Download Issues in the Treatment of Osteoarthritis

Arthritis
Issues in the Treatment of Osteoarthritis
Dr. Shafiq Qaadri, MD, Family Physician and CME Lecturer,Toronto, ON.
Introduction
With the demographic shift in Canada—
the “greying” of its population—arthritis is
a growing health concern. Aleading cause
of long-term disability in Canada, arthritis
and other musculoskeletal diseases result
in $17.8 billion in lost productivity annually.1 Currently, four million Canadians are
affected by arthritis, and the number of
people afflicted is expected to double in the
next 20 years.2 Already, 33% of Canada’s
seniors have osteoarthritis,2 the most common form of arthritis in older adults.
Effective osteoarthritis care requires a
spectrum of approaches on the biopsychosocial model including: advice on carrying out daily activities (coping with
fatigue, protecting joints, using orthotics);
controlling pain through approaches such
as relaxation therapy, massage therapy,
hydrotherapy or acupuncture; using walking/assistive devices; and learning more
about arthritis from organizations or websites. Self-help groups are a particularly
valuable resource for arthritis patients.
Many patients ask about alternative
remedies such as glucosamine or chondroitin, which have shown some effectiveness in studies. A full discussion of
complementary therapies for arthritis is
presented on the Arthritis Society website at www.arthritis.ca.
Medication remains the mainstay for
controlling arthritis pain of all types. Pharmacological options include analgesics
such as acetaminophen, the traditional
non-steroidal anti-inflammatory drugs
(NSAIDs) such as ibuprofen and naproxen, and the newer NSAIDs, the cyclooxygenase-2 (COX-2) selective inhibitors.
Acetaminophen is a first-line agent for
mild to moderate pain, while NSAIDs are
preferred for moderate to severe pain.3
At least 20 different NSAIDs are available in Canada,4 and there is no single
agent suitable for all patients. When selecting a drug, physicians must carefully consider each patient’s full medical history and
50 GERIATRICS & AGING • October 2002 • Vol 5, Num 8
risk factors, including peptic ulcer disease,
diabetes, kidney problems and a family history of heart disease. This is particularly
important in geriatric populations, as elderly patients often are taking concomitant
medications, and are therefore especially
prone to drug side effects and interactions.
Planning an individual course of
action for each patient becomes even
more important when taking into
account recent warnings issued by
Health Canada that point to possible cardiovascular toxicity associated with two
COX-2 selective inhibitors, rofecoxib
(Vioxx™) and celecoxib (Celebrex™).5,6
Although these drugs are less likely to
produce gastrointestinal (GI) problems in
some patients, they may increase the risk
of thrombotic cardiovascular events.
Many patients are concerned about
the recent media reports on arthritis medications, particularly the COX-2 inhibitors.
The controversy surrounding arthritis
treatments provides physicians with an
educational opportunity to re-evaluate
treatment options and choice of drugs.
Traditional NSAIDs
Traditional NSAIDs include ibuprofen
(Advil™), diclofenac (Voltaren™) and
naproxen (Naprosyn™, Anaprox™).
These drugs have been used for many
years to treat pain, and are proven to have
both anti-inflammatory and analgesic
effects. Traditional NSAIDs appear equally effective. However, patients may vary
in their response to each NSAID in idiosyncratic ways that are not fully elucidated. A two-week drug trial of a NSAID at
recommended doses is adequate to determine whether that particular medication
is effective for an individual patient.4
Although they work well to ease
musculoskeletal pain, NSAIDs do not
slow or stop joint damage. Even if they
are taken with proton pump inhibitors
(PPIs) or misoprostol as GI protectants,
they should be taken at the minimum
effective dosage since they can cause
serious upper gastrointestinal complications—stomach upset, bleeding ulcers
and death—as well as renal toxicity and
platelet dysfunction. It has been reported
that 3,900 Canadians are hospitalized
each year due to the side effects associated with taking traditional NSAIDs.7
Elderly patients are particularly vulnerable to serious NSAID-related gastrointestinal complications, since the risk
rises with advancing age and with increasing numbers of concomitant diseases. A
history of upper GI ulcers poses another
risk factor for serious GI complications.4
COX-2 Selective Inhibitors
Traditional NSAIDs inhibit both the
COX-1 enzyme, which protects the
mucosa lining of the GI tract, and the
COX-2 enzyme, which appears to trigger
pain and inflammation. The COX-2 selective inhibitors, as their name suggests,
target the COX-2 enzyme while sparing
the COX-1 enzyme.
Currently, there are three different
COX-2 selective inhibitors available in
Canada: celecoxib (Celebrex™), rofecoxib
(Vioxx™) and meloxicam (Mobicox™).
Celecoxib and rofecoxib, known as “coxibs”,
inhibit the COX-2 enzyme by binding to its
side pocket. Meloxicam is an “oxicam”
derivative with a different mechanism of
action; it binds to the COX-2 enzyme at a
different site known as the “extra space”.
When rofecoxib and celecoxib were
introduced to the Canadian market in
1999, physicians and patients alike welcomed them as an important new pain
relief option for people who couldn’t tolerate the GI side effects of traditional
NSAIDs. They became hugely successful—probably one of the highest-prescribed drug classes in Canada.
The coxibs are also the most expensive drugs in this class. In Ontario alone,
they accounted for approximately 60% of
the total NSAID costs in the year 2001.8 A
one-month supply (excluding pharmacy
mark-up and dispensing fee) of celecoxib
or rofecoxib is $37.50, whereas the same
Osteoarthritis Treatment
supply of meloxicam is $23.40.9 As a point
of comparison, the 2001 costs of all traditional NSAIDs combined made up
approximately 12% of the total expenditure in this class.8 Although COX-2 selective inhibitors are more expensive than
traditional NSAIDs, the cost benefits of the
latter can be misconstrued when the additional expense of PPIs needed to provide
GI protection, as well as the costs of treating the GI complications associated with
taking traditional NSAIDs, are considered.
Table 1
Considerations in Prescribing
Non-steroidal Anti-inflammatory Drugs
Thoroughly assess your patients before prescribing
Have patients return for assessment within a few weeks
Remember all NSAIDs may interact with other drugs
All NSAIDs tend to lower the effectiveness of antihypertensive medication
COX-2 inhibitors should be started at the lowest recommended dose for
patients over 65 or with low body weight
The Research
All NSAIDs are contraindicated in patients with active GI ulcer disease
Recently, a meta-analysis of two large
clinical trials with rofecoxib and celecoxib suggested these drugs may not be as
safe as originally thought. They may
slightly increase the risk of cardiovascular problems and, at high doses, may
result in rates of ulcer complications similar to traditional NSAIDs.
“Dear Healthcare Professional” letters
issued earlier this year to physicians
regarding celecoxib and rofecoxib followed
a meta-analysis published last year in The
Journal of the American Medical Association,
which concluded that “available data raise
a cautionary flag about the risk of cardiovascular events”.6 The JAMA study included two major randomized trials—CLASS
(Celecoxib Long-term Arthritis Safety
Study)10 and VIGOR (Vioxx Gastrointestinal Outcomes Research Study)11—along
with two smaller ones of approximately
1,000 patients each.
The results from VIGOR suggested a
higher risk of thrombotic cardiovascular
events such as myocardial infarction
(MI), unstable angina and ischemic stroke
in patients taking rofecoxib, compared
with those taking naproxen. It has been
argued, however, that these results may
be due to the high doses of rofecoxib
used in this study or a possible cardioprotective effect of naproxen, and further
research is needed to address these questions. In the CLASS trial, there was no
increased risk for patients taking celecoxib compared to ibuprofen or the traditional NSAID diclofenac. However,
unlike VIGOR, the CLASS trial permitted
aspirin use, providing an antiplatelet
effect that may explain these results.
Always monitor your patients for adverse reactions
The JAMA meta-analysis took
CLASS and VIGOR results one step further. JAMA researchers calculated the
annualized rate of MI in users of COX-2
inhibitors in these trials, and compared it
with the rate in patients taking a placebo
(this placebo group of 23,407 patients was
drawn from a separate meta-analysis of
trials examining primary prevention of
cardiac events). The JAMA study showed
a significantly higher annualized rate of
MI in the COX-2 users (0.74% for rofecoxib and 0.80% for celecoxib) when
compared to the placebo group (0.52%).
Health Canada has also cautioned
that celecoxib, when taken in high daily
doses, produces the same rate of complicated ulcers as traditional NSAIDs. This
finding comes from the CLASS study,
which compared celecoxib (400mg twice
daily) with diclofenac (75mg twice daily)
and ibuprofen (800mg three times daily).
When the annualized incidence of complicated and symptomatic ulcers was
combined, celecoxib users had a similar
rate to diclofenac users, and a significantly lower rate than ibuprofen users.
Evidence suggests that meloxicam,
the most recent COX-2 selective inhibitor
to enter the Canadian market, may be a
safer and as effective option when prescribing in this class of drugs for
osteoarthritis. In the Therapeutic Products
Directorate’s Canadian Adverse Reaction
Newsletter this past spring, Health Canada
reported on the possible adverse reactions
associated with COX-2 selective inhibitors,
including meloxicam, celecoxib and rofe-
coxib. The report suggested that patients
taking meloxicam had little increased risk
of cardiovascular adverse reactions, compared with those taking celecoxib and
rofecoxib.12 This data must be interpreted
cautiously, as neither patient exposure nor
the amount of time the drug was on the
market was taken into consideration. Furthermore, factors such as pre-existing
medical conditions, the prevalence of cardiovascular disease in the population for
whom the drugs are indicated, and the
concomitant use of drugs that can cause
cardiovascular reactions or drug interactions, were not considered in this report.
There is also data to support meloxicam’s GI tolerability. According to a
study of rheumatoid arthritis patients,
the overall incidence rate of GI events
did not differ significantly in the meloxicam group compared to placebo.13
Another study of osteoarthritis patients
found no differences in the incidence of
GI adverse events between meloxicam
and placebo.14
The COX-2 safety debate raises
important clinical questions for physicians. Should patients taking rofecoxib or
celecoxib always take low-dose aspirin,
and, if so, will this negate the GI benefits
of the COX-2 inhibitors? Do other
NSAIDs, such as ibuprofen or diclofenac,
have either anti- or prothrombotic effects?
Do the negative cardiovascular effects
seen in VIGOR persist at lower doses of
rofecoxib? Although these drugs have
had great success with many patients,
much more research is still required.
www.geriatricsandaging.ca 51
Osteoarthritis Treatment
NSAIDs
The Current Cyclooxygenase Concept
Heme groups
(participate in
cyclooxygenase reaction)
Result in
non-specific
inhibition of
the COX
active site
Prostaglandin synthase
Active sites for
COX
Membrane
phospholipids
activated PL-A2
Arachidonic acid
Lipoxygenase
COX-1
(constitutive)
Desireable outcomes
Homeostatic
functions
Protective function in GI tract (PGE2)
Maintenance of renal perfusion
Thromboxane (TXA2) promotes:
vasoconstriction
platelet aggregation
52 GERIATRICS & AGING • October 2002 • Vol 5, Num 8
Leukotrienes
& lipoxins
COX-2
(inducible)
Preferred inhibitions
Inflammatory
response
Prostaglandin (PGE2): edema, pain
Prostacyclin (PGI2): vasodilation
prevents platelet activation
Osteoarthritis Treatment
Prescribing NSAIDs to Elderly
Arthritis Patients
Until studies answer some of the aforementioned questions, a few considerations can be made to ensure safe
prescribing of COX-2 selective inhibitors
and traditional NSAIDs (Table 1). Before
initiating therapy with either a COX-2
inhibitor or traditional NSAID, it is
important to thoroughly assess a patient.
Note should be made of general health,
and particular attention paid to the cardiovascular profile and potential for
hypertension, heart failure, renal disease
and fluid retention, as well as GI sequelae. Patients who start taking a new medication for their arthritis pain should
return for assessment within a few weeks,
so the therapy’s effectiveness can be evaluated and any adverse effects identified.
It is crucial to always be aware that
COX-2 inhibitors and traditional NSAIDs
may interact with other drugs. For example, they may increase the clinical effects
of oral anticoagulants, hypoglycemic
agents and anticonvulsants, so the dosage
of these drugs must be adjusted if any one
of them is taken along with a traditional
NSAID or COX-2 inhibitor.4 NSAIDs and
COX-2 inhibitors also tend to lower the
effectiveness of antihypertensive medication, so it is imperative to monitor blood
pressure regularly if these two drugs are
taken in combination.4 When possible, it
is best to avoid prescribing either traditional NSAIDs or COX-2 inhibitors for
patients with fluid retention, hypertension or heart failure. Recent studies suggest that NSAIDs increase the risk of
relapse in patients already diagnosed
with heart failure. For example, a 2002
Dutch study found that current use of
NSAIDs was associated with a substantially increased risk of heart failure relapse
(but not with a first occurrence).15 In 2000,
Australian researchers found NSAIDs
were responsible for about 19% of hospital admissions for chronic heart failure.16
When starting patients on a new
COX-2 selective inhibitor—especially
older patients and those at risk of developing cardiovascular disease—one option
may be meloxicam, as it is as effective as
other NSAIDs and has not been found to
be associated with cardiovascular toxicity. COX-2 inhibitors should be started at
the lowest recommended dose in patients
older than 65 years and/or with a low
body weight (less than 50kg). If rofecoxib
is prescribed to patients with a history of
ischemic heart disease, it should be in low
doses. Many experts recommend that
these patients also take low-dose aspirin,
but it is important to inform patients of
the possible increased risk of GI ulcers.
All NSAIDs—both selective and
non-selective—are contraindicated in
patients with active peptic ulcer disease,
active GI bleeding, active inflammatory
bowel disease, significant hepatic impairment or active liver disease and severe
renal impairment, according to the latest
Health Canada information. Patients
with risk factors for GI complications
should be informed about symptoms of
GI bleeding and should be monitored for
new or severe upper-GI symptoms.
Conclusion
There is risk associated with all prescription medications, but it can be minimized
when patients are evaluated thoroughly by
their physicians, monitored carefully and
encouraged to report all side effects. When
it comes to treating arthritis with traditional NSAIDs or the newer COX-2 selective inhibitors, it should be kept in mind
that all NSAIDs—selective or non-selective—are equal in their ability to relieve
pain and reduce inflammation. The choice
of therapy depends on individual risk factors for heart disease and GI complications.
Now more than ever, physicians need to
know their patients and carefully tailor
treatment to each individual.
◆
Acknowledgements: In areas of continuing
medical education and public awareness,
Dr. Shafiq Qaadri is commercially associated with companies including Pfizer,
Boehringer Ingleheim, GlaxoSmithKline
and Merck Frosst Canada.
References
1. ArthroScope, The Arthritis Society of Canada,
from http://www.arthritis.ca/resources%
20for%20advocates/arthroscope/default.asp?
s=1.
2. The Arthritis & Autoimmunity Research
Centre Foundation, from
http://www.uhn.ca/foundations/aarc/pag
es/research/facts.htm.
3. Guideline for the management of pain in
osteoarthritis, rheumatoid arthritis and juvenile chronic arthritis; American Pain Society:
March, 2002.
4. Huang SHK. Rheumatology: 7. Basics of
therapy. Can Med Assoc Journal
2000;163:417-23.
5. Important Drug Safety Information—Vioxx
(Dear Health Care Professional Letter).
Pointe-Claire—Dorval (QC): Merck Frosst
Canada; 2002 April 15, from www.hcsc.gc.ca/hpbdgps/therapeut/zfiles/english
/advisory/industry/vioxx_e.html
6. Mukherjee D, Nissen SE, Topol EJ. Risk of
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7. Tamblyn R, Berkson L, Dauphinee WD, et al.
Unnecessary prescribing of NSAIDs and the
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1997:127;429-38.
8. IMS Health. Cox-2 inhibitors increase size of
anti-arthritic market, from http://www.ims
healthcanada.com/htmen/3_1_38.htm.
9. 2000/01 Report Card for Ontario Drug Benefit Program.
10. Silverstein FE, Faich G, Goldstein JL, et al.
Gastrointestinal toxicity with celecoxib vs.
non-steroidal anti-inflammatory drugs for
osteoarthritis and rheumatoid arthritis: the
CLASS study: a randomized controlled trial.
Celecoxib Long-term Arthritis Safety Study.
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11. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of
rofecoxib and naproxen in patients with
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N Engl J Med 2000;343:1520-8.
12. Health Canada. Canadian adverse reaction
newsletter. April 2002;12(2). http://www.hcsc.gc.ca/hpb-dgps/therapeut/zfiles/ english/publicat/adrv12n2_e.html.
13. Furst DE, Kolba KS, Fleischmann R, et al.
Dose response and safety study of
meloxicam up to 22.5 mb daily in rheumatoid arthritis: A 12-week multicentre, double
blind, dose response study versus palcebo
and diclofenac. J Rheumatol 2002;29:436-46.
14. Yocum D, Fleischmann R, Dalgin P, et al.
Safety and efficacy of meloxicam in the treatment of osteoarthritis. Arch Intern Med
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16. Page J, Henry D. Consumption of NSAIDs
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Arch Intern Med 2000:160;777-84.
www.geriatricsandaging.ca 53