Study protocol- Lumbar Epidural steroid injections for Spinal Stenosis (LESS): a double-blind randomized controlled trial of epidural steroid injections for lumbar spinal stenosis among older adults.

Abstract

Lumbar spinal stenosis is one of the most common causes of low back pain among older adults and can cause significant disability. Despite its prevalence, treatment of spinal stenosis symptoms remains controversial. Epidural steroid injections are used with increasing frequency as a less invasive, potentially safer, and more cost-effective treatment than surgery. However, there is a lack of data to judge the effectiveness and safety of epidural steroid injections for spinal stenosis. We describe our prospective, double-blind, randomized controlled trial that tests the hypothesis that epidural injections with steroids plus local anesthetic are more effective than epidural injections of local anesthetic alone in improving pain and function among older adults with lumbar spinal stenosis.
We will recruit up to 400 patients with lumbar central canal spinal stenosis from at least 9 clinical sites over 2 years. Patients with spinal instability who require surgical fusion, a history of prior lumbar surgery, or prior epidural steroid injection within the past 6 months are excluded. Participants are randomly assigned to receive either ESI with local anesthetic or the control intervention (epidural injections with local anesthetic alone). Subjects receive up to 2 injections prior to the primary endpoint at 6 weeks, at which time they may choose to crossover to the other intervention.Participants complete validated, standardized measures of pain, functional disability, and health-related quality of life at baseline and at 3 weeks, 6 weeks, and 3, 6, and 12 months after randomization. The primary outcomes are Roland-Morris Disability Questionnaire and a numerical rating scale measure of pain intensity at 6 weeks. In order to better understand their safety, we also measure cortisol, HbA1c, fasting blood glucose, weight, and blood pressure at baseline, and at 3 and 6 weeks post-injection. We also obtain data on resource utilization and costs to assess cost-effectiveness of epidural steroid injection.
This study is the first multi-center, double-blind RCT to evaluate the effectiveness of epidural steroid injections in improving pain and function among older adults with lumbar spinal stenosis. The study will also yield data on the safety and cost-effectiveness of this procedure for older adults.
Clinicaltrials.gov NCT01238536.

Full text

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STUDY PROTOCOLOpen Access
Study Protocol- Lumbar Epidural Steroid
Injections for Spinal Stenosis (LESS): a double-
blind randomized controlled trial of epidural
steroid injections for lumbar spinal stenosis
among older adults
Janna L Friedly1*†, Brian W Bresnahan1†, Bryan Comstock1†, Judith A Turner1†, Richard A Deyo2†, Sean D Sullivan1†,
Patrick Heagerty1†, Zoya Bauer1†, Srdjan S Nedeljkovic3†, Andrew L Avins4†, David Nerenz5†and Jeffrey G Jarvik1†
Abstract
Background: Lumbar spinal stenosis is one of the most common causes of low back pain among older adults and
can cause significant disability. Despite its prevalence, treatment of spinal stenosis symptoms remains controversial.
Epidural steroid injections are used with increasing frequency as a less invasive, potentially safer, and more cost-
effective treatment than surgery. However, there is a lack of data to judge the effectiveness and safety of epidural
steroid injections for spinal stenosis. We describe our prospective, double-blind, randomized controlled trial that
tests the hypothesis that epidural injections with steroids plus local anesthetic are more effective than epidural
injections of local anesthetic alone in improving pain and function among older adults with lumbar spinal stenosis.
Methods: We will recruit up to 400 patients with lumbar central canal spinal stenosis from at least 9 clinical sites
over 2 years. Patients with spinal instability who require surgical fusion, a history of prior lumbar surgery, or prior
epidural steroid injection within the past 6 months are excluded. Participants are randomly assigned to receive
either ESI with local anesthetic or the control intervention (epidural injections with local anesthetic alone). Subjects
receive up to 2 injections prior to the primary endpoint at 6 weeks, at which time they may choose to crossover
to the other intervention.
Participants complete validated, standardized measures of pain, functional disability, and health-related quality of
life at baseline and at 3 weeks, 6 weeks, and 3, 6, and 12 months after randomization. The primary outcomes are
Roland-Morris Disability Questionnaire and a numerical rating scale measure of pain intensity at 6 weeks. In order
to better understand their safety, we also measure cortisol, HbA1c, fasting blood glucose, weight, and blood
pressure at baseline, and at 3 and 6 weeks post-injection. We also obtain data on resource utilization and costs to
assess cost-effectiveness of epidural steroid injection.
Discussion: This study is the first multi-center, double-blind RCT to evaluate the effectiveness of epidural steroid
injections in improving pain and function among older adults with lumbar spinal stenosis. The study will also yield
data on the safety and cost-effectiveness of this procedure for older adults.
Trial Registration: Clinicaltrials.gov NCT01238536
* Correspondence: friedlyj@uw.edu
† Contributed equally
1Comparative Effectiveness, Cost and Outcomes Research Center, University
of Washington, Seattle, WA, USA
Full list of author information is available at the end of the article
Friedly et al. BMC Musculoskeletal Disorders 2012, 13:48
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© 2012 Friedly et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.

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Background
Lumbar spinal stenosis is one of the most common
causes of low back pain among older adults and can
result insignificant disability [1]. The cause of spinal ste-
nosis is often multifactorial and the clinical presentation
can be variable. Degenerative changes in the spine such
as spondylosis, facet arthropathy, disc degeneration, and
scoliosis may all contribute to the development of spinal
stenosis. The symptoms of lumbar spinal stenosis range
from low back pain to neurogenic claudication with
lower extremity pain, weakness or sensory changes and
are often aggravated by walking. Because spinal stenosis
can affect the central canal as well as the lateral recesses
and intervertebral foramen variably, symptoms can
involve single or multiple myotomes and dermatomes.
Because the causes of spinal stenosis are most frequently
degenerative changes, the symptoms often, but not
always, worsen over time. Lumbar spinal stenosis is
often associated with poor patient health outcomes and
functioning, high resource utilization, and substantial
payer, patient, and health-system costs.
Despite the prevalence of symptomatic lumbar spinal
stenosis among older adults, treatment remains con-
troversial, with limited comparative effectiveness
evidence. Common treatments include conservative
measures such as non-steroidal anti-inflammatory drugs
(NSAIDS), activity modification, and physical therapy, as
well as more invasive treatments such as epidural ster-
oid injections (ESI) and surgery [1]. Although surgery
provides some benefit to certain individuals with spinal
stenosis [2,3], the results of surgical treatment tend to
be modest and may be accompanied by short and long
term postoperative surgical complications [4]. Consistent
with the general trend of using more minimally- inva-
sive treatment approaches in health care, ESIs are being
used with increasing frequency as a less invasive, poten-
tially safer and more cost-effective treatment. However,
there is a lack of evidence examining the efficacy, safety,
and effectiveness of ESI for symptoms of spinal stenosis.
Despite the lack of data demonstrating effectiveness in
patients with spinal stenosis, an estimated 25% of all
ESIs performed in the Medicare population and 74% of
ESIs in the Veterans Affairs system are for spinal steno-
sis [5,6].
A few cohort studies suggest that ESI may provide
short-term pain relief [7,8]. However, the results of
RCTs have been less favorable. One early RCT [9]
demonstrated no advantage of ESI over saline or local
anesthetic injections. However, some argue that the
poor results of this trial were a consequence of inade-
quate technique and do not reflect the current practice
of performing ESI with fluoroscopic guidance to ensure
appropriate placement of the steroid medication [10].
Only one RCT of fluoroscopically-guided ESI com-
pared to injections with local anesthetic alone has been
published [11]. This study, while showing improvement
in each group, found no advantage of the steroid injec-
tion over an injection of local anesthetic alone [11].
However, this study suffered significant methodological
limitations including lack of statistical power, no pri-
mary outcome measure, un-blinding of patients and
researchers and a high dropout rate (21/60 patients).
The overall objective of this multi-center, double-blind
RCT is to evaluate the effectiveness of ESI plus local
anesthetic versus local anesthetic alone in improving
pain and function among older adults with back pain
and lumbar spinal stenosis. We hypothesize that patients
randomized to receive ESI with local anesthetic will
show significantly greater improvement in pain and
function compared to patients randomized to receive
local anesthetic only. We will also examine whether ESI
is differentially effective in improving pain and function
for different patient subgroups (African-Americans vs.
Caucasians and patients undergoing a transforaminal vs.
interlaminar approach). Finally, we will compare
resource use and costs in the two treatment groups as
well as incremental cost-effectiveness and incremental
cost utility from both payer and societal perspectives.
Methods/design
Study design
The Lumbar Epidural steroid injections for Spinal Ste-
nosis (LESS) study is a double-blind RCT of ESI plus
local anesthetic injections versus local anesthetic injec-
tions for the treatment of pain associated with lumbar
spinal stenosis in older adults. Patients, study investiga-
tors, and the research staff collecting data will remain
blinded to patient treatment allocation.
The patient follow-up has three distinct phases–from
randomization and baseline injection to the primary
endpoint at six weeks, from optional crossover at six
weeks until nine weeks, and the follow-up period from
nine weeks to one year after randomization (see Figure
1). Randomization will occur just prior to the first injec-
tion. There is a follow-up visit at three weeks from ran-
domization, at which time the participants may have a
second injection if they choose, and blood is drawn to
obtain cortisol, HbA1c and fasting glucose levels.
As an inducement to study enrollment, we will allow
crossover after the primary outcome data have been col-
lected at six weeks. Participants may crossover to the
other blinded treatment arm if they believe they had
insufficient benefit from the first two injections. Also at
six weeks, patients will return to discuss potential cross-
over and to again have blood drawn for cortisol, HbA1c
and fasting glucose measures. Those who choose not to
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crossover at six weeks will be allowed to have one addi-
tional injection of the same type as originally assigned at
the nine-week time point, if they desire. After nine
weeks, patients and physicians will be allowed to make
treatment decisions per usual care. This may include
ESIs or other treatments as determined by the patient
and physician.
Subjects and setting
The LESS trial is part of a research program to study
older adults with back pain, the Back pain Outcomes
using Longitudinal Data (BOLD) project. The project
involves building a registry designed to capture data
from patients enrolled in three large integrated health
care systems in the United States. The BOLD registry
will provide a mechanism for collecting outcomes data
on a large number of patients with back pain and will
serve as a portal for entry into studies such as the LESS
trial. We will also be recruiting patients from several
academic medical centers. Each participating clinical site
obtained local Institutional Review Board (IRB) approval
prior to subject recruitment. Patients with spinal
stenosis referred for an ESI are asked if they would like
to participate in the LESS trial. Prior to recruitment, the
treating physician determines whether the patient is an
appropriate candidate for ESI based on history, physical
examination and imaging studies. The physician intro-
duces the study at the end of this consultation if the
patient is deemed an appropriate candidate for ESI.
Each potential participant is invited to view an educa-
tional video that describes the study and provides
detailed information about the procedures and implica-
tions of participation in the study. Patients provide writ-
ten informed consent when enrolling in the study.
Eligibility criteria
Study inclusion and exclusion criteria are listed in Table
1. Inclusion criteria were chosen to include older adults
with at least moderate pain and disability related to neu-
rogenic claudication from central spinal stenosis. Sub-
jects will need to have CT or MRI evidence of central
lumbar spinal stenosis (mild, moderate or severe)
according to the criteria of Boden et al. [12] Patients
with lateral recess or foraminal stenosis without the
Figure 1 Study Flow Chart.
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presence of central canal stenosis are not included in
this study. The exclusion criteria were chosen for safety
concerns as well as to eliminate known confounders
that might influence the results of the study or hinder
participation and follow-through with study protocol. In
addition, we are excluding patients with a history of
lumbar fusion or decompression surgery (i.e. laminect-
omy) as well as interspinous process spacer procedures
as this may impact the injection technique as well as
outcomes. To ensure that treatment results are not
influenced by prior ESI use, we are also excluding
patients with a history of lumbar ESI within the last six
months.
Baseline and follow up assessments
Patients with spinal stenosis who are being referred for
an ESI as part of their treatment plan are invited to par-
ticipate in this study by the treating physician. Interested
patients are then screened for eligibility by the research
coordinator at the site. If eligible, the potential partici-
pant is asked to participate in the study and to complete
the informed consent process. A study physician reviews
each potential participant’s imaging studies to determine
the eligibility criterion of presence of central spinal
canal stenosis and to categorize the stenosis as mild,
moderate or severe.
Baseline questionnaires assess demographic, clinical,
and disease-history information and include patient self-
report measures of pain, function, fear avoidance [13],
and pain catastrophizing [14]. We also ask patients at
baseline about their preferences for assignment to the
ESI versus the control intervention, and to rate their
expectations of pain relief. All medications used for pain
at baseline are documented by medical record review as
well as co-morbidities measured by the Charlson
Comorbidity index [15].
Our primary outcomes are measures of function and
pain. These include the Roland-Morris Disability Ques-
tionnaire, a back pain-specific functional status ques-
tionnaire adapted from the generic Sickness Impact
Profile (SIP). It consists of 24 yes/no items, which repre-
sent common dysfunctions in daily activities experienced
by patients with low back pain. The other primary out-
come measure is pain recorded on an 11-point numeri-
cal rating scale(NRS) measuring average leg and back
pain (separately) in the past week. The primary outcome
measures are completed at 3 days, 14 days, 3 weeks, 6
weeks, and 3, 6 and 12 months post-randomization.
Secondary outcome measures include the Brief Pain
Inventory (BPI) Interference scale [16], the Patient
Health Questionnaire (PHQ-8)measure of depression
[17], Generalized Anxiety Disorder (GAD-7) measure
[18], Swiss Spinal Stenosis Questionnaire (SSSQ)
[19-21], and the EQ-5D [22]. These are administered at
all follow-up time points with the exception that the
SSSQ, BPI, PHQ-8, GAD-7 and EQ-5D are not adminis-
tered at Days 3 and 14.
At baseline and at three weeks and six weeks post-
injection, we draw blood to measure HbA1c and fasting
blood glucose and morning blood cortisol levels to
monitor for hyperglycemia and adrenal suppression fol-
lowing steroid administration. Because patients are
blinded to treatment assignment, these are checked in
all patients regardless of treatment received. In addition,
Table 1 Inclusion and Exclusion Criteria
Inclusion CriteriaExclusion Criteria
Pain in the low back, buttock, and/or lower extremity (pain NRS > 4)
with standing, walking and/or spinal extension (buttock/leg > back pain)
Roland-Morris score of at least 7
Cognitive impairment that renders the patient unable to give informed
consent or provide accurate data.
Fibromyalgia diagnosis, chronic widespread pain, lower extremity
amputation, Parkinson’s, head injury, stroke, other neurologic conditions.
Severe vascular, pulmonary or coronary artery disease that limits
ambulation including recent myocardial infarction (within the last 6
months).
Spinal instability requiring surgery.
Severe osteoporosis as defined by multiple compression fractures or a
fracture at the same level as the stenosis.
Metastatic cancer.
Excessive alcohol consumption or evidence of non-prescribed or illegal
drug use as determined by the TICS screening questionnaire (1 or more
positive answer).
Possible pregnancy or other condition that precludes the use of
fluoroscopy.
Concordant pain with internal rotation of the hip (or known hip joint
pathology).
Active local or systemic infection.
Allergy to local anesthetic, steroid or contrast.
Mild-moderate-severe lumbar central canal spinal stenosis identified by
MRI or CT according to the criteria of Boden et al. [12]
Lower extremity symptoms consistent with neurogenic claudication
Must be able to read English and complete the assessment instruments
Age 50 or older
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at each in-person visit, we check blood pressure and
weight because these can also be affected by steroid
administration.
Other measures include patient-completed resource
utilization questionnaires to collect information on pre-
scription and over-the-counter medication use, medical
visits outside the health plan, and other patient burdens
and costs during four 3-week periods throughout the
12-month study. Resource use and costs for utilization
within each health system are available through the elec-
tronic health information systems (pharmacy and medi-
cal use).
Randomization
Treatment assignments are stored centrally in a secure
database at the study data coordinating center in Seattle,
Washington. For each recruitment site, we utilize per-
muted-block randomization to achieve roughly balanced
groups. We use random blocks of size 4, 6, 8, or 10 that
are not divulged to the research assistants involved in
recruitment in order to avoid bias in the recruitment
process. Two pre-filled opaque syringes are obtained for
every study procedure, one filled with the steroid and
the other with the local anesthetic. The randomized
treatment assignment is obtained via a password-pro-
tected study website by the clinical nurse or assistant
not involved with subsequent data collection indicating
which syringe should be labeled ‘inject’ or ‘discard’. The
clinical nurse or assistant confirms the use of the opa-
que syringe marked ‘inject’ by the physician performing
the injection. The physician, the research staff conduct-
ing follow-up interviews, and the patient are therefore
all blinded to treatment received.
Procedure
The procedure is performed in a fluoroscopy suite
under strict aseptic conditions. The patient is placed
prone on the procedure table. Standard fluoroscopy is
used for localization of the spinal/vertebral level to be
treated and needle placement for the injection. Fluoro-
scopic target identification and needle tip entry into the
targeted anatomic space is done using previously
described procedural techniques [23]. The skin over the
back is prepped and draped in a sterile manner using
Betadine or chlorhexidine. Local anesthesia with 0.5%-
1% lidocaine is injected in the subcutaneous tissues. The
epidural and local anesthetic injections are performed
using a 20-25 gauge spinal Quinke or 17-20 gauge
Tuohy needle. Appropriate needle tip placement is con-
firmed by fluoroscopy with the injection of 0.5-1.5 cc of
iopamadol, ioxehol or equivalent contrast. A fluoro-
scopic image is obtained following the injection to
demonstrate washout of the contrast. This image is
saved in the research file. Practitioners are instructed to
choose the injection level (e.g., L5-S1) to correspond
with one spinal level below the site of maximal canal
stenosis for the interlaminar approach injections and at
the root level of the greatest symptoms for transforam-
inal injections. Once an approach (transforaminal versus
interlaminar) is chosen for an individual patient, the
approach remains consistent for any repeat procedures
throughout the trial.
Epidural steroid injectate is 1-3 ml of 0.25-1% lido-
caine followed by 1.5-3 ml of 40 mg/ml triamcinolone
(i.e. 60-120 mg triamcinolone) in an opaque syringe.
The choice of which steroid to use is at the discretion
of the treating physician based on his or her usual clini-
cal practice. Betamethasone (6-12 mg), dexamethasone
(8-10 mg) or methylprednisolone (60-120 mg) may also
be used. The needles are then removed and the patient
taken to the recovery area.
The control procedure is identical to the ESI except
that the epidural injectate is 1-3 cc of .25%-1% lidocaine
followed by 1.5-3 cc of .25%-1% lidocaine in an opaque
syringe. The total volume of injectate is the same for
the ESI and the control injection to avoid differential
treatment effects based on volume.
Blinding
Every effort is made to maintain blinding of the patients
and evaluators during the course of the trial. All base-
line and follow up interviews are conducted by a study
research assistant who remains blinded to the rando-
mized assignment of the patient throughout the study.
The research assistant also completes assessments of
blinding at all follow up time points. All datasets have
the randomization code masked until all pre-specified
analyses are conducted to ensure that the research team
remains unaware of patient assignment. Patients are
asked to guess which treatment they actually received at
2 weeks, 5 weeks, and 3 months after the initially rando-
mized injection ("ESI”, “local anesthetic”, or “don’t
know”) and to provide a reason for and confidence in
treatment guesses other than “don’t know”. Specific
instances of un-blinding will be recorded and the study
statistician will monitor treatment guesses to diagnose
systematic problems with the blinding procedure or
over the course of conducting the study. Using Fisher’s
exact test, we will formally compare treatment guesses
between arms 2 weeks after randomization when the
study results are reported.
Analytic approach
We are utilizing “intent-to-treat” [24] analyses for the
primary effectiveness evaluation, which evaluates out-
comes based on the treatment arm to which individuals
are assigned. Crossover is not allowed until after the
outcome measures have been collected at the study
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primary endpoint of 6 weeks; therefore, the primary
results will reflect the treatment to which the participant
was randomized. The evaluable patient subset is defined
as those patients with data available for analysis based
on their initially randomized treatment. Consideration
of missing data is essential to characterize the potential
for selection bias through attrition. Characteristics of
patients with missing follow-up data will be compared
to those with complete data. In sensitivity analyses, we
will impute missing outcome data in multiple ways to
assess its impact on the primary analyses.
Primary analyses
Our primary analysis will evaluate the effect of ESI +
local anesthetic compared to local anesthetic alone
using repeated measures analysis of covariance
(ANCOVA). Each ANCOVA model will adjust for the
respective outcomes measured at baseline and a dummy
variable indicating study recruitment site. From the
ANCOVA models, we will report on the means and
standard deviations of six-week outcome measures for
each group and an adjusted estimate of the mean differ-
ence (95% CI) between groups. We will adjust the pri-
mary analysis for important baseline characteristics that,
despite randomization, differ between groups and are
associated with the outcomes.
Secondary analyses
We will conduct two subgroup analyses to assess evi-
dence for treatment effect on the primary outcome mea-
sures within categories defined by race and injection
approach (transforaminal/interlaminar). We do not
hypothesize that the treatment effect will be larger or
smaller in one subgroup compared to another, only that
there is a significant treatment effect within each
subgroup.
We will assess secondary outcomes using ANCOVA
models for continuous measures and logistic regression
models for binary measures. These analyses will include
assessment of group differences in clinically meaningful
changes in pain and function (e.g., at least a 30%
improvement on the Roland Morris Disability Question-
naire and pain scores).
Secondary analyses will consider the complete time
profile for the primary outcome measures of pain and
function through 12 months using methods appropriate
for the analysis of repeated measures. Crossover and
missing data will complicate analysis of follow-up data.
Long-term outcomes will be evaluated using linear
mixed effects models for repeated measures in both
intent-to-treat and as-treated analyses. We will tabulate
crossover rates by randomized treatment arm and com-
pare the rates using Chi-squared tests and logistic
regression as appropriate. To assess the impact of
crossover on the overall evaluation of ESI, we will exam-
ine longitudinal models of outcome that incorporate a
time-varying covariate indicating when treatment
occurred.
Economic outcome measures
The economic evaluation will include an assessment of
health care utilization, costs, and cost-effectiveness for
the steroid group compared to those receiving local
anesthetic alone in the intention-to-treat sample. The
co-primary economic outcomes will be incremental per
participant average costs compared to per participant
Roland Morris Disability Questionnaire improvement
and incremental cost per quality-adjusted life year
(QALY) gained from both a payer and societal perspec-
tive [25]. The QALY will be calculated using the EQ-
5D, a standardized health outcome instrument used to
estimate “utility weights” for cost-utility analysis http://
www.euroqol.org. We will estimate incremental cost-
effectiveness ratios for six weeks, six months and one
year using advanced sensitivity analyses to adjust para-
meter ranges for uncertainty in clinical, cost, or effec-
tiveness variables [26]. The impact of complications and
adverse effects on resource utilization and costs will be
summarized for both groups.
The primary economic research question is whether
treatment with steroid combined with anesthetic will be
safer and more effective than treatment with local anes-
thetic alone, at a differential cost within willingness-to-
pay thresholds of U.S. payers, using an incremental cost
per QALY gained approach. The one-year societal per-
spective analysis will include direct and indirect costs,
using standardized payer-based reimbursement amounts
(i.e., unit costs). In summarizing overall costs, we will
include costs reported by participants via resource use
questionnaires, in addition to the sum of estimated
reimbursed amounts associated with care used. Within-
health-system resource utilization will be assessed using
clinical, pharmacy and administrative data from the par-
ticipating health plans’ electronic systems. We will use
the health plan data to assess medical utilization events
(e.g., office visits, surgeries, tests) and the pharmacy data
to assess filled prescriptions. Average unit prices for
resource use (pharmacy and medical) will be applied to
participants’ health system utilization using a reimburse-
ment database containing payer expenditures within
each health system. These unit cost estimates (i.e., payer
reimbursement amounts) will come from an indepen-
dent, private insurance claims data warehouse, i.e., Mar-
ketscan®[27].
The secondary economic question is whether steroid
injections represent good value for money as evidenced
by non-QALY incremental cost-effectiveness ratios (i.e.,
cost per improvement in back-related functioning and
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cost per improvement in back pain, using Roland Morris
Disability Questionnaire and other pain/function mea-
sures). Other consequences (outcomes) will be described
in relation to cost or use profiles (e.g., ranges of the
Roland Morris Disability Questionnaire, pain numeric
rating scale measures, categories of medication use, ima-
ging or other diagnostic testing, and other provider use).
Marketscan®data will be used for unit cost estimates.
During four, three-week time periods over the course
of the twelve month study (weeks: 1-3, 4-6, 24-26, and
50-52), participants will complete Resource Utilization
Questionnaires to record information related to out-of-
pocket (out-of-system) costs, time related to seeking
back pain treatment, daily use of prescription and over-
the-counter medication use, and additional back thera-
pies, along with use or purchases of other back-care
products. We will describe the participant-reported data
by randomized groups. Additional descriptive analyses
will include assessing treatment group differences in dis-
aggregated EQ-5D items representing activities of daily
living (mobility, self-care, usual activities, pain/discom-
fort, anxiety/depression).
The effectiveness measures for the cost-effectiveness
analysis will be obtained directly from the primary sta-
tistical analysis. The cost-effectiveness assessment will
use a decision-tree framework to quantitatively assess
the costs and effects for the randomized groups. Short-
term cost-effectiveness outcomes will use the intention-
to-treat approach, while longer-term, one-year outcomes
will use empirical approaches to estimate EQ-5D and
Roland Morris Disability Questionnaire outcomes in
relation to cost. The assessment will allow for different
resource use patterns and test ranges of assumptions for
treatments and procedures. Empirical data from LESS
and from external sources which included the relevant
outcome measures [28,29] will be used to estimate the
expected effects and costs for ESI-randomized partici-
pants, modeling outcomes of Roland Morris Disability
Questionnaire and EQ-5D at three, six, and 12 months.
These data will be used to model treatment groups
under the assumption that no crossover occurs at the
six-week endpoint and participants do not deviate from
their randomized treatment during the 12-month study,
rather than modeling diverse crossover treatment pat-
terns and associated outcomes for participants, which
will be presented descriptively. Data on improvement or
decrement in outcomes will be used to estimate the tra-
jectory of Roland Morris Disability Questionnaire or
EQ-5D for treatment groups. Presenting ranges of cost-
effectiveness estimates using different approaches will
allow for a “triangulation” of results to assess consis-
tency, so that payers and policy makers can have com-
prehensive information for decision-making. The
analysis will be influenced by published data on
treatment patterns and guidelines, in addition to asses-
sing trends in Marketscan®data during several years.
Costs will be estimated in 2013 US$, the year the study
will conclude. As is standard practice in cost-effective-
ness analyses of 12 months or less, no discounting of
costs or effects will be performed for the 12-month
study. Sensitivity analyses will be conducted by testing a
20% range versus base case values for cost parameters
and effectiveness measures, as well as using probabilistic
sensitivity analysis approaches [26]. Additional testing
will be performed on cost-effectiveness parameters hav-
ing the greatest impact on the variability of cost-effec-
tiveness estimates.
Sample size
Our target is to enroll up to 400 patients with half rando-
mized to ESI + local anesthetic and half to local anes-
thetic alone. We determined overall sample size based on
the primary outcome (Roland Morris Disability Ques-
tionnaire) with two subgroup analyses (race: Caucasian/
non-Caucasian; approach: interlaminar/transforaminal).
We will use ANCOVA as the primary method of analysis
with the following parameters: 85% follow-up at 6 weeks;
two-sided Type 1 error rate of a = 0.05; and adjustment
for recruitment site and the outcome measured at base-
line. For the purpose of sample size estimation, we con-
servatively assume six-week Roland Morris Disability
Questionnaire scores will have a standard deviation of 7.5
for each group and a correlation between baseline scores
and six-week scores of 0.3. For the combined (n = 400)
assessment of ESI + local anesthetic vs. local anesthetic
alone, the LESS study has 83% power to detect between-
group mean differences as small as 2.25 points on the
Roland Morris Disability Questionnaire.
Subgroup analyses were powered to detect clinically
meaning differences between treatments within each
subgroup; we did not power the study for the hypothesis
of a larger treatment effect within one subgroup com-
pared to another (e.g. an interaction). We adjusted the
overall two-sided Type 1 error rate of a = 0.05 using a
Bonferroni correction for two tests of the data. Using
ANCOVA methods, a sample size of n = 200 (100 per
group) provides 83% power to detect between-group
mean differences of 3.25 points on Roland Morris Dis-
ability Questionnaire.
While formal interim analyses of treatment effect are
not planned for this study, we will generate blinded var-
iance estimates for the primary outcomes measured at 6
weeks after a minimum of 100 patients have been
enrolled. Conservative estimates of outcome variance
and 6-week retention utilized in the initial design of the
study yielded an overall upper-bound sample size of n =
400. Adaptive sample size re-estimation will be con-
ducted to provide more precise overall sample size
Friedly et al. BMC Musculoskeletal Disorders 2012, 13:48
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requirements given the observed variance and retention
rate, while maintaining the overall Type 1 error rate and
power for the stated effect sizes [30].
Discussion
As there has been scant research focusing on ESI in
older adults with pain due to spinal stenosis, little is
known about treatment risks and benefits for this popu-
lation. Although it has been demonstrated that surgery
can be effective for severe spinal stenosis, there are
many elderly patients for whom surgery carries substan-
tial risk. There is a need for safer, less-invasive treat-
ment options for older adults with the hope of reducing
functional disability and promoting independence.
Although ESI is a promising treatment alternative and is
widely used in clinical practice, its effectiveness is
unknown. Compared to young and middle-age adults, a
much higher percentage of older adults have co-morbid
conditions such as diabetes that may increase the risks
due to systemic absorption of corticosteroids.
As in most clinical trials, we anticipate that recruit-
ment may be a challenge. Patients suffering from pain
may be reluctant to delay what they might consider to
be definitive therapy. We have developed strategies to
increase our chances of successful recruitment including
the use of a patient-education video, which was a suc-
cessful strategy in our prior trials [29]. We have multiple
clinical recruitment sites and have added additional clin-
ical sites to attain our recruitment targets. We also have
included an optional crossover design to maximize our
ability to recruit patients with severe pain into the trial.
The results of this study should provide compelling
evidence as to whether or not epidural steroid injections
are effective in improving function and pain in the
elderly with lumbar spinal stenosis. The LESS trial will
provide high-quality data for shorter-term outcomes (six
weeks) and longer-term (one-year) outcomes. The
patient-reported outcomes, the electronic medical and
pharmacy utilization records, and supporting economic
data providing reimbursed amounts for resources used
will enable a robust evaluation of the comparative bene-
fits and harms associated with epidural steroid injections
with anesthetic versus local anesthetic alone.
Abbreviations
ANCOVA: Analysis of co-variance; BOLD: Back pain Outcomes using
Longitudinal Data; BPI: Brief Pain Inventory Interference; CEA: Cost
effectiveness analysis; ESI: Epidural steroid injection; GAD-7: Generalized
Anxiety Disorder measure; LESS: Lumbar Epidural steroid injections for Spinal
Stenosis; PHQ-8: Patient Health Questionnaire (PHQ-8); SSSQ: Swiss Spinal
Stenosis Questionnaire (SSSQ); NRS: Numerical rating scale; QALY: Quality
adjusted life year.
Acknowledgements
Funding for this study is provided by the AHRQ, CHOICE award number
1R01HS019222-01.
Author details
1Comparative Effectiveness, Cost and Outcomes Research Center, University
of Washington, Seattle, WA, USA.2Departments of Family Medicine and
Internal Medicine, Oregon Health Sciences University, Portland, OR, USA.
3Department of Anesthesiology, Perioperative and Pain Medicine, Brigham
and Women’s Hospital, Boston, MA, USA.4Division of Research, Kaiser
Permanente Northern California, Oakland, CA, USA.5Neuroscience Institute,
Henry Ford Hospital, Detroit, MI, USA.
Authors’ contributions
All authors contributed to development of the research protocol, manuscript
writing and editing. All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Received: 25 January 2012 Accepted: 29 March 2012
Published: 29 March 2012
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Pre-publication history
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doi:10.1186/1471-2474-13-48
Cite this article as: Friedly et al.: Study Protocol- Lumbar Epidural
Steroid Injections for Spinal Stenosis (LESS): a double-blind randomized
controlled trial of epidural steroid injections for lumbar spinal stenosis
among older adults. BMC Musculoskeletal Disorders 2012 13:48.
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