anti- inflammatory drugs and its uses

1. Dr. TAREK NASRALLA

2. What do know about NSAIDs
 Is there is best NSAIDs
 Is there is safest NSAIDs

4.  Every day the world nearly 4 million patients suffer
from pain of different intensity: 10-15% of moderate
pain, 30-40% of the average pain intensity, 60-80%
of severe pain. Studies show that more than 30
million people in the world take NSAIDs daily , and
that the complications of their reception, primarily
gastrointestinal, constantly growing

5. Over-the-Counter Anti-inflammatory
Drugs
 NSAIDs that can be purchased over the
counter include:
 ibuprofen
 naproxen sodium
 aspirin

6. Nonsteroidal Antiinflammatory
Drugs (NSAIDs)

7.  Inflammation is a defense reaction caused
by tissue damage or injury
 Can be elicited by numerous stimuli
including:
• infectious agents
• antigen-antibody interaction
• ischemia
• thermal and physical injury

8. Peripheral mechanisms of pain

9. Characterized by:
1. Redness (rubor): vasodilatation of capillaries to
increase blood flow
2. Heat (calor): vasodilatation
3. Pain (dolor): Hyperalgesia, sensitization of nociceptors
4. Swelling (tumor): Increased vascular permeability
(microvascular structural changes and escape of
plasma proteins from the bloodstream)
5. Loss of function (functio laesa)
• Inflammatory cell transmigration through
endothelium and accumulation at the site of injury

11. Mediators of Inflammation
1. Vasoactive amines (Histamine, Serotonin)
2. Platelet activating factor (PAF)
3. Complement system
4. Kinin system
5. Cytokines
6. Nitric oxide
7. Adhesion Molecules
8. Arachidonic acid metabolites:
• Prostaglandins (PGs)
• Thromboxane A2 (TXA2)
• HETE (hydroxy-eicosatetraenoic acid)
• Leukotrienes (LTs)
mediated by cyclooxygenases (COX)

12. Inflammatory responses occur in
three distinct phases:
1. An acute transient phase, characterized by:
– local vasodilation
– increased capillary permeability
2. A delayed, subacute phase, most prominently
characterized by:
– infiltration of leukocytes and phagocytic cells
3. A chronic proliferative phase, in which:
– tissue degeneration and fibrosis occur

13. NSAIDs
 Structurally diverse agents with anti-inflammatory
activity
 Activity is attributed to their ability to inhibit
cyclooxygenase (COX)
 Cyclooxygenase involved in the biosynthesis of
prostaglandins
 Prostaglandins are a class of eicosanoids
 Eicosanoids are any product derived from arachidonic
acid, a twenty carbon fatty acid
 Eicosanoids also include, thromboxanes, lipoxins,
and leukotrienes.

15. Mechanism of
action of NSAIDs

16. Analgesic effect
 Mechanism of Action
 selectively inhibiting prostaglandin synthesis
(prostaglandin synthetase) centrally (hypothalamus) and
peripherally
 Prostaglandins
stimulate peripheral nerve endings producing pain
impulses that are carried to the CNS (prostaglandin G2 &
H2)
 Enhance local inflammation (prostaglandin E2)
 Produce localized edema (E2)
 Constrict blood vessels (local ischemia, G2 & H2)

17. Two main forms of Cyclooxygenases (COX)
• Cyclooxygenase-1 (COX-
1)
• Produces prostaglandins
that mediate homeostatic
functions
• Constitutively expressed
• Plays an important role in
• Gastric mucosa
• Kidney
• Platelets
• Vascular endothelium
• Cyclooxygenase-2
(COX-2)
• Produces
prostaglandins that
mediate
inflammation, pain,
and fever.
• Induced mainly in
sites of inflammation
by cytokines

19. Mechanism of action of NSAIDs
1. Antiinflammatory effect
Due to the inhibition of the enzymes that produce
prostaglandin H synthase (cyclooxygenase, or
COX), which converts arachidonic acid to
prostaglandins, and to TXA2 and prostacyclin.

20.  NSAID inhibition of PG production alleviates most
of the pathologic effects associated with
inflammation, but it also interferes with the
physiologic role of these molecules
 Consequently, long-term therapy with nonspecific
NSAIDs is frequently limited by their adverse effects,
particularly those caused by erosion of gastric
mucosal protection
—— GI bleeding
2. The mechanisms of NSAIDs

21. 3. Pharmacodynamic Effects of NSAIDs
Positive
Analgesic : refers to the relief of pain by a mechanism other than
the reduction of inflammation (for example, headache);
- produce a mild degree of analgesia which is much less than the
analgesia produced by opioid analgesics such as morphine
anti-inflammatory: these drugs are used to treat inflammatory
diseases and injuries, and with larger doses - rheumatoid disorders
antipyretic : reduce fever; lower elevated body temperature by
their action on the hypothalamus; normal body temperature is not reduced
antiplatelet : inhibit platelet aggregation, prolong bleeding time;
have anticoagulant effects

22. - Reduces platelet aggregation
- Most of these drugs will potentiate the action of oral
anticoagulants such as coumadin, by their effects on platelet
aggregation
- An 80 mg dose of asprin will increase bleeding time for 2 folds
NSAIDs and Platelets/Endothelial Cells
Note: Selective inhibition of COX-2 will inhibit the production of PGI2 but not of
thromboxaneA2, which is produced by COX-1. SO ?
3. Pharmacodynamic Effects of NSAIDs

23. Gastric irritant
Decreased renal perfusion
Bleeding
4. Adverse Effects associated with NSAIDs
Non-selective

24. For patients presenting to hospital with upper gastrointestinal (UGI)
bleeding - a significant percent were using NSAIDs
Note: OTC use of NSAIDs was more prevalent than was prescribed NSAID usage
4. Adverse Effects associated with NSAIDs
Gastrointestinal reactions

25. NSAIDs - Gastric Irritant Effects: Molecular Mechanisms
PGs reduce H+ secretion and increase mucous production
Consequently, NSAIDs cause some degree of gastric upset due to
inhibition of PG synthesis
- Misoprostol. a
synthetic prostaglandin
analogue, can also
decrease the risk of
NSAID-induced
ulceration and
complications
- PPIs can reduce the
risk of peptic ulcer
formation

26. Afferent
arteriole
Efferent
arteriole
ACEI/
ARB
 NSAIDS,
 Low
volume
 Poor renal
perfusion
normal
4. Adverse Effects associated with NSAIDs
NSAIDs – Effects on Renal Function
PGs not participated
PGs vasodilator when
angiotensin II or
catercholamines elevated

27. 5. Drug interactions

28.  Aspirin irreversibly inactivates
COX-1 and COX-2 by acetylation of
a specific serine residue.
 This distinguishes it from other
NSAIDs, which reversibly inhibit
COX-1 and COX-2.

29. Antipyretic effect
The antipyretic effect of NSAIDs is
believed to be related to:
• inhibition of production of
prostaglandins induced by interleukin-1
(IL-1) and interleukin-6 (IL-6) in the
hypothalamus
• the “resetting” of the thermoregulatory
system, leading to vasodilatation and
increased heat loss.

30. Therapeutic uses
1.Inflammation
 NSAIDs are first-line drugs used to arrest
inflammation and the accompanying pain of
rheumatic and nonrheumatic diseases, including
rheumatoid arthritis, juvenile arthritis,
osteoarthritis, psoriatic arthritis, ankylosing
spondylitis, Reiter syndrome, and
dysmenorrhea.
 Pain and inflammation of bursitis and tendonitis
also respond to NSAIDs.

31.  NSAIDs:
•Do not significantly reverse the
progress of rheumatic disease
•they slow destruction of cartilage
and bone
•allow patients increased mobility
and use of their joints.

32.  Treatment of chronic inflammation requires use of
these agents at doses well above those used for
analgesia and antipyresis
 The incidence of adverse drug effects is increased.

33.  Drug selection is generally dictated by the
patient's ability to tolerate the adverse
effects, and the cost of the drugs.
 Antiinflammatory effects may develop only
after several weeks of treatment.

34. 2. Analgesia
 NSAIDs alleviate mild-to-moderate pain by:
 decreasing PGE- and PGF-mediated
increases in pain receptor sensitivity.
 They are more effective against pain
associated with integumental structures (pain
of muscular and vascular origin, arthritis, and
bursitis) than with pain associated with the
viscera.

35. 3. Antipyresis
 NSAIDs reduce elevated body
temperature with little effect on
normal body temperature.

36. Classification
Non-selective COX inhibitor
Selective COX inhibitor
Salicylates
Acetaminophen
Indomethacin
et al
selection
chemcial
constitution

37. NSAIDs
Propionic acid derivatives
 Ibuprofen
 Naproxen
 Fenoprofen
 Ketoprofen
 Flurbiprofen
 Oxaprozin
Acetic acid derivatives
 Indomethacin
 Sulindac
 Etodolac
 Ketorolac
 Diclofenac (Safety alert by FDA)
 Nabumetone

38. NSAIDs
Enolic acid (Oxicam) derivatives
 Piroxicam
 Meloxicam
 Tenoxicam
 Droxicam
 Lornoxicam
 Isoxicam
Fenamic acid derivatives
( Fenamates )
 Mefenamic acid
 Meclofenamic acid
 Flufenamic acid
 Tolfenamic acid

39. NSAIDs
Selective COX-2 inhibitors (Coxibs)
 Celecoxib (FDA alert)
 Rofecoxib (withdrawn from market) - increased cardiovascular
thrombotic events
 Valdecoxib (withdrawn from market) - increased cardiovascular
thrombotic events
 Parecoxib FDA withdrawn
 Lumiracoxib TGA cancelled registration
 Etoricoxib FDA withdrawn
 Firocoxib used in dogs and horses
Sulphonanilides
 Nimesulide (systemic preparations are banned by several countries for
the potential risk of hepatotoxicity)
Others
 Licofelone acts by inhibiting LOX (lipooxygenase) & COX and hence
known as 5-LOX/COX inhibitor

41. COX-1 compared to COX-2
COX-1 COX-2
Expression
Tissue
localization
Role “Housekeeping” and
maintenance
Ubiquitous Inflammatory and
neoplastic sites (small
amounts in kidney, uterus,
ovary, CNS [neocortex,
hippocampus])
Pro-inflammatory and
mitogenic functions (?
neuronal plasticity)
Constitutive
(activated by
physiologic stimuli
Inducible by pro-
inflammatory stimuli (LPS,
TNF, IL-2, IFN etc)

42. Aspirin (acetylsalicylic
acid)
Nonacetylated salicylates:
 sodium salicylate
 magnesium salicylate
 choline salicylate
 sodium thiosalicylate
 sulfasalazine
 mesalamine
 salsalate

43. Pharmacologic properties:
Salicylates are weak organic
acids;
aspirin has a pKa of 3.5.
These agents are rapidly
absorbed from the intestine as
well as from the stomach,
where the low pH favors
absorption.

44. Salicylates are hydrolyzed rapidly by
plasma and tissue esterases to acetic
acid and the active metabolite
salicylic acid.
esterases

46. Metabolism

47.  Salicylates have a t1/2 of 3—6 hours
after short-term administration.
 Long-term administration of
high doses (to treat arthritis) or
toxic overdose
 increases the t1/2 to 15—30 hours
because the enzymes for glycine and
glucuronide conjugation become
saturated.

49. Unmetabolized salicylates are
excreted by the kidney.
If the urine pH is raised above 8,
clearance is increased
approximately fourfold as a result
of decreased reabsorption of the
ionized salicylate from the tubules.

50. Salicylates are used to treat:
 rheumatoid arthritis
 juvenile arthritis
 osteoarthritis
other inflammatory disorders
5-Amino salicylates (mesalamine,
sulfasalazine)
 can be used to treat Crohn's disease.

51. Salicylic acid is used topically to
treat:
plantar warts
fungal infections
corns

52. Aspirin
 has significantly greater
antithrombotic activity than other
NSAIDs

53. 1. Gastrointestinal effects
 most common adverse effects of high-dose
aspirin use (70% of patients):
 nausea
 vomiting
 diarrhea or constipation
 dyspepsia (impaired digestion)
 epigastric pain
 bleeding, and ulceration (primarily
gastric).

54. These gastrointestinal effects are
thought to be due to:
1.a direct chemical effect on gastric
cells or
2.a decrease in the production and
cytoprotective activity of
prostaglandins, which leads to
gastric tissue susceptibility to
damage by hydrochloric acid.

55. The gastrointestinal effects may
contraindicate aspirin use in patients
with an active ulcer.
Aspirin may be taken with
prostaglandins to reduce gastric
damage.
Decrease gastric irritation by:
Substitution of enteric-coated or
timed-release preparations, or
the use of nonacetylated
salicylates, may decrease gastric
irritation.

56. 2. Hypersensitivity (intolerance)
 Hypersensitivity is relatively uncommon
with the use of aspirin (0.3% of
patients); hypersensitivity results in:
 rash
 bronchospasm
 rhinitis
 Edema, or
 an anaphylactic reaction with shock,
which may be life threatening.
 The incidence of intolerance is highest
in patients with asthma, nasal polyps,
recurrent rhinitis, or urticaria.
 Aspirin should be avoided in such
patients.

57.  Cross-hypersensitivity may exist:
 to other NSAIDs
 to the yellow dye tartrazine, which is
used in many pharmaceutical
preparations.
Hypersensitivity is not associated with:
 sodium salicylate or
 magnesium salicylate.

58. The use of aspirin and other salicylates
to control fever during viral infections
(influenza and chickenpox) in children
and adolescents is associated with an
increased incidence of Reye's syndrome,
an illness characterized by vomiting,
hepatic disturbances, and encephalopathy
that has a 35% mortality rate.
Acetaminophen is recommended as a
substitute for children with fever of
unknown etiology.

59. May decrease the glomerular filtration
rate, particularly in patients with renal
insufficiency.
Occasionally produce mild hepatitis
Prolong bleeding time.

60. Aspirin irreversibly inhibits platelet
COX-1 and COX-2 and, thereby, TXA2
production, suppressing platelet
adhesion and aggregation.
The use of salicylates is
contraindicated in patients with
bleeding disorders
Salicylates are not recommended
during pregnancy; they may induce:
postpartum hemorrhage
 premature closure of the fetal
ductus arteriosus.

61. Drug interactions

62. In adults, salicylism (tinnitus, hearing
loss, vertigo) occurs as initial sign of
toxicity after aspirin or salicylate
overdose or poisoning.
In children, the common signs of
toxicity include hyperventilation and
acidosis, with accompanying lethargy
and hyperventilation.

63.  Treatment of Aspirin Toxicity
includes:
1. correction of acid—base
disturbances
2. replacement of electrolytes and
fluids
3. cooling
4. alkalinization of urine with
bicarbonate to reduce salicylate
reabsorption
5. forced diuresis, hemodialysis
6. gastric lavage or emesis

64. NSAIDs are absorbed rapidly after oral
administration.
 These agents are extensively bound to
plasma proteins, especially albumin.
 They cause drug interactions due to the
displacement of other agents,
particularly anticoagulants, from serum
albumin; these interactions are similar
to those seen with aspirin.

65. • NSAIDs are
metabolized in the liver
excreted by the kidney
• The half-lives:
#1 -45 h ----# most: 10 -20 h

66.  These agents commonly produce:
 gastrointestinal disturbances
 cross-sensitivity with aspirin
• Non-dose-related acute renal failure and
nephrotic syndrome:
– in combination with ACE inhibitors
– More nephrotoxic:
» Indomethacin
» Meclofenamate
» Tolmetin
» phenylbutazone

67. Antiinflam
matory
Antipyre
sis
Analgesi
aPrototypeChemical Class
+++++++++AspirinSalicylates
Marginal++++++Acetaminoph
en
Para-
aminophenols
+++++++++++IndomethacinIndoles
+++++++++Tolmentin,
mefenamic
acid
Pyrrol acetic
acids
+++++++++++Ibuprofen,
naproxen
Propionic acids
++++++++++Phenylbutazo
ne, piroxicam
Enolic acids
+++++++NabumetoneAlkanones
+++++++++++CelecoxibSulfonamide

68. Propionic acid derivatives
(Ibuprofen, Fenoprofen, ketoprofen ,
naproxen)
There is no reported interaction of ibuprofen or
ketoprofen with anticoagulants.
Fenoprofen has been reported to induce
nephrotoxic syndrome.
Long-term use of ibuprofen is associated with an
increased incidence of hypertension in women.

69. Sulindac, tolmetin, Ketorolac
 Sulindac:
 is a prodrug that is oxidized to a sulfone and then to the
active sulfide
 has a relatively long t1/2 (16 h) because of enterohepatic
cycling.
 Tolmetin:
 has minimal effect on platelet aggregation;
 it is associated with a higher incidence of anaphylaxis
than other NSAIDs.
 Tolmetin has a relatively short t1/2 (1 h).
 Ketorolac:
 is a potent analgesic with moderate anti-inflammatory
activity
 can be administered:
 intravenously or
 topically in an ophthalmic solution.

70. Indomethacin
• Pharmacologic effects :
(1) Inhibit COX nonselectively .
(2) Inhibit phospholipase A and C.
(3) Reduce PMN migration.
(4) Decrease T cell and B cell proliferation.
Peak concentrations can be achieved in 1 to 2
hours (in fasting subjects, onset is delayed
by food intake).
(10-40 time more potent anti-inflammatory
than aspirin)

71. Indomethacin
• Therapeutic uses:
Because of its toxicity and side effect, it is not
routinely used for analgesia or antipyretic.
The major uses of indomethacin are in the treatment
of rheumatoid arthritis, ankylosing spondylitis,
osteoarthritis, and acute gout.
to speed the closure of patent ductus arteriosus in
premature infants (otherwise, it is not used in
children);
It inhibits the production of prostaglandins that
prevent closure of the ductus.

72. Indomethacin
• A half-life of about 2.5 hours.
• Daily dosage ranges from 75 mg – 100 mg
taken in two to three doses.
• Up to half of those using indomethacin may
experience some side-effects and almost one-
third will discontinue use
• Indomethacin’s use has declined as newer
agents with a lower side-effect profile have
emerged.

73. Indomethacin
• Adverse effect:
(1) Common side-effects include gastrointestinal
symptoms (ulceration, nausea, abdominal
pain) and headaches (15 percent to 25
percent of patients).
(2) Occasional:Tinnitus, dizziness, or confusion
(3) Hematologic reactions:
(4) Hypersensitivity reactions: asthma (aspirin-
sensitive patients may exhibit cross-reactions
to indomethacin).

74. Ibuprofen
• Most frequently used NSAID
• Introduced to the OTC market in 1985, it is
available in 200 to 800 mg tablets by
prescription, and 200 mg tablets OTC
• Frequently used as an antipyretic in adults and
children, as its longer duration of action makes
it a popular alternative to acetaminophen

75. Ibuprofen
• Peak plasma levels are achieved within 15
to 30 minutes of ingestion
• Rapid onset of action can be quite beneficial
for quick relief of pain
• Half-life of about 2 hours, it must be taken
every 6 to 8 hours to maintain effect
• An anti-inflammatory regimen requires
2400 – 3200 mg daily

76. Ibuprofen
• Taken in three separate doses, allowing it to
be taken at meal times, lessening the
likelihood of gastric irritation.
• Sufficient analgesia should be achieved by
daily dosages of less than 2400 mg per day.
• Approximately 10 percent to 15 percent of
individuals must discontinue use secondary
to gastrointestinal symptoms.

77. Chemically similar to ibuprofen.
Naproxen is available as the OTC preparation.
Due to naproxen's long half-life
(approximately 12 hours), the daily
recommended dosage of 750 – 1000 mg can be
taken on a twice daily schedule, reducing
gastric upset due to only two exposures and
improving compliance.
Onset of pain relief can begin within 1 hour in
patients taking naproxen
Naproxen

78. Peak plasma levels are achieved within 2 to 4
hours
Incidence of upper gastrointestinal bleeding in
OTC use is double that of OTC ibuprofen
The pharmacokinetic profile of naproxen in
children aged 5 - 16 years is similar to that in
adults although the clearance is generally higher in
children than in adults.
Naproxen enters breast milk achieving
concentrations of approximately 1% of those in
plasma
Naproxen

79. PIROXICAM
• Piroxicam is an oxicam derivative of enolic acid.
• Piroxicam has t1/2 of 45 hours.
• Other oxicam NSAIDs include meloxicam,
tenoxicam, and droxicam
• piroxicam is generally well tolerated but side effects
can include headache, dizziness, somnolence,
dyspepsia, abdominal discomfort, diarrhea,
peripheral edema and hypersensitivity reactions

80. MECLOFENAMATE, MEFENAMIC ACID
• t1/2 of 2 hours.
• A relatively high incidence of gastrointestinal
disturbances is associated with these agents.

81. NABUMETONE
• Only nonacid NSAID currently available
• Once-a-day treatment; half-life is 24 hours
• Compared with NSAIDs, nabumetone is associated
with reduced:
• inhibition of platelet function
• incidence of gastrointestinal bleeding.
• Nabumetone inhibits COX-2 more than COX-1.
.

82. KETOROLAC
• Toradol.
• Not typically employed for its anti-inflammatory
properties.
• It is the only NSAID available for intramuscular
or intravenous injection as well as oral
administration.

83. KETOROLAC
• Although it also has anti-inflammatory and
antipyretic properties, it is most commonly
marketed and used as an analgesic, particularly in
postoperative patients.
• As an analgesic, ketorolac offers great promise as
it avoids the most common shortcomings of
opioids, i.e., tolerance, withdrawal effects, and
respiratory depression.

84. KETOROLAC
• Interestingly, Tokish et al (1992) recently reported
that 28 of 30 National Football League team
medical staffs commonly use ketorolac
intramuscular injections on game days for pain
relief.
• Due to high risk of renal effects, duration of
ketorolac treatment is typically held to less than 5
days.

85. COX-2 Selective agents
O Celecoxib [Celebrex]
O Rofecoxib [Vioxx]
O Valdecoxib [Bextra]
Othat inhibit COX-2 more than COX-1 have
been developed and approved for use.
OThe rationale behind development of these
drugs was that:
A. inhibition of COX-2 would reduce the
inflammatory response and pain
B. not inhibit the cytoprotective action of
prostaglandins in the stomach, which
is largely mediated by COX-1.

86. Patients with rheumatoid arthritis were treated with
celecoxib (100, 200, or 400 mg twice daily),
naproxen 500 mg twice daily, or a placebo for 12
weeks.
Rates of gastroduodenal ulceration with naproxen
were statistically higher (*P < 0.01) than rates with
celecoxib or a placebo. (Data from Simon LS,
Weaver AL, Graham DY, et al: Anti-inflammatory
and upper gastrointestinal effects of celecoxib in
rheumatoid arthritis. JAMA 282:1921–1928, 1999.)
Incidence of endoscopic gastroduodenal ulcers with a COX-2
specific inhibitor Celecoxib

87. COX-2 inhibitor
200 mg tablets
Peak Plasma levels = 3 hours
Half-life (approximate-effective)
= 11 hours
Problems include:
Liver and kidneys
Heart ?

88. Celecoxib is now the only selective COX-2 inhibitor
available in the US
- withdrawal of rofecoxib (Vioxx, Merck & Co) Sept 2004
- suspension of valdecoxib (Bextra, Pfizer) Apr 2005
Note: The fact that it now carries exactly the same
warning for gastrointestinal risk as the older nonselective
NSAIDs is quite remarkable, new drugs—were
supposedly less risky to the gastrointestinal tract than the
older nonselective agents
Celecoxib includes a boxed warning, highlighting the
potential for increased risk of cardiovascular events and
the well described, serious, potential life-threatening
gastrointestinal bleeding associated with their use.
Celecoxib: Current Status

89. Celecoxib: cardiovascular events
OCelecoxib compared with
placebo is not associated with an
increased risk for cardiovascular
events for duration of use from
12 to 52 weeks.
OCelecoxib compared with
nonselective NSAIDs is not
associated with increased
cardiovascular endpoints.

90. ORofecoxib and valdecoxib have been
removed from the market due to a
doubling in the incidence of heart
attack and stroke
OCelecoxib remains on the market and
is approved for:
OOsteoarthritis and rheumatoid
arthritis
OPain including bone pain, dental
pain, and headache
OAnkylosing spondylitis.

96. 1. 137 reports on the effectiveness of OA
treatments reveals that acetaminophen, the
most widely used over-the-counter treatment,
does not provide a clinically significant
reduction in pain
2. Only slightly more effective than
acetaminophen was celecoxib, which was
surprising because past studies had
demonstrated a greater effect for the COX-2
inhibitor
3. IA placebo was significantly better than oral
placebo, and active IA treatments were more
effective than active oral treatments

97. oFor stiffness, naproxen, ibuprofen, diclofenac,
and celecoxib were more effective than oral
placebo and acetaminophen, and injected
hyaluronic acid was better than injected
placebo. However, injected placebo was not
significantly better than oral placebo
oFor function, all interventions except injected
corticosteroids were better than oral placebo.
Naproxen, ibuprofen, diclofenac, and celecoxib
were more effective than acetaminophen.
Hyaluronic acid was better than injected
placebo or injected corticosteroids

98. • Authors write, "A clear understanding of the
role of placebo, pain pathophysiology, and
patient preferences should be key factors
facilitating shared decision making in treating
patients with knee OA."
• Glucosamine and chondroitin were similar to
NSAIDs overall in pain relief, although a meta-
analysis of high-quality trials found that
glucosamine was only slightly more effective
than placebo. Topical NSAIDs were similarly
effective as oral NSAIDs for localized OA, with
fewer gastrointestinal adverse events.

99. • The primary treatment goals for
symptomatic OA of the knee are to
reduce pain, improve joint mobility,
and limit functional
impairment.[1] Secondary treatment
goals aim to reduce disease
progression, improve muscular
strength, and preserve the patient's
independence and quality of life

100. QUESTIONS?!

101. You are seeing a 60-year-old man with a 3-month
history of right knee pain. Your examination along
with a plain radiograph confirm OA. According the
previous review , what should you most keep in
mind as you treat this patient?
1. Celecoxib is more effective than nonselective
NSAIDs
2. NSAIDs may promote a higher risk for cardiovascular
events only after years of regular use
3. NSAIDs may promote a higher risk for cardiovascular
events only at high doses
4. Topical NSAIDs may be similarly effective as oral
NSAIDs for this patient

102. Which one of the following treatments might
be most effective for this patient in reducing
pain related to knee OA?
1. Acetaminophen
2. Celecoxib
3. Naproxen
4. IA hyaluronic acid

103. • Maryellen is a 38-year-old mother of 2 young
children, She presents to you with pain and
slight inflammation in her right knee.
• She notes increased pain after long days
of caring for her children, stiffness after
sitting in the same position for any
extended period of time, and mild pain
when kneeling or bending.
• She also complains of stiffness when she
first wakes up in the morning.
• She has no other medical concerns.
• Her family history is unremarkable;

104. • She reports a history of a skiing accident at
age 22 years, after which she had arthroscopy
and partial medial meniscectomy.
• She gained a lot of weight with her second
pregnancy and remains at least 30 pounds
heavier than she was before delivery. Her body
mass index is 29.4 kg/m2.
• Blood tests rule out infection, and she is RF
and anti CCP negative.
• She has minor bone spurs surrounding her
femoral-tibial joint on standing film, trace joint
space collapse.
• She is diagnosed with osteoarthritis (OA) of
her knee.

105. • The most recent 2013 AAOS (American academy of
orthopedic surgeon) recommendations for less
invasive alternatives to knee replacement
strongly recommend that patients with
symptomatic OA of the knee participate in
strengthening low-impact aerobic exercises
(such as Pilates classes), along with self-
management programs and neuromuscular
education.[1]
• In contrast, Zumba classes involve high-impact
aerobic exercise.
• Alternative treatment options, including glucosamine
and chondroitin or avocado-soybean unsaponifiables,
lack clear evidence to support their use

106. Maryellen returns in 6 months for a follow-up visit. She reports that she enjoys
working out on the Pilates reformer machine, and sees some initial benefits, but
she only has the time to go once or twice a week.
She tried taking brisk walks around the block with her children, but that caused
more pain and swelling.
She also notes that she tried over-the-counter glucosamine/chondroitin
supplements, but she had no noticeable benefit. She then tried using topical
creams and gels, including topical capsaicin and topical nonsteroidal anti-
inflammatory drugs (NSAIDs), which afforded some benefit for a short duration.
At this point, she sits with an ice pack on her knee every evening while reading
to her children in bed.
She continues to have pain, swelling, and stiffness, but she adamantly refuses
surgical options.
Which one of the following is appropriate for Maryellen, according
to the AAOS guidelines for the treatment of knee OA?
• Acupuncture
• Weight loss
• Lateral heel wedge
• Acetaminophen 3500 to 4000 mg/day

107. • AAOS recommends weight loss for patients
with a body mass index greater than or equal
to 25 kg/m2 who have symptomatic OA of
the knee, to facilitate functional
improvement.[1]
• There is inconclusive evidence to support
the use of acupuncture, and lateral heel
wedges are not recommended.
• The dosage of acetaminophen given here
exceeds recommendations, and AAOS has
not found sufficient evidence to recommend
for or against acetaminophen for OA of the
knee

108. Maryellen is able to lose 10 pounds in 3 months, and
she reports some definite improvement. However, she
still complains of pain and swelling, especially with cold,
rainy weather. You send her for magnetic resonance
imaging, which confirms OA of knee, chondromalacia
grade 2 (roughing on joint surface). At this point, she is
requesting medication to help her manage her pain and
swelling.
Which one of the following medications might you
recommend?
• Ibuprofen with codeine
• Fentanyl patch
• Cyclooxygenase inhibitors
• Tricyclic antidepressant

109. • Selective cyclooxygenase (COX-
2) inhibitors and nonselective
NSAIDs, in either oral or topical
formulations, are recommended
for symptomatic OA of the knee,
as is the mild opioid tramadol.
• There is less support for the use
of stronger opioids or tricyclic
antidepressants, and more
concern over their possible
adverse effects.

110. • Peggy is a 61-year-old female with a 10-year
history of worsening OA symptoms that until
recently were most pronounced in her left
knee.
• She has no history of knee surgery. She is
currently taking over-the-counter
acetaminophen (200 mg daily for pain) but
reports minimal to no relief.
• Until 6 months ago, she had been playing golf
a few times a week, but she is now forced to
use a cart and limit her excursions to no more
than once a week because of pain and
inflammation.

111. • She has recently lost about 5 pounds, or nearly 3% of
her total body weight.
• She has tried doing low-impact aerobic exercises and
is now enrolled in yoga classes.
• However, she sees no substantial improvement in her
symptoms.
• Her medical history includes a hysterectomy at age
54 years, mild to moderate hypertension (being
managed with a calcium channel blocker), and
irritable bowel syndrome.
• She has come to the office because of pain in her
right knee when walking or climbing stairs and also
when kneeling or squatting.
• She says she especially notices the pain toward the
end of the day.

112. • She says the pain level is much less after she rests,
but then the pain is replaced by stiffness.
• When asked how long the stiffness persists, she says
that her knee usually feels much better after she
moves around for a few minutes.
• The pain, swelling, and stiffness are substantially
interfering with her otherwise active lifestyle, and she
is seeking treatment options.
Which one of the following options would you
recommend to manage Peggy's OA?
• Cortisone injections
• Switch from acetaminophen to topical diclofenac
• Arthroscopy
• Work with a nutritionist to help her lose more weight

113. Studies have demonstrated the
safety and efficacy of topical
diclofenac, in contrast to inconsistent
evidence regarding the use of
acetaminophen.
Peggy has already begun losing
weight on her own.
Cortisone injections and arthroscopy
may be appropriate in the future.

114. Case 2, continued
• Peggy begins using topical diclofenac and
experiences some relief.
• However, when she returns at 6 months, her OA has
progressed.
• Standing knee film confirms 50% joint space collapse
medially.
• She reports increasing pain when walking, running,
bending, or kneeling, and substantial pain and
difficulty when climbing stairs.
• She has increased joint stiffness, especially when
awakening in the morning, as well as joint swelling
after extended periods of motion.
• On exam she has grade I/II effusion.
• You analyze her joint fluid and rule out gout and
infection.

115. Given Peggy's current condition and
her strong wish to return to playing
golf without riding in a cart, which one
of the following management options
would be best to explain to her at this
time?
• Arthroscopy with debridement
• Intra-articular steroid injections
• Obtain magnetic resonance imaging
before proceeding with any further
treatment

116. Intra-articular corticosteroid (IA-CS)
injections can provide short-term relief for
patients with symptomatic OA of the knee
who have not responded to oral
analgesics or NSAIDs, or who have
effusion or synovitis.

117. Case 2, continued
Peggy is hopeful that the injections will allow her to return to
walking the golf course and is also intent on delaying the need for
total knee replacement as long as possible. She receives 1
injection every 3 months for 15 months, with decreasing beneficial
effects. At her 18-month visit, she declines to have any more
corticosteroid injections. She also admits, with some frustration,
that she is back to riding in the cart during golf outings, which
causes her to feel "ancient."
Which one of the following options do you
recommend for Peggy now?
• Arthroscopy
• Viscosupplementation with a high-molecular-weight formulation
• Viscosupplementation with a low-molecular-weight formulation
Unloader bracing

118. Clinical evidence supports the use of
intra-articular hyaluronic acid (IA-HA)
injections (viscosupplementation), in
particular a high-molecular-weight
formulation, for patients with OA of the
knee. It is useful to explain to patients that
viscosupplementation with the high-
molecular-weight formulation has greater
and longer-lasting benefit compared with
the low-molecular-weight formulation. The
evidence supporting unloader bracing is
inconclusive

119. Peggy has a good response to high-molecular-weight
injections. She returns 3 years later with clear
indications of progressive OA: a positive magnetic
resonance imaging scan for displaced meniscal tear,
loose bodies, and mechanical symptoms of catching and
locking. Her goal is still to delay total knee replacement
as long as possible.
Which one of the following options might you
recommend for Peggy now?
• Platelet-rich plasma injections
• Lavage
• Arthroscopic debridement
• Total knee replacement can no longer be delayed

120. Although the AAOS does not generally
recommend arthroscopic debridement for
symptomatic OA of the knee,[1]
Peggy does have a meniscal tear and
loose body with her diagnosis of OA,
suggesting arthroscopic debridement
could be beneficial.

121. Peggy undergoes arthroscopic surgery and has a
good initial response. However, she appears in
your office 4 months later with recurrent pain and
inflammation.
How would you manage Peggy's postoperative pain
and inflammation?
• Viscosupplementation
• Corticosteroid injections
• Prepare her for total knee replacement
• Repeat debridement

122. Because Peggy's goal is to delay total
knee replacement as long as possible,
postsurgical viscosupplementation is the
best option. High-molecular-weight
viscosupplementation affords more
durable benefits than corticosteroid
injections.

123. In this 42-year-old woman, osteoarthritis (OA) of the
knee has progressed, and she now has moderate pain
when walking or kneeling, substantial pain when
climbing stairs, morning joint stiffness, and joint swelling
after extended periods of motion. Examination is notable
for grade I/II effusion. She has been adhering well to her
current regimen of muscle-strengthening exercises, low-
impact aerobic exercises, and topical diclofenac. Which
one of the following represents the best next step in
managing her OA?
1. Switch topical diclofenac to acetaminophen 3500 to 4000
mg/day
2. Switch topical diclofenac to oral diclofenac
3. Switch topical diclofenac to oxycodone
4. Switch topical diclofenac to intra-articular corticosteroid
injections

124. Which one of the following is an accurate statement
to make when counseling a patient with moderate
knee OA who enquires about intra-articular
hyaluronic acid injections (viscosupplementation)?
1. The AAOS recommends viscosupplementation only
for patients with severe knee OA
2. The response rate to viscosupplementation, in terms
of reduced pain and better function, is about 30% in
patients with knee OA
3. In patients with knee OA, the benefits of
viscosupplementation usually last for at least 6
months
4. Injection site reactions to viscosupplementation in
patients with knee OA generally take about 1 week to
resolve

125. A 59-year-old man has a primary diagnosis of meniscal
tear and a concomitant diagnosis of medial-
compartment knee OA. He has symptoms of pain,
catching, and locking. He is currently being treated with
muscle-strengthening exercises, nonsteroidal anti-
inflammatory drugs, and intra-articular injections of
triamcinolone acetonide. He wishes to delay total knee
replacement surgery as long as possible. Which one of
the following is an option for him that is recommended
by the AAOS?
1. Switch to triamcinolone hexacetonide
2. Unloader bracing
3. Arthroscopic debridement

126. Thank you!
QUESTIONS?!