Comparing Intra-articular Corticosteroid to Intra-articular Ketorolac Knee Injections

Introduction and Background

Min et al. performed a double blind study comparing triamcinolone to ketorolac in a total of
32 patients with subacromial impingement syndrome and found improved outcomes in University
of California Los Angeles shoulder rating scale, improved active abduction, forward flexion
strength and patient satisfaction scores. Shortcomings of this study included short-term
follow up (4 weeks), lack of control of other forms of treatment of subacromial impingement
including physical therapy and injection without ultrasound which limits the ability to
determine the accuracy of injections. Many of the patients also had a lack of an MRI, thus
being unable to determine if the patients had an undiagnosed rotator cuff tear or other
pathology that may have influenced outcomes.

Karthikeyan et al. performed a similar trial analyzing tenoxicam (another non-steroidal
anti-inflammatory medication) to methylprednisolone in 58 patients.Six weeks after
injection, Constant-Murley shoulder scores, Disabilities of the Arm, Shoulder and Hand
scores were significantly improved in the steroid group compared to tenoxicam injection.

Oztuna et al. randomized thirty patients with grade II to III osteoarthritis with an
effusion to aspiration and oral tenoxicam for 10 days or aspiration and intra-articular
tenoxicam. The patients were followed at 2, 4 and 8 weeks and then at 3 month intervals.
Patients with intra-articular tenoxicam had significantly fewer effusions at 1 year and a
more rapid relief in joint pain.

Unlu et al analyzed 69 patients with knee arthritis and compared weekly injections of
tenoxicam for 3 weeks to PO tenoxicam for three weeks. They compared these two groups to
patients who received only physical therapy. No significant difference was found between
oral and intra-articular administration. Both oral and intra-articular tenoxicam had a
significant improvement on knee pain

Several studies have noted safe intra-articular injection of ketorolac following knee
arthroscopy.

Given the findings of the investigations described above, this study will compare the
equivalence of intra-articular ketorolac injection to intra-articular betamethasone
injection for symptomatic treatment of knee osteoarthritis. In all of the studies reviewed
above for the study, the only complication that was listed was a syncopal episode that
occurred with corticosteroid administration.

Research Questions and Hypotheses

This study will compare the efficacy of intra-articular betamethasone injection to
intra-articular ketorolac injection for symptomatic treatment of knee osteoarthritis. The
null hypothesis of this study is that intra-articular ketorolac injection is not equivalent
to intra-articular corticosteroid in decreasing patient symptoms as measured by Western
Ontario and McMaster University Index (WOMAC) scores (primary outcome). Secondary outcomes
include changes in KOOS and KOS-ADL scores and physical exam findings

If equivalence is proven, this study may provide a safer alternative medication compared to
betamethasone for intra-articular injections for osteoarthritic pain control.

Methods and Procedures

Patients will be recruited from all St. Luke's Orthopaedic Specialists (SLOS) offices where
knee osteoarthritis is treated in associated with St. Luke's Health and University Network.

The study will be double-blinded, with two study arms: 1) 4cc of 1% lidocaine, 1cc of 0.9%
normal saline and 1cc (6 mg) of betamethasone; and 2) 2cc (60 mg) of ketorolac and 4cc of 1%
lidocaine. The medication will be prepared by a site-specific designee (essential personnel)
who has the appropriate, up-to-date HIPPA (Healkth insurance portability and Accountability
Act) and CITI (Collaborative Institutional Training Initiative) training required and
prepares injections in the routine scope of SLOS practice. The contents of the injection
will be blinded to the investigators by covering the syringe with a white tape. The
medication will be generated at the time of patient enrollment at the office where the
injection will be performed.

Patients will be randomized by the following procedure. A spreadsheet will be generated with
study patient identifier numbers in numerical order (1, 2, 3, 4, etc.). This spreadsheet
will be located on a password-protected database that can be continuously updated across the
St. Luke's Network by multiple study personnel at the same time. A random number generator
(http://randomizer.org) will be used to generate a series of binary numbers, either 0 or 1.
The number 0 will represent betamethasone, while the number 1 will represent ketorolac. This
number will then be attached to the study patient identifier number.

When a patient is determined to be eligible for enrollment into the study, their medical
record number will be entered into the password-protected spreadsheet database as the next
patient by a site-specific designee. At that point the site-specific designee will provide
the medication as described earlier to the injector. The injector and patient will remain
unaware as to the contents of the syringe.

Prior to injection, patients will receive the following study questionnaires: WOMAC, Knee
Injury and Osteoarthritis Outcome Score Physical Function Short Form (KOOS-PS), and Knee
Outcome Survey Activities of Daily Living Scale (KOS-ADL). These study questionnaires were
created with Google Forms and be stored on the same spreadsheet as described earlier.
Patients will be instructed to return the completed questionnaires to the office during an
office visit, by mail or fill them out online prior to study injection as well as 2 weeks, 1
month, 3 months and 6 months.

Patients' medical history will be taken and a clinical exam performed before the injection
is given. Demographic information, including body mass index (BMI), duration of disease, and
gender, will be obtained. Number and type of prior injections will also be documented if
known by the patient or documented in the patient's chart. The clinical exam will include
joint laxity, passive range of motion, presence of contractures, and tenderness on a scale
of 0-3 (0 = no tenderness, 1 = patient winces and 3 = withdrawal). A three-view x-ray will
also be obtained if there is no recent image on file. Other treatment modalities, including
physical therapy, knee off-loading brace, acetaminophen, and current oral non-steroidal
treatment, will be noted. Finally, Kellgren-Lawrence Staging will be performed for the
medial, lateral and patellofemoral joints. This information will be documented in the
password-protected Google Spread Sheet.

A standard superolateral injection site will be used during medication administration. This
site is considered to be the most accurate, especially among experienced hands. The
administration site will be cleaned with an ethanol swab and allowed to dry. An 18 gauge
needle connected to a syringe filled with the study drug will be administered. If there is
no effusion, a 22 gauge needle with 6cc of the study drug will be injected into the
administration site. All of the study drug will be administered in an intra-articular
fashion. The needle will be removed and a bandage applied. It will be documented if patient
felt relief immediately following injection. If the patient has a history of diabetes, they
will record morning fasting levels of glucose for 10 days following administration of study
drug and then documented into the password-protected Google spreadsheet.

All patients will be provided with the option for a home or outpatient physical therapy
regimen to follow for treatment of their arthritis. During follow up they will be asked
about compliance with therapy and will be documented into the password-protected Google
spreadsheet.

Clinical follow up will performed at 1, 3 and 6 months after injection. A repeat examination
and questionnaire will be performed and documented at that time. The investigators will
allow patients to receive a second corticosteroid administration on or after the three month
visit as is current standard of care at St Luke's University Health Network.

If a recent MRI has been obtained within the year prior to or during treatment, this
information will also be documented.

In knee osteoarthritis patients, common concerns with corticosteroid injections include skin
color changes, systemic elevations in blood sugar, and may place the patient at a higher
risk for infection in immunocompromised individuals. Typically injections of corticosteroids
are limited and often not given more than once every three months. Ketorolac is a
non-steroidal anti-inflammatory medication that has a more limited mechanism of action and
may be a safer alternative to corticosteroid injections. Expected adverse effects of
ketorolac include localized bruising, compensatory effusion, minor localized bleeding, and a
flare reaction. Both of these medications are currently used by practitioners at St. Luke's
University and Health Network for osteoarthritis. The goal of this study is to directly
compare ketorolac's efficacy and safety to betamethasone

Statistics

Sample size calculation to assess equivalence was based on research by Unlu et al (2005)
that compared WOMAC scores in patients with knee osteoarthritis who received intra-articular
tenoxicam, oral tenoxicam or exercise only. Three was identified as the smallest clinically
meaningful margin to determine equivalence of intra-articular ketorolac to intra-articular
betamethasone as the active comparator. At α = 0.5 and β= 0.90, 204 patients per group
(N=408) are required. To guard against missing or otherwise unusable data, 10% was added to
that minimum sample size, for a total of 448 patients.

The primary outcome (change in WOMAC scores) will be analyzed via repeated measures analysis
of variance (ANOVA), and the secondary outcomes will be analyzed via selected ANOVA and
nonparametric tests as deemed appropriate. For all analyses, p < .05 will denote statistical
significance, with no adjustment for the multiple comparisons.

Plan for the Dissemination of Project Results

This project will be submitted to the annual residents' and fellows' Research Symposium at
the Bethlehem campus in the spring of 2016, as well as apply to present at appropriate
national meetings. This project will also be submitted to orthopaedic and related journals.

This study will be registered with ClinicalTrials.Gov.

Personnel Qualifications

Primary personnel responsible for the compilation and publication of the results would
include Gregory F Carolan, MD (principle investigator), Paul Morton, MD, Shane McGowan, MD
and John Anagostakos. Personnel administering the injections and obtaining consent will be
the physicians or physician assistants (listed in attached) of the St. Luke's Orthopaedic
Specialists group who, in the scope of their current practice, evaluate and treat patients
with knee osteoarthritis. All listed personnel will maintain appropriate CITI and HIPPA
training.

Inclusion Criteria:

- Knee osteoarthritis as demonstrated on x-ray as Kellgren-Lawrence stage II or higher
(Kellgren & Lawrence, 1957)

- Clinical symptoms and physical exam consistent with osteoarthritis

Exclusion Criteria:

- Prior treatment with corticosteroid injections within the last 1 year

- Failure of past treatment with corticosteroid injections

- Medical treatment including oral medication, physical therapy, or other analgesia use
within the last 20 days prior to injection

- Pregnant

- Under 18

- Serious systemic disease

- Gout arthropathy

- Inflammatory joint disease including rheumatoid or psoriatic arthritis

- Metabolic bone disease

- Anserine bursitis or pain referred from other structures such as ipsilateral hip or
lumbar spine

- Patients with a significant effusion that requires aspiration