Discontinuing NSAIDs

Knee osteoarthritis (OA) is a major cause of disability among Veterans and is the primary
indication of knee replacement in the VA. Nonsteroidal anti-inflammatory drugs (NSAIDs) are
the most commonly prescribed medications for knee OA. Though short-term studies have
demonstrated that NSAIDs are more effective than placebo and acetaminophen, there are no
long-term data supporting their use. This is of concern, because long-term use of NSAIDs is
associated with significant morbidity and mortality. Guidelines have been published to
improve safe use of NSAIDs; however, adherence to these evidence-based recommendations is low
in the VA. There is therefore an important need to determine if the long-term use of NSAIDs
offers any incremental benefit over safer alternatives. This is especially true for Veterans,
a population at high risk for NSAID-induced toxicity.

Cognitive behavioral therapy (CBT) is an effective and safe treatment alternative for OA.
This modality is becoming increasingly available in the VA for treatment of chronic pain as
well as other chronic disorders such as depression, post-traumatic stress disorder and
insomnia. CBT can be successfully administered over the telephone and thus stands to benefit
Veterans living in more remote areas with limited access to hospital or community-based
outpatient clinics.

In this study, the investigators propose to conduct a 2-phase randomized withdrawal trial
(RWT). The trial will focus on recruiting Veterans with knee OA who have been using NSAIDs
for at least 3 months.

In the first phase of the study, 544 Veterans with knee OA will be randomized to continue
NSAIDs or to placebo for 4 weeks. This double-blind phase will enable us to infer whether
placebo is non-inferior to continued NSAID use. In the second phase, subjects in the NSAIDs
group will continue NSAIDs and those on placebo will stop taking the placebo and participate
in a 10-week CBT program. The second, single-blind, phase will allow us to infer whether CBT
is non-inferior to NSAIDs. All study data will be collected over the telephone thus enabling
Veterans who have difficulty arranging transportation to the VA to participate.

The investigators will test for between-group differences in knee pain measured using the
well-validated Western Ontario and McMaster Universities Osteoarthritis Index (primary
outcome) at 4 and 14 weeks. The investigators will also test for between group differences in
lower extremity disability, subjects' global impression of change and use of co-therapies
(secondary outcomes). As recommended for non-inferiority trials, the investigators will
perform both an intent to treat and per protocol analysis. Lastly, the investigators will
estimate the potential cost-effectiveness of the CBT protocol compared with continued NSAID
use.

Though it would be ideal for subjects randomized to the active study drug to continue their
current NSAID, having the VA pharmacy formulate multiple different active drugs and
maintaining the blind is not possible. Therefore, the investigators will include a 2-week
run-in period where study subjects will replace their NSAID with meloxicam. Meloxicam was
chosen as the study drug because it is the most commonly prescribed at the investigators'
center and has a favorable safety profile compared to other NSAIDS.

If successful, the trial will improve the quality of care delivered to Veterans with chronic
knee pain due to OA. The proposed strategy is particularly appealing because it replaces the
widespread use of NSAIDs with a safer alternative, enables delivery of care to Veterans with
limited access, and is likely to be cost saving.

Inclusion Criteria:

Subjects will include those for whom a discontinuation trial of NSAIDs is most appropriate:
1) Veterans with knee pain despite NSAID use and/or 2) Veterans at relatively higher risk
of NSAID toxicity 55-59 as ascertained by meeting 1 or more of the following 4 criteria:

- Answer affirmatively to the question: "Do you have some knee pain on most days over
the past 3 months?"

- Have 1 or more risk factors for NSAID-induced nephrotoxicity (age greater than 60
years, atherosclerotic cardiovascular disease, current diuretic use, chronic renal
insufficiency, congestive heart failure (New York Heart Association class I-II. Note,
Class III and IV are excluded).

- Have 1 or more risk factors for NSAID-induced gastrointestinal toxicity (history of
peptic ulcer disease, age > 65 years, concurrent use of daily ASA or corticosteroids),
and are currently on a gastro-protective agent.

- Have 1 or more risk factors for NSAID-induced cardiovascular toxicity (prevalent
cardiovascular disease, hypertension, hypercholesterolemia, diabetes, smoking, family
history of early heart disease or age greater than 55 years for women).

In addition, subjects must:

- Be age 20 years or older. While the usual cut off for knee OA is approximately 40
years, the investigators chose to lower the age cutoff as younger Veterans have a
higher than expected risk of OA (see B.1).

- Have radiographic evidence of knee OA reported in the VistA electronic system.

- Be using an NSAID (other than daily ASA) for knee pain on most days of the month for
at least the past 3 months.

- Be able to understand and speak English and have a telephone.

- Be willing to engage in a CBT program, to discontinue (or replace) their NSAID, and to
restrict co-therapies to acetaminophen for 14 weeks.

Exclusion Criteria:

- Subjects desiring escalation of analgesics for their current level of knee pain as
determined by endorsement of the following statement: "Is your knee pain bad enough
that you want to talk to your doctor about taking stronger pain medications?"

- Current use of opioids and/or Celebrex.

- Current use of an NSAID (not including ASA) for a painful condition in addition to
knee OA.

- Contraindications to chronic NSAID use: current use of warfarin or antiplatelet agent
other than ASA, allergy to any NSAID, active upper gastrointestinal ulceration in the
previous 30 days, upper gastrointestinal bleeding in the past year, history of
gastroduodenal perforation or obstruction, cardiovascular event within the past 6
months (myocardial infarction, cerebrovascular event, coronary-artery bypass graft,
invasive coronary revascularisation, or new-onset angina), severe congestive heart
failure (New York Heart Association class III-IV), evidence of serious anemia,
hepatic, renal (including nephrotic syndrome), or blood coagulation disorders, and
pregnancy.

***Though the investigators are proposing a RWT - and thus will not be initiating NSAID
therapy - it would not be appropriate to continue NSAIDs (even when prescribed) in
high-risk patients. The investigators acknowledge that these exclusion criteria limit
generalizability, but the investigators feel justified to ensure subjects' safety.***

- Previous hyaluronic acid knee injections (within 6 months) or corticosteroid knee
injections (within 3 months).

- Scheduled knee hyaluronic acid or corticosteroid injections, arthroscopy, or knee
surgery.

- Co-morbid conditions that include the following: known other causes of arthritis
(infectious arthritis, rheumatoid arthritis, connective tissue disease, or psoriatic
arthritis), gout or pseudogout attack within the last 12 months, peripheral neuropathy
or cardiopulmonary disease that limits walking more than knee pain, bone metastases or
Paget's disease involving the lower extremities, and history of drug or alcohol abuse
within the past 2 years, bilateral knee replacements or knee pain in the replaced knee
only.

- Current involvement in litigation or receiving workmen's compensation.

- Hearing, cognitive impairment or mental illness, as determined by chart review that
would preclude participation in a CBT program.

- For Women of Childbearing Age: Must not currently be pregnant, agree to avoid getting
pregnant during the course of the study and should inform the study team if pregnancy
occurs at any time during study participation.

- Previous meloxicam use discontinued due to lack of effective symptom relief

- Contraindications to prolonged NSAID use, per PI discretion.