, or walkers)
Patellar taping (for patients with OA of the knee who have
symptomatic patellofemoral compartment involvement)
Appropriate footwear
Lateral-wedged insoles (for genu varum)
Bracing
Occupational therapy
Joint protection and energy conservation
Assistive devices for activities of daily living
ACR 2000

50. 52

51. 53
Foot, ankle brace Wrist, hand brace Neck brace
Spinal brace
Join Supports

52. Physical & Occupational
Therapy
Physical therapy – with heat or cold treatments & an
exercise program – helps to maintain & restore joint
range of motion & to ↓ pain & muscle spasms.
Pts should be warned not to fall asleep on the heat
source or to lie on it for more than brief periods to avoid
burns
Exercise programs & quadriceps strengthening can
improve physical functioning & ↓ disability, pain, &
analgesic use
Exercises should be taught & then observed before the
pt exercises at home, ideally 3-4 times daily
The pt should be instructed to ↓ the number of
repetitions if severe pain develops with exercise
54

53. Physical & Occupational
Therapy (cont’d)
Walking:
With weak or deconditioned muscles, load is transmitted
excessively to joints → weight-bearing activities can
exacerbate symptoms
But: avoidance of activity by those with hip or knee OA
leads to further deconditioning or weight gain
Pt education, muscle stretching & strengthening, &
supervised walking can improve physical function &↓ pain
in patients with knee OA
Occupational therapist can recommend exercises &
methods of protecting the affected joint from excessive
forces + provide assistive & orthotic devices, such as
canes, walkers, braces, heel cups, splints, or insoles for
use during exercise or daily activities
55

54. Pharmacologic Therapy for OA
56

55. 57

56. Acetaminophen
Place in Therapy
ACR: first-line drug therapy for pain management in OA (of knee and hip,
but not OA of the hand) because of its relative safety, efficacy, & < cost
compared to NSAIDs
Pain relief with acetaminophen has been reported as similar to that obtained
with NSAIDs, although many patients respond better to NSAIDs
The European League Against Rheumatism also stresses the importance
of acetaminophen as first-line drug therapy for OA
It is a weak COX-1 & COX-2 inhibitor in peripheral tissues & possesses no
significant anti-inflammatory effects. Recent evidence suggests that
acetaminophen may inhibit a third enzyme, COX-3, in the CNS.
The AAOS 2013 was not able to recommend for or against the use of
acetaminophen in the management of knee arithritis!
58

57. 59
MOA

58. Acetaminophen (cont’d)
ADRs
is one of the safest analgesics
risk of hepatotoxicity, & possibly renal toxicity with long-
term use
overdose: serious hepatotoxicity, including fatalities
maximum dose of acetaminophen should be not be
exceeded in any patient population, & chronic use of
even the maximum 4 g/day can affect the liver
should be used cautiously in patients with liver disease
or in those who abuse alcohol: acute liver failure can
develop at doses < 4 g/daily
60

59. Acetaminophen (cont’d)
FDA: chronic alcohol users (3 & > drinks daily)
should be warned regarding ↑ risk of liver damage
or GI bleeding with acetaminophen
The National Kidney Foundation strongly
discourages the use of OTC combination
analgesic products (e.g., acetaminophen &
NSAIDs) because this is associated with ↑
prevalence of renal failure
Pts should be warned about potential toxicity if
they inadvertently ingest > the recommended
dose when using both nonprescription and
prescription products containing acetaminophen
61

60. Acetaminophen (cont’d)
Drug–Drug Interactions
isoniazid can ↑ risk of hepatotoxicity
chronic ingestion of maximal doses of acetaminophen may
intensify the anticoagulant effect in patients taking warfarin →
closer monitoring
Dosing & Administration
for chronic OA, acetaminophen should be administered in a
scheduled manner (around the clock – ATC)
may be taken with or without food
can be taken at 325-650 mg every 4-6 hours, but total dose
must not exceed 4 g daily
in chronic alcohol intake or in underlying disease, duration
should be ↓ & dose should not exceed 2 g daily
62

61. NSAIDs
Place in Therapy
ACR: consider NSAIDs for OA patients in whom acetaminophen is
ineffective
All NSAIDs display comparable analgesic & antiinflammatory
efficacy & are similarly beneficial in OA
Because nonspecific NSAIDs & COX-2 selective inhibitors have similar
efficacy, drug selection often depends on toxicity & cost
Prostaglandins made by COX-2 enzyme, contribute to pain sensations
in OA & other conditions + implicated in some physiologic processes,
including renal function, tissue repair, reproduction, & development
COX-2 inhibitors (“coxibs”) are efficacious in relieving OA & other
pain & some do have improved GI safety
63

62. MoA
64

63. NSAIDs (cont’d)
COX-2 enzyme found in blood vessel endothelial cells leads to
production of prostaglandin I2 (prostacyclin), which has
antithrombotic effects
COX-1 enzyme found in platelets forms thromboxane A2
(prothrombotic)
blocking COX-2 alone could upset hemostatic balance, in favor
of thromboxane A2, with prothrombotic events possible
whether the “prothrombotic imbalance” explanation accounts for
↑ cardiovascular risk seen with COX-2 selective inhibitors is
unknown
Rofecoxib was withdrawn from the market in 2004 because of ↑
cardiovascular events, & celecoxib is less often used now &
carries a black box warning for cardiovascular & GI risks, as do
other NSAIDs at this time
65

64. NSAIDs (cont’d)
The most important pharmacokinetic difference in NSAIDs is a
serum t
1/2: 1 hour for tolmetin to 50 hours for piroxicam
elimination largely hepatic, with a small fraction renally
excreted
penetrate joint fluid: ~ 60% of blood levels
individual patient response differs among NSAIDs
trial adequate in time (2 to 3 weeks) & dose is needed
pts must understand this approach, appreciate need of
adherence to medication therapy in the trial period
combining 2 NSAIDs ↑ ADRs without providing additional
benefit
coxibs: similar analgesic benefits to traditional NSAIDs & to
each other
66

65. NSAIDs ADRs
GI Effects
are the most common ADRs of nonselective NSAIDs
minor complaints: nausea, dyspepsia, anorexia, abdominal pain,
flatulence, & diarrhea  affect 0-60% of pts
to ↓them, NSAIDs should be taken with food or milk, except for enteric-
coated products, which should not be taken with milk or antacids
potential to cause GI bleeding: the most common sites of GI injury
are the gastric & duodenal mucosae
incidence of gastric ulcers with NSAID use is ~11-13%, & duodenal
ulcers 7-10%
NSAIDs may cause perforations, gastric outlet obstruction, &
bleeding (1.5-4% of pts/yr)
risk ↑ to 9%/yr for pts with risk factors
For pts taking NSAIDs, there is a poor correlation between GI
ulceration & symptoms
67

66. NSAIDs ADRs (cont’d)
a key part of the clinician’s decision to start NSAID therapy for OA pt is his risk
for GI toxicity (Homework: Patients at high risk of GI toxicity from NSAIDs?)
ACR recommends CBC yearly to detect a silent bleeding ulcer characterized by
an asymptomatic ↓Hct
Fecal occult blood is an unreliable predictor of complications
Misoprostol protects against both gastric & duodenal NSAID-induced ulcers &
their associated serious GI complications but frequently causes diarrhea &
abdominal cramps + is contraindicated in pregnancy & in women of childbearing
age who are not maintaining adequate contraception
PPIs are also protective, but not sucralfate or H2RAs
At present, use of either a coxib, or an NSAID in combination with either a PPI or
misoprostol is recommended for treatment of OA patients who are at high risk for
GI complications
GI Effects of coxibs.
 fewer endoscopically observed ulcers compared to traditional NSAIDs
 data regarding perforation, obstruction, or bleeding are more difficult to obtain as very large
numbers of patients are required for such studies
68

67. NSAIDs ADRs (cont’d)
With lumiracoxib, there was a significant ↓ risk of serious
GI events (perforation, gastric outlet obstruction,
bleeding) compared to naproxen, but in those taking
aspirin, there was no difference in risk
(withdrawn because of increased risk of hepatotoxicity)
etoricoxib: significantly fewer upper GI uncomplicated
clinical events with etoricoxib than with diclofenac, but
no ↓in more serious complicated events
etoricoxib is currently sold in 63 countries but received an
FDA nonapproval (further data necessary to demonstrate
a favorable risk-to-benefit ratio)
69

68. NSAIDs ADRs (cont’d)
Cardiovascular Risk of COX-2 Inhibitors & Traditional NSAIDs.
In 2004, rofecoxib was withdrawn from the market after analysis
of the Adenomatous Polyp Prevention on Vioxx (APPROVe)
trial, where rofecoxib appeared to double the risk of
cardiovascular events compared to placebo
VIGOR trial also showed ↑risk
celecoxib use in the Adenoma Prevention with Celecoxib (APC)
trial also ↑ CV risk
CLASS trial showed a small but not significantly ↑ risk
Prevention of Spontaneous Polyps (PreSAP) study, with
celecoxib used at 400 mg/day, & Alzheimer’s Disease
Antiinflammatory Prevention Trial (ADAPT) study, using 200 mg
twice daily, did not show ↑ risk
70

69. NSAIDs ADRs (cont’d)
More recently, in a meta-analysis of randomized trials (> 100,000)
pts, rofecoxib ↑ risk of arrhythmias, relative to placebo and to other
NSAIDs, & also in comparison to celecoxib, which did not significantly
↑ arrhythmia
→ new FDA regulations & new labeling on all NSAIDs & meta-
analyses of randomized controlled trials of coxibs & of NSAIDs
Much remains to be defined about these risks, regarding class
effects, effect of dose & duration, & the population studied
COX-2 selectivity is relative: Some traditional NSAIDs, such as
diclofenac, possess some COX-2 selectivity
rofecoxib is more COX-2 selective than celecoxib → better GI
protection & ↑ cardiovascular risk (TxA2 prostacyclin)
selective COX-2 inhibitor may tilt the balance in favor of TxA2, thus
promoting platelet aggregation (beneficial for preventing GI bleeds,
but posing a prothrombotic risk to the cardiovascular system)
71

70. NSAIDs ADRs (cont’d)
Considerations for Pts at Risk for Both GI & CV Events
for those with ↑ GI risk but not on aspirin consider COX-
2 selective inhibitor or a traditional NSAID + PPI
for those taking regular low-dose aspirin for CV risk
(with or without ↑ GI risk), a traditional NSAID + PPI,
or a COX-2 selective inhibitor + PPI can be
considered
treatment with the lowest dose possible for the shortest
duration possible is warranted
72

71. 73
ACG 2009: Prevention of NSAID-Induced
Ulcers

72. NSAIDs ADRs (cont’d)
Other Toxicities
kidney diseases:
acute renal insufficiency, tubulointerstitial nephropathy,
hyperkalemia, & renal papillary necrosis
Clinical feature: ↑ SrCr & BUN, hyperkalemia, ↑ BP, peripheral
edema, & weight gain
Mechanisms: direct toxicity, & inhibition of local
prostaglandins that promote vasodilation of renal blood
vessels & preserve renal blood flow
Pts at high risk:
conditions with ↓ renal blood flow - chronic renal insufficiency,
CHF, severe hepatic disease, nephrotic syndrome, advanced
age

medications - diuretics, ACEIs, cyclosporine, or aminoglycosides
74

73. NSAIDs ADRs (cont’d)
Such pts need close monitoring of SrCr at baseline & 3-7
days of drug initiation
For those with impaired renal fxn, the NKF recommends
acetaminophen as the drug of choice
Coxibs can also pose renal risks, and there is no evidence
that they are safer than nonspecific NSAIDs
it is prudent to prescribe all coxibs & other NSAIDs with
caution in pts who are at ↑ risk for renal dysfunction
Coxibs & NSAIDs rarely cause drug-induced hepatitis; most
frequently diclofenac & sulindac
Pt monitoring: should periodic liver enzymes (AST & ALT),
with cessation of therapy if these values exceed 2-3 times the
normal range 75

74. NSAIDs ADRs (cont’d)
Other ADRs: hypersensitivity reactions, rash, & CNS (drowsiness,
dizziness, headaches, depression, confusion, & tinnitus)
NSAIDs are generally avoided in patients with asthma who are
aspirin-intolerant, studies indicate that celecoxib is well tolerated
Celecoxib is a sulfonamide → C/I for those with sulfa allergies
However, some pts with sulfa allergies have shown no reaction to celecoxib
All nonspecific NSAIDs inhibit COX-1–dependent TXA production
reversibly in platelets → ↑ risk of bleeding → normalization of
platelet function 1-3 days after the drug is stopped
Nonacetylated salicylates & nabumetone, which have partial COX-
2 selectivity, may be preferable to nonspecific NSAIDs
Coxibs do not block TXA synthesis & should pose even less bleeding
risk
Pts receiving warfarin & coxibs should be followed closely (Coxibs
inhibit CYP2C9)
76

75. NSAIDs ADRs (cont’d)
NSAIDs should be used with great caution & only if
definitely necessary during pregnancy: risk of
bleeding in fetus
In late pregnancy, all NSAIDs should be avoided
because they may enhance premature closure of the
ductus arteriosus (Homework: what will be the result?)
NSAIDs have a pregnancy risk factor of C/D (third
trimester)
Aspirin is also listed as C/D (D in third trimester if used
at full dose)
Acetaminophen has a pregnancy risk factor of B
77

76. NSAIDs: Drug–Drug and
Drug–Food Interactions
NSAIDs are prone to drug interactions due to high
protein binding, detrimental renal effects, and
antiplatelet activity.
The most potentially serious
lithium,
Warfarin,
oral hypoglycemics,
high-dose methotrexate,
antihypertensives,
ACEIs,
β-blockers,
diuretics
78

77. NSAIDs interactions (cont’d)
some NSAIDs + cardioprotective doses of aspirin:

Ibuprofen 400 mg or > may block aspirin’s antiplatelet
effect if it is taken prior to aspirin
pts are advised to take a single dose of ibuprofen at least
30 minutes after taking aspirin, or take aspirin at least 8
hours after taking ibuprofen
other nonselective NSAIDs, such as naproxen, also may
cause such interactions
celecoxib levels ↑ with fluconazole administration
Enzyme inducers such as rifampin, carbamazepine, &
phenytoin ↓celecoxib levels
celecoxib inhibits CYP2D6 →potential to ↑
concentrations of antidepressants & lithium
79

78. 80

79. 81

80. Topical Therapies
Topical products can be used alone or in combination with oral
analgesics or NSAIDs
Capsaicin
releases & ultimately depletes substance P from afferent
nociceptive nerve fibers  decreasing pain trasmission.
Is an OTC product available as a cream, gel, or lotion in conc.
from 0.025% to 0.075%
ADRs are primarily local, with 1 in 3 patients experiencing
burning, stinging, &/or erythema that usually subsides with
repeated application
Some pts - coughing
must be used regularly, & it may take up to 2 wks to take effect 
not for acute pain.
the recommended use is 4 t.d., a 2 t.d. application may enhance
long-term adherence & still provide adequate pain relief
82

81. Topical therapies (cont)
Topical diclofenac
in a DMSO carrier is safe & effective
Topical rubefacients
containing methylsalicylate, trolamine salicylate, &
other salicylates, may have modest, short-term efficacy in
the treatment of acute pain associated with
musculoskeletal conditions, including OA.
They act as topical counterirritants, rather than by local
inhibition of COX-2 enzymes
Chronic OA pain may respond less favorably than acute
pain
Clinically significant ADR: rare local skin reactions
NICE guideline recommends NOT to use rubefacients
for people with OA.

82. Glucosamine & Chondroitin
stimulate proteoglycan synthesis from articular cartilage in
vitro
A recent large, well-controlled study: no significant
clinical response to glucosamine therapy alone,
chondroitin therapy alone, or combination glucosamine–
chondroitin therapy when compared to placebo
But in subgroup analyses pts with moderate to severe knee
pain showed a response to combination glucosamine–
chondroitin (did not reach the predetermined threshold for
pain reduction)
Safety of glucosamine & chondroitin was similar to that of
placebo
Because of relative safety of these agents, a trial of
glucosamine–chondroitin may be reasonable in patients
considering alternatives to traditional OA treatments
84

83. Glucosamine & Chondroitin
(cont’d)
Dosing should be at least 1,500 mg/day of glucosamine &
1,200 mg/day of chondroitin
Glucosamine component should be the sulfate salt rather than
the hydrochloride salt (better absorbed)
Glucosamine ADRs:
GI (gas, bloating, cramps).

If made from shellfish should not be used in pts with shellfish
allergies

Does not significantly ↑ blood glucose
Chondroitin ADRs:
the most common ADR is nausea
Depending on the source of chondroitin (cattle, pig, or shark),
may be a risk to persons who are allergic to shark
85

84. MOA of corticosteroids
86

85. 87

86. 88

87. Intraarticular Therapy
Intraarticular injection of corticosteroids or hyaluronan represents
an alternative to oral agents for the treatment of joint pain.
These modalities usually are reserved for patients unresponsive
to other treatments because of the relative invasiveness of
intraarticular injections compared with oral drugs, the small risk of
infection, and the cost of the procedure.
89
2 method for intra-articular injection

88. 90

89. Corticosteroids (CSs)
intraarticular injections
Intraarticular glucocorticoid injections can provide
excellent pain relief, particularly when a joint effusion is
present
Alone as monotherapy or adjunctive with analgesic
Aspiration of effusion & injection of glucocorticoid are
carried out aseptically, with examination of aspirate
recommended to exclude crystalline arthritis or infection
After injection, pt should minimize activity & stress on
the joint for several days
Initial pain relief may be seen within 24-72 hrs after
injection, with peak about 1 wk after injection & lasting
up to 4-8 wks
91

90. CSs (cont’d)
equipotent doses of methylprednisolone acetate &
triamcinolone hexacetonide have similar efficacy
Average doses for injection of large joints in adults are:

10-20 mg of triamcinolone hexacetonide

20-40 mg of methylprednisolone acetate
Usually 3-4 injections per year because of the potential
systemic effects of steroids, & because the need for
more frequent injections indicates little response to the
therapy
ADRs associated with intraarticular injection of
corticosteroids can be local or systemic (Homework)
potential risk of cartilage destruction with steroid
injections has not been established.

91. Hyaluronate (HA)
intraarticular injections
High-molecular-weight HA is an important
constituent of synovial fluid
may also have anti-inflammatory effects
concentration & molecular size of synovial HA ↓ in
OA, administration of exogenous HA products could
reconstitute synovial fluid & ↓ symptoms & can
temporarily & modestly ↑ viscosity.
Hyaluronan provides greater pain relief for a
longer time than intraarticular corticosteroids,
but corticosteroids work more rapidly.
93

92. NICE 2014 Update
Do not offer intra-articular hyaluronan
injections for the management of
osteoarthritis. [2014]
Efficacy is modest and inconsistent.
Prices of hyaluronan injections are
expensive.
94

93. 95

94. Opioid Analgesics
At low doses can be useful in pts who experience
no relief with acetaminophen, NSAIDs,
intraarticular injections, or topical therapy.
are particularly useful in pts who cannot take
NSAIDs because of renal failure, & for pts in
whom all other treatment options have failed &
who are at high surgical risk, precluding joint
arthroplasty
Low-dose opioids are the initial intervention,
usually given in combination with
acetaminophen
96

95. Opioid analgesics (cont)
Oxycodone is the most extensively studied of the
agents recommended for OA. However, other narcotic
analgesics such as morphine, hydromorphone,
methadone, and transdermal fentanyl are also
effective.
SR compounds usually offer better pain control
throughout the day, & are used when simple opioids are
ineffective.
typical opioid-related ADRs:
nausea, somnolence, constipation, & dizziness
Should be used cautiously in elderly patients
If pain is intolerable & limits activities of daily living, & the
pt has sufficiently good cardiopulmonary health to
undergo major surgery, joint replacement may be
preferable to continued reliance on opioids

96. Tramadol
Tramadol is a centrally acting synthetic opioid oral
analgesic that also weakly inhibits the reuptake of serotonin
and norepinephrine.
with or without acetaminophen has modest analgesic
effects in pts with OA & can be add-on therapy in pts taking
concomitant NSAIDs or coxibs
As with opioid analgesics, may be helpful for pts who
cannot take NSAIDs or coxibs
should be initiated at a lower dose (100 mg/d) & may be
titrated as needed for pain control to a dose of 200 mg/d
available in combination tablet with acetaminophen & as a SR
tablet
Opioid-like ADRs: N&V, dizziness, constipation, HA, &
somnolence are common with tramadol
98

97. 99

98. Alternatives
In addition to pharmacologic
agents, acupuncture has
been examined in OA.
However, NICE guideline
recommends NOT to offer
acupuncture to OA patients
Electrotherapy, laser,
transcutaneous electrical
nerve stimulation or TENS
can be used.
NICE 2008

99. TENS
101

100. Surgery
Types of procedures vary according to the site
and the degree of involvement.
Various surgical interventions include the
following:
1.Surgical interventions for OA of the knee
Arthroscopic lavage
Using a saline lavage to wash out the joint
Joint realignment (realignment osteotomy)
Joint fusion (arthrodesis)
Surgically fusing the joint to eliminate motion
Joint replacement (arthroplasty)
2.Surgical interventions for OA of the hip
Joint realignment (realignment osteotomy)
Joint fusion
Joint replacement (arthroplasty)
102

101. Evaluation of therapeutic
outcomes
Pt monitoring in OA is patient-specific: pain or ↓ function, pt’s
risk of ADRs
To monitor efficacy
baseline pain can be assessed with a visual analog scale
baseline range of motion for affected joints
baseline radiographs
additional tests of OA severity may include:

measurement of grip strength,
50-foot walking time,
patient & physician global assessment of OA severity
↓ use of analgesics or NSAIDs would suggest a beneficial
effect of nonpharmacologic interventions
disease-specific QoL is valuable in assessing clinical
response to interventions
103

102. Evaluation of therapeutic
outcomes (cont’d)
ADR monitoring:
With NSAIDs: GI, cardiovascular, renal, & other risks, as well
as age and comorbidities, should be assessed
When assessing toxicity of therapy, pts should be asked
first if they are having any “problems” with their medications
(open-ended question) followed with more direct questions
relating to the most common adverse effects associated with
the respective medication.

Symptoms of abdominal pain, heartburn, nausea, or change in
stool color provide valuable clues to the presence of GI
complications

monitoring for HTN, weight gain, edema, skin rash, CNS ADRs
(HA & drowsiness)
baseline SrCr, CBC, & serum transaminases are repeated at 6-
12-mo intervals to identify GI, renal, hepatic, and hematologic
toxicities.
104

103. Evaluation of therapeutic
outcomes (cont’d)
intraarticular corticosteroids: improvement should begin
with 2-3 days & last 4-8 wks
Pts should be advised about possible injection site reactions,
& systemic effects, especially for those with HTN & DM (more
likely for higher doses given more frequently)
For pts receiving intraarticular HA, improvement can begin
within 3-4 wks & can last several months, & pts should be
advised about possible injection-site reactions & allergic
reactions
For pts receiving opioids or tramadol, relief from pain is
expected to occur rapidly
Pts should be monitored carefully & cautioned about sedation,
dysphoria, nausea, risk of falls, constipation, & development
of tolerance
105

104. Clinical case
G.R., a 190-lb, 60-yo school teacher, developed painful,
tender swelling in the right knee ~1 year ago.
Since then, she has experienced intermittent pain in the right
knee & hip.
She now has moderate morning stiffness in the hip & knee &
some joint stiffness after inactivity.
Her pain is ↑ significantly by ambulation.
Examination of her joints revealed Heberden's nodes in both
hands, limitation of flexion of the right hip to 45 degrees,
patellar crepitus, & mild tenderness at the joint margin of the
right knee.
Laboratory studies were all normal, including negative RF.
What S&S of OA are present in G.R.?
How should G.R. be treated?
106

105. Clinical case (cont’d)
G.R. starts a regimen of acetaminophen 1 g QID PRN &
returns to the clinic 4 wks later.
She states that most joint-related symptomatically & general
functioning have improved; however, she claims that the pain
& stiffness in her right knee is more bothersome now than 1
month ago.
What is the best treatment option for G.R. at this visit?
What is the role of the NSAIDs and/or COX-2 inhibitors in
managing G.R.'s OA?
107

106. 108