Dr. TAREK NASRALLA

What do know about NSAIDs

Is there is best NSAIDsIs there is safest NSAIDs

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

Over-the-Counter Anti-inflammatory Drugs

NSAIDs that can be purchased over the counter include:

ibuprofennaproxen sodiumaspirin

Nonsteroidal Antiinflammatory Drugs (NSAIDs)

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

Peripheral mechanisms of pain

Characterized by:1.Redness (rubor): vasodilatation of capillaries to

increase blood flow2.Heat (calor): vasodilatation3.Pain (dolor): Hyperalgesia, sensitization of nociceptors4.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

Mediators of Inflammation

1. Vasoactive amines (Histamine, Serotonin) 2. Platelet activating factor (PAF)3. Complement system4. Kinin system5. Cytokines6. Nitric oxide7. Adhesion Molecules8. Arachidonic acid metabolites:

• Prostaglandins (PGs)• Thromboxane A2 (TXA2)• HETE (hydroxy-eicosatetraenoic acid)• Leukotrienes (LTs)

mediated by cyclooxygenases (COX)

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

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.

Cyclooxygenase

Mechanism of action of NSAIDs

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)

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

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.

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

3. Pharmacodynamic Effects of NSAIDs

PositiveAnalgesic : 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

- 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

Gastric irritant

Decreased renal perfusion

Bleeding

4. Adverse Effects associated with NSAIDs

Non-selective

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

NSAIDs - Gastric Irritant Effects: Molecular Mechanisms 

PGs reduce H+ secretion and increase mucous productionConsequently, 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

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

5. Drug interactions

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.

Antipyretic effectThe 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.

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.

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.

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.

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.

2. AnalgesiaNSAIDs 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.

3. Antipyresis NSAIDs reduce elevated body

temperature with little effect on normal body temperature.

Classification

Non-selective COX inhibitor Selective COX inhibitor

Salicylates Acetaminophen Indomethacin et al

selection

chemcial constitution

NSAIDsPropionic acid derivatives Ibuprofen Naproxen Fenoprofen Ketoprofen Flurbiprofen Oxaprozin Acetic acid derivatives Indomethacin Sulindac Etodolac Ketorolac Diclofenac (Safety alert by FDA) Nabumetone

NSAIDsEnolic acid (Oxicam) derivatives Piroxicam Meloxicam Tenoxicam Droxicam Lornoxicam Isoxicam Fenamic acid derivatives( Fenamates ) Mefenamic acid Meclofenamic acid Flufenamic acid Tolfenamic acid

NSAIDsSelective 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

COX-1 compared to COX-2COX-1 COX-2

Expression

Tissuelocalization

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)

Aspirin (acetylsalicylic acid)

Nonacetylated salicylates:

sodium salicylate magnesium salicylate choline salicylatesodium thiosalicylate sulfasalazine mesalamine salsalate

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.

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

esterases

Metabolism

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.

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.

THERAPEUTIC USES OF SALICYLATES:

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.

Salicylic acid is used topically to treat: plantar warts fungal infectionscorns

Aspirin has significantly greater antithrombotic activity than other NSAIDs

ADVERSE EFFECTS: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).

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.

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.

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.

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.

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.

.3MISCELLANEOUS ADVERSE EFFECTS AND CONTRAINDICATIONS

May decrease the glomerular filtration rate, particularly in patients with renal insufficiency.

Occasionally produce mild hepatitis

Prolong bleeding time.

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.

Drug interactions

ASPIRIN TOXICITY

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.

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, hemodialysis6. gastric lavage or emesis

OTHER NONSTEROIDAL ANTIINFLAMMATORY DRUGS

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.

• NSAIDs are metabolized in the liver excreted by the kidney

• The half-lives: #1 -45 h ----# most: 10 -20 h

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

Antiinflammatory

Antipyresis

Analgesia Prototype Chemical Class

+++ +++ +++ Aspirin SalicylatesMarginal +++ +++ Acetaminoph

enPara-aminophenols

++++ ++++ +++ Indomethacin Indoles+++ +++ +++ Tolmentin,

mefenamic acid

Pyrrol acetic acids

++++ +++ ++++ Ibuprofen, naproxen

Propionic acids

++++ +++ +++ Phenylbutazone, piroxicam

Enolic acids

+++ ++ ++ Nabumetone Alkanones++++ +++ ++++ Celecoxib Sulfonamide

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.

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.

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)

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.

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.

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).

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

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

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.

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

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

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

MECLOFENAMATE, MEFENAMIC ACID

• t1/2 of 2 hours.

• A relatively high incidence of gastrointestinal disturbances is associated with these agents.

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 .

.

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.

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 .

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.

COX-2 Selective agentsO 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.

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

CELECOXIB COX-2 inhibitor

200 mg tabletsPeak Plasma levels = 3 hoursHalf-life (approximate-effective) = 11 hours

Problems include:Liver and kidneysHeart ?

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

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.

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.

NSAID ADVERSE EFFECTS

DRUG-DRUG INTERACTIONS

OA&

NSAIDS

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

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

• 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.

• 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

QUESTIONS?!

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

Which one of the following treatments might be most effective for this patient in reducing pain related to knee OA?

1. Acetaminophen2. Celecoxib3. Naproxen4. IA hyaluronic acid

• 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;

• 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.

• 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

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

• 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

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

• 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.

• 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.

 

• 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.

• 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

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.

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.

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

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.

Case 2, continuedPeggy 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

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

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

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.

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

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.

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/day2. Switch topical diclofenac to oral diclofenac3. Switch topical diclofenac to oxycodone4. Switch topical diclofenac to intra-articular corticosteroid

injections

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 OA2. 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

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 hexacetonide2. Unloader bracing3. Arthroscopic debridement

Thank you!

QUESTIONS!?