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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-
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.
*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?
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