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Treatment of Chronic Low Back Pain With Etoricoxib, a New

Cyclo-oxygenase-2 Selective Inhibitor: Improvement in Pain and


DisabilityA Randomized, Placebo-Controlled, 3-Month Trial
Charles A. Birbara,* Anthony D. Puopolo, David R. Munoz, Eric A. Sheldon,
Antoinette Mangione, Norman R. Bohidar, and Gregory P. Geba for the Etoricoxib
Protocol 042 Study Group

Abstract: We evaluated etoricoxib, a novel COX-2specific inhibitor, in 319 patients with chronic
low back pain (LBP) in this double-blind, placebo-controlled trial. Patients were randomized to a 60
mg dose (n 103) or 90 mg dose (n 107) of etoricoxib, or placebo (n 109), daily for 12 weeks. The
primary endpoint was low back pain intensity scale (Visual Analog Scale of 0- to 100-mm) time-
weighted average change from baseline over 4 weeks. Other endpoints included evaluation over 3
months of low back pain intensity scale, Roland-Morris Disability Questionnaire (RMDQ), low back
pain bothersomeness scale, patient- and investigator-global assessments, Patient Health Survey (MOS
SF-12), rescue acetaminophen use, and discontinuation due to lack of efficacy. Etoricoxib provided
significant improvement from baseline versus placebo in pain intensity (4 weeks: 12.9 mm and 10.3
mm for 60-mg and 90-mg doses, P < .001 for each; 12 weeks: 10.5 mm and 7.5 mm for 60-mg and
90-mg doses, P .001 and .018, respectively). Etoricoxib at either dose led to significant improvement
in other endpoints, including RMDQ scores, bothersomeness scores and global assessments. Etori-
coxib given once daily provided significant relief of symptoms, and disability associated with chronic
LBP that was observed 1 week after initiating therapy, was maximal at 4 weeks, and was maintained
over 3 months.
2003 by the American Pain Society
Key words: Etoricoxib, low back pain, chronic, disability, treatment.

L
ow back pain (LBP) is a major cause of disability and bone changes.11 Despite knowledge of the factors con-
lost work time, second only to upper respiratory tributing to low back pain, the cause cannot be precisely
tract infections, and represents the most costly of all determined in individual cases. The problem of diagnosis
occupational health problems.3,11,35 The condition af- is compounded by sensitive but nonspecific imaging
flicts up to 90% of adults at some point in their lives35 studies.11 This can lead to misdiagnosis, unnecessary sur-
and often requires expensive diagnostic procedures and gery, and disability, which contribute to litigation and
hospitalizations.11 The costs associated with low back absenteeism, with associated significant costs (reviewed
pain are estimated at 20 to 50 billion dollars annually in in 22) and a negative societal impact.
the United States, with chronic LBP accounting for 75% Low back pain is most commonly treated with analge-
to 90% of that total.22 In industrialized societies, such as sic medications. Opioid and nonopioid analgesics, and
the United States, this condition is believed to have especially nonsteroidal anti-inflammatory drugs
evolved as a consequence of the modern lifestyle, which (NSAIDS) are employed. Persistent symptoms, despite an-
includes physical inactivity and being overweight, as well algesics, have traditionally led physicians to prescribe
as the extension of life span, associated deconditioning, physical rehabilitation. A more recent approach has
spinal malalignment, disc herniation and degenerative been to stress a return to normal activities, because nei-
ther bed rest, facet injections, transcutaneous nerve
Received August 23, 2002; Revised February 21, 2003; Accepted March 8, stimulation, nor traction have been shown to improve
2003.
From the *University of Massachusetts School of Medicine, Worcester, pain and disability in randomized clinical trials.11 Other
MA, Milford Emergency Associates, Milford, MA, Internal Medicine historical approaches include acupuncture, which has
Northwest, Tacoma, WA, Miami Research Institute, Miami, FL, Albert
Einstein Medical Center, Philadelphia, PA, and Merck and Co, Inc, West not proven to be effective; spinal manipulation, which
Point, PA.
may provide some, though modest, benefit; and mas-
Supported by Merck & Co, Inc, West Point, PA.
Address reprint requests to Gregory P. Geba, MD, MPH, Clinical Develop- sage therapy, which may have a role in the treatment of
ment, Merck and Co, Inc, PO Box 4, HM-202, West Point, PA 19486-0004. acute back strain.24
E-mail: gregory_geba@merck.com
2003 by the American Pain Society
The effectiveness of these medical treatments for
1526-5900/2003 $30.00 0 chronic back pain has not been confirmed.11 Although
doi:10.1016/S1526-5900(03)00633-3 most acute episodes of back pain are self-limited, ap-

The Journal of Pain, Vol 4, No 6 (August), 2003: pp 307-315 307


308 Etoricoxib in Chronic Low Back Pain
proximately 5% to 10% of patients develop symptoms without radiation to an extremity and without neurolog-
lasting 3 or more months.3 Many of these patients are ical signs) or Class 2 (pain with radiation to an extremity,
treated with NSAIDs.17,29 Despite their widespread use, but not below the knee and without neurological signs)
dual COX inhibiting NSAIDs have not previously been on the Quebec Task Force system on Spinal Disorders.1
definitively proven to be effective in the treatment of Muscle relaxants, physical therapy, and chiropractic or
LBP.17,29 In a recent review of 51 randomized, controlled alternative therapy (such as acupuncture) were permit-
trials for acute and chronic low back pain, NSAIDs ap- ted, if their use was stable for the month preceding the
peared to be somewhat effective only for short-term screening visit and was expected to remain stable for the
global improvement in patients with acute low back duration of the study. Patients with low back pain due to
pain,29 but this effect waned after more than a few secondary causes (eg, malignancy, inflammatory disease,
weeks. Patient tolerability of chronic NSAID therapy, osteoporosis, fibromyalgia, ochronosis, vertebral frac-
driven mainly by gastrointestinal symptoms, may have ture, infection, juvenile scoliosis, or congenital malfor-
been an obstacle in maintaining favorable out- mation) were excluded. Also excluded were patients
comes.17,29,36 who had surgery for low back pain within 6 months of
Treatment with conventional NSAIDs, which inhibit cy- screening, had symptomatic depression that would inter-
clo-oxygenases 1 and 2 (COX-1/COX-2), can be compli- fere with completion of the study questionnaires,
cated by gastrointestinal mucosal injury.36 This is abused drugs or alcohol within the past 5 years, used
thought to be due to NSAID-induced inhibition of opioids more than 4 days in the month before screening,
COX-1, the enzyme responsible for the generation of or had corticosteroid injections within 3 months before
gastroprotective prostanoids.14,15 The COX-2 inhibitors screening. Low dose aspirin (81 mg/day) was continued
were developed to provide the analgesic and anti-in- during the trial if used for cardiovascular prophylaxis
flammatory effects of NSAIDs, without causing gastroin- prior to enrolling in the study.
testinal adverse events mediated by COX-1 inhibi-
tion.6,23,28,30 The COX-2 inhibitors have been associated Study Design
with improved gastrointestinal tolerability compared to This randomized, placebo-controlled, parallel-group,
dual-COX-inhibiting NSAIDs.7,32,33 COX-2 also mediates double-blind study was conducted at 46 centers in the
generation of prostanoids responsible for pain, inflam- United States from March to November 2000. The study
mation, and fever,20,21 which are blocked by COX-2 in- was conducted in accordance with the principles of good
hibitors. clinical practice. The protocol was approved by the insti-
Herein we report the results of a randomized, placebo- tutional review board at each study site. At the screening
controlled, parallel-group, 12-week, double-blind, piv- visit, patients provided written informed consent, under-
otal phase III study designed to evaluate the efficacy, went a general physical examination and laboratory
safety and tolerability of etoricoxib, a novel COX-2 inhib- safety assessment, and had the following assessments:
itor, in the treatment of chronic LBP. To guide dose se- low back pain intensity scale, low back pain bothersome-
lection, we used previously available data showing the ness scale, Patient Global Assessment of Disease Status
minimal dose of etoricoxib necessary to produce maxi- (PGADS), Roland-Morris Disability Questionnaire
mal effectiveness in 2 other chronic musculoskeletal pain (RMDQ),27 Hospital Anxiety and Depression Scale
syndromes (osteoarthritis and rheumatoid arthritis) ob- (HADS),37 and the Patient Health Survey (MOS Short
tained from studies ranging from 6 weeks to 1 year (re- Form [SF]-12).31 After the screening visit, patients discon-
viewed in 9 and 18). In those studies, efficacy was maxi- tinued prestudy analgesics for a stipulated washout pe-
mal by the second to fourth week and was maintained riod of 4 to 15 days, depending upon the half-life of the
over the duration of the study. We therefore tested both previous medication used to treat LBP. At the completion
the 60 and 90 mg doses in this study and evaluated the of washout, patients returned to the study site for re-
efficacy of etoricoxib at various points over a trial of evaluation. Patients were randomized if they met the
12-weeks duration to determine onset of efficacy and following flare criteria: (1) a score of 40 mm on the low
durability of effect, and to assess the impact of etoricoxib back pain intensity scale; (2) an increase of 10 mm on the
on improving the disability often associated with this low back pain intensity scale compared to the screening
chronic pain condition. This approach to the evaluation visit; and (3) a worsening of PGADS by 1 point (on a 0 4
of chronic musculoskeletal pain is consistent with previ- point scale) compared to the screening visit.
ously published guidance.1,2,10 Within each study center, patients were randomly al-
located to the treatment groups using a computer-gen-
Materials and Methods erated random allocation schedule. Eligible patients
were randomized to a 90-mg dose of etoricoxib, a 60-mg
Study Population dose of etoricoxib, or placebo (1:1:1). All treatments
This study enrolled outpatients between 18 and 75 were double-blinded and double-dummy. Data-analysis
years of age who had low back pain for at least 3 months, personnel were also blinded during the screening pro-
were regular users, over at least the past 30 days, of cess while reviewing and making corrections to the data
either an NSAID or acetaminophen for treatment of their before the data file was locked for final statistical anal-
low back pain, and were otherwise in good health. Pa- ysis and reporting. No patients in this study were un-
tients were eligible if they were assessed as Class 1 (pain blinded prematurely.
ORIGINAL REPORT/ Birbara et al 309
The study drug was taken once daily, every morning, response. The time-weighted average response of a pa-
for a total of 12 weeks. Acetaminophen (up to 1950 mg tient who discontinued the study after only one on-treat-
daily) was provided as rescue analgesia for use through- ment visit was based on only the response at that visit.
out the study. Patients were instructed not to take rescue Analysis of covariance (ANCOVA) was used to model
analgesia within the 12 hours before each efficacy visit. treatment response as a function of treatment, study
Patients returned at 1, 2, 4, 8, and 12 weeks postrandom- center, and baseline covariate. Treatment-by-study-cen-
ization for efficacy and safety assessments. All random- ter and treatment-by-baseline-covariate interactions
ized patients underwent safety assessments at each were evaluated prior to running the final model. Time-
study visit, including measurement of vital signs, record- weighted average responses (least mean squares) for
ing of adverse experiences (AEs), laboratory safety as- each treatment group were calculated and differences
sessment (at 2, 4, 8, and 12 weeks, or at discontinuation, between groups compared using ANCOVA with treat-
and 2 weeks post-therapy), and physical examination (at ment, study center and baseline value of the dependent
4 and 12 weeks, or at discontinuation). Investigators value as the covariate. Between group differences were
evaluated all AEs according to their intensity and rela- assessed in the context of the final statistical model. A
tionship to study drug while still blinded to the treat- step-down, closed testing procedure where the 90-mg
ment. dose was first compared to placebo, followed by the
60-mg dose versus placebo, was employed to assess the
Statistical Analysis dose-response relationship. For prespecified discontinu-
The primary statistical analysis of efficacy employed a ations, prespecified AEs, or prespecified laboratory val-
modified intent-to-treat approach, which included anal- ues outside of predefined limits of change, Fishers exact
ysis of all patients who received at least one dose of test was used for pairwise comparisons of proportions of
therapy and provided data from 1 efficacy evaluation patients between treatment groups.
(97% for primary endpoint). Only observed data (at
scheduled, unscheduled, and discontinuation visits) were Results
included in each patients average response; no data The study enrolled 319 subjects. Baseline characteris-
were carried forward or imputed in the computation. A tics were generally similar in all groups (Table 1).The
per-protocol analysis, which excluded patients with a mean (SD) age was 52 ( 13) years and 61% were female.
prespecified set of significant protocol violations, also Nearly 85% of all patients were prior NSAID users. Pa-
was conducted for the primary efficacy endpoint as a tients had LBP for a mean duration of 11 ( 10) years and
supportive analysis. There were no substantial differ- had a mean pretreatment pain intensity (after flare) of
ences in results obtained using the intent-to-treat or per- 77 ( 13) mm on the low back pain intensity scale 100
protocol approaches. mm VAS. Approximately 13% of patients were classified
The prespecified hypotheses were that once-daily as having moderate to severe anxiety, but only 4% of
etoricoxib would demonstrate superior improvement in patients met classification of depression based on the
low back pain compared with placebo as assessed by the HADS questionnaire. Fig 1 summarizes the randomiza-
low back pain intensity scale time-weighted average tion and patient disposition.
over 4 weeks (primary) and 3 months (secondary), and
that etoricoxib would be safe and well tolerated over 3 Primary EndpointLow Back Pain
months. Other objectives included evaluation of effi- Intensity Scale
cacy provided by etoricoxib in terms of the RMDQ, the The etoricoxib 60-mg and 90-mg groups both pro-
low back pain bothersomeness scale, patient- and in- vided statistically significant improvement in low back
vestigator-global assessment of response to therapy, pain intensity (0- to 100-mm VAS) over the first 4
patient health survey (MOS SF-12), PGADS, use of res- weeks (primary hypothesis; 60 mg vs placebo: 12.94
cue acetaminophen and discontinuations due to lack mm [95% CI: 19.03, 6.86]; 90 mg vs placebo: 10.29
of efficacy. [16.26, 4.31); P values .001 vs placebo for both
Data from a study of corticosteroid injections for LBP doses). Over 12 weeks (secondary hypothesis) results
and from the phase IIb trials demonstrating the effect were similar (Table 2).Treatment responses to etori-
of etoricoxib in the treatment of osteoarthritis were coxib at 60 mg or 90 mg over 4 and 12 weeks were not
used to calculate the detectable difference for the pri- significantly different (P .394 and P .359, respec-
mary hypothesis. The parallel-group design with 100 tively; Fig 2).
patients per group provided 95% power to detect (
0.05, 2-tailed) a 12-mm difference between etoricoxib Additional Endpoints
and placebo with respect to the average change from All other endpoints were prespecified in the protocol.
baseline over 4 weeks on the low back pain intensity Both the 60-mg and 90-mg doses of etoricoxib provided
scale. significant improvements compared to placebo over 4
Treatment effect was measured by the time-weighted and 12 weeks in terms of RMDQ (Fig 3), the low back pain
average response by taking the time between adjacent bothersomeness scale (Fig 4), PGADS (Fig 5), and patient-
observations divided by the time from the flare/random- and investigator-global assessment of response to ther-
ization visit to the last observation and using it as the apy (Table 2). The treatment effects provided by the 2
weight for the computation of the average treatment doses of etoricoxib were not significantly different from
310 Etoricoxib in Chronic Low Back Pain

Table 1. Baseline Patient Characteristics by Treatment Group


ETORICOXIB

STATISTIC PLACEBO 60 MG 90 MG TOTAL

Age (years)
No. 107 101 106 314*
Mean (SD) 51.0 (13.7) 52.3 (13.3) 52.2 (12.4) 51.8 (13.1)
Range 23 to 75 21 to 75 20 to 75 20 to 75
Gender, [n (%)]
Female 59 (55.1) 64 (63.4) 67 (63.2) 190 (60.5)
Male 48 (44.9) 37 (36.6) 39 (36.8) 124 (39.5)
Race, [n (%)]
White 94 (87.9) 88 (87.1) 96 (90.6) 278 (88.5)
Black 8 (7.5) 6 (5.9) 5 (4.7) 19 (6.1)
Hispanic 5 (4.7) 4 (4.0) 5 (4.7) 14 (4.5)
Asian 0 (0.0) 1 (1.0) 0 (0.0) 1 (0.3)
Native American 0 (0.0) 1 (1.0) 0 (0.0) 1 (0.3)
Indian 0 (0.0) 1 (1.0) 0 (0.0) 1 (0.3)
Prior analgesic use, [n (%)]
Non-NSAID 15 (14.3) 21 (20.8) 12 (11.3) 48 (15.4)
NSAID 90 (85.7) 80 (79.2) 94 (88.7) 264 (84.6)
Duration of chronic low back pain
No. 107 101 106 314
Mean (SD) 10.7 (10.0) 12.1 (10.5) 10.8 (10.8) 11.2 (10.4)
Range 1 to 44 1 to 49 1 to 46 1 to 49
Low back pain intensity scale (100-mm VAS)
No. 107 101 105 313
Mean (SD) 76.9 (12.8) 76.9 (12.7) 77.8 (13.6) 77.2 (13.0)
Range 41 to 100 47 to 100 40 to 100 40 to 100
Low back pain bothersomeness scale (0 to 4-point Likert)
No. 107 101 105 313
Mean (SD) 3.0 (0.7) 3.0 (0.6) 3.1 (0.7) 3.0 (0.7)
Range 1 to 4 2 to 4 2 to 4 1 to 4
Patient global assessment of disease status (0 to 4-point Likert)
No. 106 101 106 313
Mean (SD) 2.9 (0.7) 2.9 (0.8) 3.0 (0.8) 2.9 (0.7)
Range 1 to 4 1 to 4 1 to 4 1 to 4
Roland-Morris Disability Questionnaire (0 to 24-point scale)
No. 107 101 106 314
Mean (SD) 14.1 (4.9) 15.4 (5.0) 14.7 (5.0) 14.7 (5.0)
Range 2 to 24 1 to 24 1 to 24 1 to 24
SF-12 Physical Component Summary Scale
No. 104 97 101 302
Mean (SD) 32.6 (8.6) 30.1 (7.4) 32.1 (8.4) 31.6 (8.2)
Range 15 to 54 15 to 55 15 to 55 15 to 55
SF-12 Mental Component Summary Scale
No. 104 97 101 302
Mean (SD) 49.1 (11.2) 47.8 (10.5) 48.3 (10.7) 48.4 (10.8)
Range 19 to 68 25 to 70 24 to 66 19 to 70

*All patients from 1 study center (2, placebo; 2, etoricoxib 60 mg; 1, etoricoxib 90 mg) were excluded from the ITT and PP analyses due to possible data integrity
issues.

each other. Incremental improvements in physical and patients required acetaminophen as rescue medication
mental components of the exploratory MOS SF-12 end- during the course of the study (average use 1.2 tablets/
point were significantly different between etoricoxib day). Differences between groups were not statistically
and placebo for the physical component only for the significant. A significantly smaller proportion of patients
90-mg dose (P .039). assigned to 60 mg or 90 mg of etoricoxib discontinued due
All patients were dispensed acetaminophen at base- to lack of efficacy compared to those on placebo (5.9%,
line for use as pain rescue medication during the treat- 11.3% and 25.2%, respectively; P values: .001, and .012
ment period (treatment weeks 1 through 12). Very few for 60-mg and 90-mg doses vs placebo, respectively).
ORIGINAL REPORT/ Birbara et al 311

Figure 1. Subject disposition. This figure presents the flow of patients through the study from screening to completion of the study.
Patients who did not complete the study are indicated. *The main reasons patients did not qualify for randomization were the
following: did not meet protocol flare criteria, patients not in good health on the basis of medical history, physical exam, and routine
laboratory tests, and patients were not taking either an NSAID or acetaminophen on a regular basis (24 of the previous 30 days) for
the treatment of low back pain. Patient lost to follow-up, withdrew consent, protocol deviation, or moved. Patients from 1 study
center (2, placebo; 2, etoricoxib 60 mg; 1 etoricoxib 90 mg) were discontinued due to possible data integrity issues.

Safety and Tolerability etoricoxib groups compared to placebo. Etoricoxib at a


Clinical adverse events were reported by 51 (46.8%), 60 dose of 90 mg led to a higher incidence of adverse
(58.3%), and 56 (52.3%) patients in the placebo, 60-mg events, judged by the investigator to be drug-related,
etoricoxib, and 90-mg etoricoxib treatment groups, re- compared to placebo (27.1% vs 11.9%; P .006), but 60
spectively, with no statistically significant differences be- mg was not significantly different from placebo (20.7%
tween active treatments and placebo. The most com- vs 11.9% P .133). There were no significant differences
monly reported adverse events were headache (5.5%, in drug-related adverse events leading to discontinua-
11.7%, and 5.6%), nausea (2.8%, 5.8%, 7.5%), diarrhea tion (events [%]: 5 [4.6%], 8 [7.8%] and 10 [9.3%] in the
(1.8%, 3.9%, 8.4%) and respiratory tract infections placebo, etoricoxib 60 mg and 90 mg groups, respec-
(6.4%, 5.8%, 2.8%) in the placebo, etoricoxib 60 mg and tively; P .29 for either active vs placebo).
etoricoxib 90 mg groups, respectively. There were no
significant differences in serious adverse events leading Discussion
to discontinuation among groups. The incidence of one In this 12-week placebo-controlled trial, etoricoxib, 60
or more clinical adverse events, serious adverse events, or 90 mg once daily, provided significant improvement
all discontinuations due to adverse events, incidence of across several important efficacy measures in the treat-
discontinuation due to specific adverse events including ment of chronic LBP. Etoricoxib was effective in terms of
gastrointestinal, edema-related, hypertension-related reducing low back pain intensity scores, the primary end-
events and adverse events of congestive heart failure or point, decreasing disability (Roland-Morris), ameliorat-
pulmonary edema were not significantly different in the ing interference in life activities (bothersomeness
312 Etoricoxib in Chronic Low Back Pain

Table 2. Efficacy Endpoints (Modified Intent-to-Treat Approach)


60 MG VS. PLACEBO 90 MG VS. PLACEBO
DIFFERENCE IN LS DIFFERENCE IN LS
ENDPOINT MEAN* (95% CI) MEAN* (95% CI)

Low back pain intensity scale over 4 weeks 12.94 10.29


(100 mm VAS; 0 no pain to 100 extreme pain) (19.03, 6.86) (16.28, 4.31)
Low back pain intensity scale over 12 weeks 10.45 7.50
(100 mm VAS; 0 no pain to 100 Extreme pain) (16.77, 4.14) (13.71, 1.28)
Low back pain bothersomeness scale over 12 weeks 0.38** 0.33**
(4 point Likert; 0 not at all to 4 extremely) (0.62,0.14) (0.57,0.09)
Patient global assessment of disease status over 12 weeks 0.29 0.31
(4 point Likert; 0 very well to 4 very poor) (0.54,0.04) (0.55,0.07)
Patient global assessment of response to therapy over 12 weeks 0.51 0.44**
(4 point Likert; 0 excellent to 4 none) (0.80,0.21) (0.74,0.15)
Roland-Morris Disability Questionnaire over 12 weeks 2.42 2.06**
(0 to 24 point Scale) (3.87,0.98) (3.46,0.65)
SF-12 Physical Component Summary Scale over 12 weeks 1.65 2.58
(0.86,4.16) (0.13,5.02)
SF-12 Mental Component Summary Scale over 12 weeks 1.68 0.92
(0.51,3.87) (3.08,1.23)
Investigator global assessment of response to therapy over 12 0.51 0.43**
weeks (4 point Likert; 0 excellent to 4 none) (0.81,0.21) (0.73,0.14)
Rescue acetaminophen use (tablets per day) over 12 weeks 0.25 0.06
(0.50,0.01) (0.31, 0.19)
Discontinuations due to lack of efficacy 19.3 13.9
(28.8,9.6) (24.1, 3.5)

*LS Least-squares.

Low back pain Intensity was measured by a question to each patient: During the past week, how much low back pain did you have?

Negative values reflect benefit of etoricoxib compared to placebo.

Positive values reflect benefit of etoricoxib compared to placebo.

P .001.

P .05.
**P .01.

scores), and led to significant positive response to ther- at doses commonly employed in the treatment of osteo-
apy as judged by global assessment of both the patient arthritis and rheumatoid arthritis compared to placebo
and the physician. in this conditionthis was true for subgroups only in 2 of
The 2 doses employed in this study gave comparable these, and in 2 other trials the differences did not reach
results. Although on some endpoints (MOF SF-12, and statistical significance. Patients with chronic low back
rate of discontinuation due to lack of efficacy) the 90-mg pain were evaluated in only 1 of these trials, which was
dose of etoricoxib appeared to provide greater efficacy deemed to be of low methodologic quality. Generally,
than the 60-mg dose, these differences were not statis- the methodological shortcomings in these previous trials
tically significant. This finding is not surprising because included lack of statistical power to detect treatment
the 60-mg dose of etoricoxib led to improvements com- effects due to small sample sizes, and study of heteroge-
pared to on-treatment baseline scores recorded at neous patient populations that may have confounded
screening prior to randomization to study drug for each the results. The use of the Quebec Task Force classifica-
of the endpoints tested. It is possible that, for individual tion was recommended by an expert panel12 to correct
patients, 90 mg might provide additional benefit, but for this deficiency and therefore was used in this study.
this cannot be concluded from the results of this study. A retrospective meta-analysis of pooled data from pla-
The magnitude of the treatment response observed cebo-controlled trials of sufficient methodological qual-
for the primary endpoint (low back pain intensity score) ity was used to obtain an estimate of the effect of NSAIDs
has been shown to be clinically meaningful.2 The robust in low back pain.17 This analysis suggested that NSAIDs
results obtained for the secondary endpoints provide provided greater efficacy compared to placebo in terms
strong support of the primary endpoint data. The im- of the prespecified endpoint defining success of the trial,
provements in pain and disability shown in this trial con- which varied according to the study, especially demon-
trast with previous trials,17 which evaluated the efficacy strable early on after initiating therapy (OR 0.53; 95%
of NSAIDs in low back pain. Koes et al17 reported that CI: 0.32, 0.89 using a fixed-effect model). However, the
although 5 of 10 previous placebo-controlled studies in meta-analysis was dominated by studies of short dura-
low back pain suggested benefits of NSAIDs, when given tion. Durability of effect beyond 2 weeks could not be
ORIGINAL REPORT/ Birbara et al 313

Figure 2. Low back pain intensity scale (0- to 100-mm VAS). Figure 3. Roland-Morris Disability Questionnaire scores (0- to
Least-squares mean change (mm) from baseline (flare/random- 24-point scale). Least-squares mean change (points) from base-
ization visit) over the 12-week treatment period (all-patients line (flare/randomization visit) over the 12-week treatment pe-
treated approach). Screening (S) to baseline (R) is the washout riod (modified intent-to-treat approach). Screening (S) to base-
period from previous analgesic. Data points for each treatment line (R) is the washout period from previous analgesic. Data
group were shifted along the x-axis to maximize legibility at points for each treatment group were shifted along the x-axis to
each time point. (Abbreviation: SE, standard error.) *P .001 maximize legibility at each time point. (Abbreviation: SE, stan-
time weighted average versus placebo. P .001 time weighted dard error.) *P .001 time weighted average versus placebo. P
average versus placebo. P .018 time weighted average .001 time weighted average versus placebo. P .004 time
versus placebo. weighted average versus placebo.

assessed because only 1 inconclusive study provided data magnitude of effect previously reported to be clinically
after more than 2 weeks of treatment. Curiously, despite meaningful.2
the anti-inflammatory effects of NSAIDs, these agents Additional validated assessment tools used to demon-
were not associated with improved outcomes in the sub- strate efficacy focused on other clinically relevant end-
group of patients with signs of radiculopathy due to root points, consistent with recommendations by an interna-
compression, which is often associated with inflamma- tional panel addressing methodology in evaluating low
tion and potentially amenable to anti-inflammatory back pain efficacy in clinical research.10 Etoricoxib pro-
therapy. However, failure of monotherapy with NSAIDs vided statistically superior efficacy compared to placebo
in this scenario may not be entirely surprising given that in all but 1 of the remaining endpoints measured (8 of 9
radiculopathic pain may also involve ischemia and neu- overall), and improvement from baseline in all endpoints
ropathic components (reviewed in 34) and thus may re- measured. This contrasts with the lack of consistency of
quire an approach that targets several mechanisms op- results in prior NSAID back pain trials. This difference
erant in such complex pain. may be explained by having adequately powered this
This is the first placebo-controlled study to evaluate study, selecting appropriate patients with confirmed an-
the efficacy and durability of benefit of a highly selective algesic-responsive pain, and applying the Quebec Task
COX-2 inhibitor in the treatment of patients with chronic Force criteria as suggested by an expert panel.29 Another
low back pain over the course of 3 months. Because the possible explanation may lie in the compliance chal-
majority of patients in this trial had a long history of back lenges of NSAIDs, which in some studies resulted in sig-
symptoms (average 11 years), consistent with previous nificant dropout due to gastrointestinal adverse ef-
reports describing the characteristics of patients with this fects.11
chronic pain syndrome,11 testing for maintenance of ef- For 1 of the secondary endpoints, testing effects on
fect was of particular importance. The results indicated quality of life using the MOS SF-12 (mental and physical
that the effects of etoricoxib appeared evident after 1 components), subjects assigned to etoricoxib did not ex-
week of therapy, were confirmed by 2 weeks, reached a perience a change from baseline that was statistically
plateau at 4 weeks, and were maintained at the 4-week significantly greater than placebo. The MOS SF-12 was
level over the remainder of the 12 weeks of the trial. chosen over the longer survey (MOS SF-36) in consider-
The RMDQ, which measures LBP-related function and ation of the numerous additional efficacy assessments
correlates with improvements in work status,12,27 is an the patients were asked to complete, and because of
endpoint ideally suited for clinical trials. This question- data suggesting its validity as a surrogate for the SF-36 in
naire employs 24 sentences to ascertain the degree of other pain models.16,31 However, despite clear improve-
symptom-limited function in activities of daily living as a ments in all other parameters, the MOS SF-12 was not
binary response (affirmative or negative). Mean differ- sensitive enough in this study of chronic low back pain to
ences from placebo for the RMDQ at 12 weeks were discriminate from placebo. Previous published findings
2.42 and 2.06 units for the etoricoxib 60-mg and have questioned the validity of the shorter question-
90-mg groups, respectively, which are consistent with a naire in studies with less than 200 patients per treatment
314 Etoricoxib in Chronic Low Back Pain

Figure 4. Low back pain bothersomeness scale (0- to 4-point Figure 5. Patients global assessment of disease status (0- to
Likert scale). Time weighted average change (points) from base- 4-point Likert scale). Least-squares mean change (points) from
line (flare/randomization visit) over the 12-week treatment pe- baseline (flare/randomization visit) over the 12-week treatment
riod (modified intent-to-treat approach). Screening (S) to base- period (modified intent-to-treat approach). Screening (S) to
line (R) is the washout period from previous analgesic. Data baseline (R) is the washout period from previous analgesic. Data
points for each treatment group were shifted along the x-axis to points for each treatment group were shifted along the x-axis to
maximize legibility at each time point. (Abbreviation: SE, stan- maximize legibility at each time point. (Abbreviation: SE, stan-
dard error.) *P .001 time weighted average versus placebo. P dard error.) *P .001 time weighted average versus placebo. P
.002 time weighted average versus placebo. P .007 time .012 time weighted average versus placebo. P .013 time
weighted average versus placebo. weighted average versus placebo. P .022 time weighted av-
erage versus placebo.

arm and placed in doubt its appropriateness as a tool to and was well tolerated. Both doses of etoricoxib were
assess efficacy in low back pain13, 25; the results of this efficacious. Onset of efficacy was observed as soon as 1
study lend further support for this view. week after initiating therapy (first efficacy assessment),
The safety profile suggests that etoricoxib was well was maximal by 4 weeks and was maintained over the
tolerated as a treatment for chronic LBP. Gastrointestinal remainder of the 3-month trial. The data from this study,
adverse events can be associated with use of dual COX-1 obtained across multiple clinical endpoints, confirm the ef-
and COX-2 inhibiting NSAIDs.19 COX-2 selective inhibi- ficacy of etoricoxib in reducing pain and disability and sup-
tors were developed based on the concept that these port its use as an effective and generally well tolerated
specific agents would have improved gastrointestinal option in the management of chronic low back pain.
tolerability relative to conventional NSAIDs.26,32 In this
study, at both doses, the rate of gastrointestinal adverse
events with etoricoxib was not significantly different
Acknowledgments
from placebo. The favorable tolerability profile observed We thank Drs J. Rush, T. Dobbins, R. Petruschke, W.
in this study may have contributed to the outcomes ob- Straus, and J. Yates for their review of this manuscript
served in terms of maintenance of pain relief, positive and for valuable comments. We gratefully acknowledge
effects on disability scores and favorable global assess- the contribution of A. Polis who provided statistical as-
ment of response to therapy over this 3-month trial. sistance, M. Dixon and C. Skalky who provided manage-
The risk of certain renal and vascular events needs to rial support of this study, K. OBrien, L. Mucciola, and A.
be considered when treating patients with NSAIDs.8,19 Pyeron for their expertise in monitoring this trial, and L.
Similar precautions have been recommended when con- Mucciola and R. Petruschke for their assistance with
sidering treatment with the available COX-2 inhibi- manuscript preparation.
tors.4,5 The incidence of renal and vascular events in the Investigators: The etoricoxib protocol 042 study group
present study was not significantly different between included the following investigators: M. Adamczk, R. Ad-
the 60-mg and 90-mg etoricoxib doses and placebo. elizzi, C. Birbara, D. Bong, D. Britt, D. Brune, B. Caciolo, R.
However, the required sample size was based on pre- Cavanaugh, T. Coats, C. Codding, G. Collins, L. Colman, E.
dicted efficacy differences and not on estimates of po- DeNoia, D. Evanko, C. Fisher, Jr, F. Fried, E. Gillie, J.
tential differences in adverse event profile. Thus, addi- Green, R. Halley, D. Herrington, G. Hill, R. Jackson, R.
tional studies might be pursued to further determine Jones, R. Karr, T. Lefton, D. MacPeek, J. Malachowski, A.
whether any advantages exist, for an individual patient, Mangione, D. Mehta, A. Mollen, D. Munoz, T. Murphy, N.
or subgroups of patients, for 1 of the doses employed. Nayak, T. OBarr, D. Orchard, D. Petrone, K. Pryhuber, A.
In conclusion, in this 12-week treatment trial, etori- Puopolo, G. Pyke, W. M. Ryan, L. Schiffman, B. Schwartz,
coxib significantly reduced pain scores, lessened disabil- E. Sheldon, N. L. Smith, R. Swezey, L. Warrick, M. Weitz,
ity, reduced impact of back pain on sense of well being and J. Zuzsga.
ORIGINAL REPORT/ Birbara et al 315

References 19. McCarthy DM: Comparative toxicity of non-steroidal an-


ti-inflammatory drugs. Am J Med 107:37S-46S, 1999
1. Atlas SJ, Deyo RA, Patrick DL, Convery K, Keller RD, Singer
20. Meade EA, Smith WL, DeWitt DL: Differential inhibition
DE: The Quebec task force classification for spinal disorders
of prostaglandin endoperoxidase synthase (cyclooxygenase)
and the severity, treatment, and outcomes of sciatic and
isozymes by aspirin and other nonsteroidal anti-inflamma-
lumbar spinal stenosis. Spine 21:2885-92, 1996
tory drugs. J Biol Chem 268:6610-6614, 1993
2. Bombardier C, Hayden J, Beaton DE: Minimally clinical
21. Mitchel JA, Akarasereenont P, Thiemermann C, Flower
important difference: low back pain: outcome measures.
RJ, Vane JR: Selectivity of nonsteroidal anti-inflammatory
J Rheumatol 28:431-8, 2000
drugs as inhibitors of constitutive and inducible cyclooxy-
3. Borenstein DG: Chronic low back pain. Rheum Dis Clin genase. Proc Natl Acad Sci USA 90:11693-11697, 1994
North Am 22:439-56, 1996 22. Nachemson AL: Newest knowledge of low back pain: a
4. Boyd IW, Mathew TH, Thomas MC: COX-2 inhibitors and critical look. Clin Orthop 279:8-20, 1992
renal failure: the triple whammy revisited. Med J Aust 173: 23. Noble SL, King DS, Olutade JI: Cyclooxygenase-2 enzyme in-
274, 2000 hibitors: place in therapy. Am Fam Physician 61:3669-3676, 2000
5. Brater DC, Harris C, Redfern JS, Gertz B: Renal effects of 24. Philadelphia Panel evidence-based clinical practice
COX-2 selective inhibitors. Am J Nephrol 21:1-15, 2001 guidelines on selected rehabilitation interventions for low
6. Buttgereit F, Burmester GR, Simon LS: Gastrointestinal back pain. Phys Ther 81.1641-1674, 2001.
toxic side effects on nonsteroidal anti-inflammatory drugs 25. Riddle DL, Lee KT, Stratford PW: Use of SF-36 and SF-12
and cyclooxygenase-2-specific inhibitors. Am J Med 19(suppl health status measures: a quantitative comparison for
3A):13S-19S, 2001 110 groups versus individual patients. Med Care 39:867-878,
7. Cannon GW, Breedveld FC: Efficacy of cyclooxygenase- 2001
2-specific inhibitors. Am J Med 19(suppl 3A):6S-12S, 2001 110 26. Riendeau D, Percival MD, Brideau C, Charleson S, Dube
8. Clive DM, Stoff JS: Renal syndromes associated with non- D, Ethier D, Falgueyret JP, Friesen RW, Gordon R, Greig G,
steroidal anti-inflammatory drugs. N Engl J Med 310:563-72, Guay P, Mancini J, Ouellet M, Wong E, Xu L, Boyce S, Visco D,
1984 Girard Y, Prasit P, Zamboni R, Rodger IW, Gresses M, Ford-
Hutchinson AW, Young RN, Chan CC: Etoricoxib (MK-0663):
9. Cochrane DJ, Jarvis B, Keating GM: Etoricoxib. Drugs 62: preclinical profile and comparison with other agents that
2637-51, 2002 selectively inhibit cyclooxygenase-2. J Pharmacol Exp Ther
10. Deyo RA, Battie M, Beurskens AJ, Bombardier C, Croft P, 296:558-566, 2001
Koes B, Malmivaara A, Roland M, Von Korff M, Waldell G: 27. Roland M, Morris R: A study of the natural history of back
Outcome measures for low back pain research: a proposal pain: part 1: development of a reliable and sensitive mea-
for standardized use. Spine 23:2003-2013, 1998 sure of disability in low-back pain. Spine 8:141-144, 1983
11. Deyo RA, Weinstein JN: Low back pain. N Engl J Med 28. Simon LS: Role and regulation of cyclooxygenase-2 dur-
344:363-370, 2001 ing inflammation. Am J Med 106:37S-42S, 1999
12. Dionne CE, Von Korff M, Koepsell TD, Deyo RA, Barlow 29. van Tulder MW, Scholten RJPM, Koes BW, Deyo RA: Non-
WE, Checkoway H: A comparison of pain, functional limita- steroidal anti-inflammatory drugs for low back pain: a sys-
tions, and work status indices as outcome measures in back tematic review within the framework of the Cochrane col-
pain research. Spine 24:2339-2345, 1999 laboration back review group. Spine 25:2501-2513, 2000
13. Gandek B, Ware JE, Aaronson NK, Alonso J, Apolone C, 30. Verburg KM, Maziasz TJ, Weiner E, Loose L, Geis GS,
Bjorner J, Ballinger M, Fukuhara S, Kaasa S, Leplege A, Sul- Isakson PC: Cox-2-specific inhibitors: definition of a new
livan M: Cross-validation of item selection and scoring for therapeutic concept. Am J Ther 8:49-64, 2001
the SF-12 Health Survey in nine countries: results from the
IQOLA Project. International Quality of Life Assessment. 31. Ware JE Jr, Kosinski M, Keller SD: A 12-Item short-form
J Clin Epidemiol 51:1171-1178, 1998 health survey: construction of scales and preliminary tests of
reliability and validity. Med Care 34:220-233, 1996
14. Hawkey CJ: Nonsteroidal anti-inflammatory drug gas-
tropathy. Gastroenterology 119:521-535, 2000 32. Watson DJ, Harper SE, Zhao PJ, Quan H, Bolognese JA,
Simon TJ: Gastrointestinal tolerability of the selective cyclo-
15. Hernandez-Diaz S, Rodriguez LA: Association between oxygenase-2 (Cox-2) inhibitor rofecoxib compared with
nonsteroidal anti-inflammatory drugs and upper gastroin- non-selective Cox-1 and Cox-2 inhibitors in osteoarthritis.
testinal tract bleeding/perforation: an overview of epidemi- Arch Int Med 160:2998-3003, 2000
ologic studies published in the 1990s. Arch Intern Med 160:
2093-2099, 2000 33. Weaver AL: Rofecoxib: clinical pharmacology and clinical
experience. Clin Ther 23:1323-1338, 2001
16. Jenkinson C, Layte R: Development and testing of the UK
34. Winkelstein BA, Weinstein JN, DeLeo JA: The role of me-
SF-12 (short form health survey). J Health Serv Res Policy
chanical deformation in lumbar radiculopathy: an in vivo
2:14-18, 1997
model. Spine 27:27-33, 2002
17. Koes BW, Scholten RJPM, Mens JMA, Bouter LM: Efficacy
35. Wipf JE, Deyo RA: Low back pain. Med Clin North Am
of non-steroidal anti-inflammatory drugs for low back pain:
79:231-246, 1995
a systematic review of randomized clinical trials. Ann Rheum
Dis 56:214-223, 1997 36. Wolfe MM, Lichtenstein DR, Singh G: Gastrointestinal
tolerability of nonsteroidal anti-inflammatory drugs. N Engl
18. Matsumoto AK, Melian A, Mandel DR, McIlwain HH, Bo-
J Med 340:1888-1899, 1999
renstein D, Zhao PL, Lines CR, Gertz BJ, Curtis S: A random-
ized, controlled, clinical trial of etoricoxib in the treatment 37. Zigmond A, Snaith RP: The hospital anxiety and depres-
of rheumatoid arthritis. J Rheumatol 29:1623-1630, 2002 sion scale. Acta Psychiatr Scand 67:361-370, 1983