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Cyclobenzaprine and Back Pain
A Meta-analysis
Robert Browning, MD;
Jeffrey L. Jackson, MD, MPH;
Patrick G. O'Malley, MD, MPH
Arch Intern Med. 2001;161:1613-1620.
ABSTRACT
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Background Back pain is a common problem for which cyclobenzaprine hydrochloride
is frequently prescribed.
Objective To perform a systematic review of cyclobenzaprine's effectiveness in
the treatment of back pain.
Methods We searched MEDLINE, PsycLIT, CINAHL, EMBASE, AIDSLINE, HEALTHSTAR,
CANCERLIT, the Cochrane Library, Micromedex, Federal Research in Progress,
and the references of reviewed articles, and contacted Merck, Sharpe and Dohme
for English-language, randomized, placebo-controlled trials of cyclobenzaprine
in adults with back pain. Outcomes included global improvement and 5 specific
domains of back pain (local pain, muscle spasm, range of motion, tenderness
to palpation, and activities of daily living). Study quality was assessed
using the methods of Jadad. Summary outcomes were obtained using a random-effects
model.
Results Patients treated with cyclobenzaprine were nearly 5 times (odds ratio,
4.7; 95% confidence interval, 2.7-8.1) as likely to report symptom improvement
by day 14 as were those treated with placebo. Slightly fewer than 3 individuals
(2.7; 95% confidence interval, 2.0-4.2) needed treatment for 1 to improve.
The magnitude of this improvement was modest, with an effect size of 0.38
to 0.58 in all 5 outcomes (local pain, muscle spasm, tenderness to palpation,
range of motion, and activities of daily living). Treatment efficacy for these
5 outcomes was greatest early, in the first few days of treatment, declining
after the first week. Patients receiving cyclobenzaprine also experienced
more adverse effects, the most common being drowsiness.
Conclusions Cyclobenzaprine is more effective than placebo in the management of
back pain; the effect is modest and comes at the price of greater adverse
effects. The effect is greatest in the first 4 days of treatment, suggesting
that shorter courses may be better. Studies comparing the relative value of
acetaminophen, nonsteroidal anti-inflammatory drugs, and cyclobenzaprine individually
and in combination in the treatment of back pain are needed.
INTRODUCTION
BACK AND NECK pain are common, accounting for 1.8% of all office visits
in the United States, approximately 200 000 visits per year.1 Among adults presenting with a physical complaint,
these problems are second only to upper respiratory tract infections as a
reason for seeking medical care.2-4
Since only about a fourth of patients with a physical symptom seek medical
attention,5 back and neck pain are even more
prevalent in the general population. It is estimated that up to half of working
adults experience back pain each year,6 and
70% of all adults experience it at some time in their life.7
Most episodes are self-limited, with 90% of patients recovering to full activity
within 1 month.8 Even among the 2% with sciatica,
more than half improve substantially within 6 weeks and only 5% to 10% eventually
require surgery.6
Guidelines for treating back pain recommend empirical therapy, with
no radiologic evaluation in most patients.7-10
The Agency for Health Care Policy and Research (AHCPR) back pain guidelines,11 released in 1994, suggest that acetaminophen is the
safest and most effective medication for acute low back problems and that
nonsteroidal anti-inflammatory drugs (NSAIDs), although effective, should
be used sparingly since they can cause gastrointestinal irritation, ulceration,
and, less commonly, renal or allergic problems. The panel recommended that
muscle relaxants not be used, because they were believed to be no more effective
than NSAIDs; their use in combination with acetaminophen or NSAIDs had no
additional demonstrated benefit; and adverse effects, including drowsiness,
are common.
Despite these guidelines, cyclobenzaprine hydrochloride is still commonly
used in the management of acute back pain. National Ambulatory Medical Care
Survey data from 1995 to 1997 indicate that among 7 million ambulatory visits
to primary care physicians for back pain, 13% of the patients received cyclobenzaprine.12 Because cyclobenzaprine is frequently used for the
management of back pain, we conducted a meta-analysis of the English-language
literature to assess the efficacy of this treatment option.
MATERIALS AND METHODS
For this review, we searched MEDLINE (January 1966-December 1999), PsycLIT
(November 1887-December 1999), CINAHL (1982-1999), EMBASE (January 1974 December
1999), AIDSLINE, HEALTHSTAR, CANCERLIT, and Micromedex using the text word
and keyword (all languages) cyclobenzaprine. An additional
search using the Medical Subject Heading terms dibenzocycloheptenes and propylamines was combined with the following
text words: back pain, backache, low back pain, lumbago, acute muscle spasm, or muscle spasm. We used the Cochrane Library, searching the clinical
trials registry for randomized trials, and the Cochrane Database of Systematic
Reviews for systematic reviews. We searched Federal Research in Progress to
identify unpublished literature. We searched the references of reviewed articles
for additional articles missed by the computerized database search. We also
contacted Merck, Sharpe and Dohme, West Point, Pa.
Studies were screened for inclusion (through review of the abstract
or the published article, if the abstract was unclear) based on the following
criteria: randomization, placebo control, at least one group receiving cyclobenzaprine,
and measurable outcomes reported. Studies evaluating cyclobenzaprine in the
treatment of muscle spasticity of central nervous system origin were excluded
from this meta-analysis. Authors of abstracts that appeared promising were
contacted and asked to provide data.
Included study quality was assessed using a 6-item instrument developed
and validated by Jadad et al.13 The 6 items
in this scale include description of randomization, adequacy of blinding,
description of withdrawals and dropouts, appropriateness of statistical analysis,
description of inclusion and exclusion criteria, and method for assessing
adverse treatment effects. The study quality was assessed independently in
duplicate, with substantial interrater agreement ( , 0.79). Disagreements
were arbitrated by consensus.
Abstracted data included setting, country of origin, treatment characteristics
(dose, duration, and follow-up), demo graphics, number of participants enrolled,
follow-up losses, adverse effects, and outcomes. Outcomes were extracted as
either dichotomous or continuous variables (or both), depending on how they
were reported in the studies.
All analyses were done using Stata 6.0 (Stata Corp, College Station,
Tex). Assessment for publication bias was done using the methods of Egger
et al14; heterogeneity was assessed visually
with Galbraith plots15 and Q ( 2)
statistics using the methods of Mantel-Haenszel.16
Although most pooled results were homogeneous, the more conservative random-effects
model using the method of DerSimonian and Laird16
was used to calculate summary odds ratios (ORs), risk differences, and standardized
mean differences. Analysis of the continuous outcome involved comparing standardized
differences in means between control and treatment groups. Mean outcome scores
for the 5 continuous outcomes (local pain, muscle spasm, tenderness to palpation,
range of motion, and activities of daily living) were standardized by dividing
the means for the placebo and treatment groups in each study by their SD.
The differences between these standardized outcome scores, also known as effect sizes, were calculated for each study and analyzed.
This approach is especially appropriate when studies measure the same concept
but use various continuous scales. By standardization, the study results are
transformed to a common scale (SD units) that facilitates pooling.
Several measures of the sensitivity of the meta-analysis results to
various assumptions were conducted. The sensitivity of the results to the
existence of unpublished studies was assessed using a "file drawer" test,17 conducted by determining how many studies with negative
results (OR, 1.0; standardized mean difference, 0), each with variance and
size equal to the average found among the included studies, would have to
exist to negate our findings. A test for the relative influence of each individual
study on the results was determined by sequentially dropping individual studies
and calculating summary measures. We explored several sources of heterogeneity,
including year of publication, type of syndrome (acute vs chronic back pain),
study quality scores, and duration and dose of therapy using metaregression.
RESULTS
Our literature search produced 315 articles, 2018-37
of which appeared to be potential candidates for inclusion in the analysis.
Of these 20, 7 were excluded because 119 was
non-English, 228-29 were observational
studies, 120 had no independent cyclobenzaprine
arm, and 323, 26-27
had no placebo arm, leaving 1318, 21-22,24-25,30-37
that met the inclusion criteria. One of these18
was an abstract for which the authors provided additional information and
data. Another article36 included results from
2 independent trials, producing a final total of 14 studies (Table 1).
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Table 1. Characteristics of the Included Studies*
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These 14 randomized controlled trials were of moderate quality, with
a mean quality score of 4.3 (95% confidence interval [CI], 3.3-5.3; median,
4.0; range, 1-8). While all studies were randomized and placebo controlled,
there were several specific quality problems (Table 1), including inadequate description of the randomization
method in 9,18, 21-22,25, 30-32,35, 37
failure to describe the placebo as identical to the active medicine in 10,18, 21-22,25, 30-33,35, 37
no description of or excessive withdrawals in 3,18, 32, 37
no intention-to-treat analysis in 11,21-22,24-25,30, 32-36
inadequate description of the selection or exclusion criteria in 2,30-31 and no sample size calculations in
all.18, 21-22,24-25,30-37
None of the studies directly tested patients for the effectiveness of blinding,
but all but 3 of the studies21, 34, 37
had significantly greater adverse effects in the treatment than the placebo
group, suggesting failure to maintain blinding. One of the studies31 had an inadequate discussion of adverse medication
effects. Many studies18, 21, 24, 30, 33-37
either were sponsored by or received editorial support from pharmaceutical
companies.
Although some of the trials had treatment arms with other drugs, including
diazepam,30-32,35-36
diflunisal (Dolobid),21 and methocarbamol,22 only cyclobenzaprine and placebo data from each trial
were abstracted. Cyclobenzaprine was given in 10-mg tablets, except in 2 studies,18, 21 in which 5-mg tablets were used.
The daily dose ranged from 10 to 60 mg, titrated based on the adverse effects,
with a median dose of 30 mg/d. One study21
used a twice-daily dose of cyclobenzaprine, and the remainder of the studies18, 22, 24-25,30-37
used 3 times daily doses. The study duration averaged 12.3 days, ranging from
7 to 18 days (median, 14 days).
All 14 studies18, 21-22,24-25,30-37
focused on low back pain in association with muscle spasm, although 533-37
also included data on cervical or neck pain and muscle spasm. Eleven studies18, 21-22,24-25,30, 33-36
included only acute back pain, with 331-32,37
evaluating chronic low back pain. Exclusion criteria were consistent between
the studies: all excluded persons with spasticity or rigidity due to central
nervous system pathological features, those with worker's compensation, and
those involved in litigation. Patients with glaucoma; urinary retention; urinary
tract infection; cardiac, pulmonary, hepatic, hematological, or renal diseases;
rheumatoid arthritis; irreversible ankylosis; irreversible contractures; and
mental disorders were also excluded. Excluded drugs included tranquilizers,
antidepressants, corticosteroids other than oral contraceptives, muscle relaxants,
and analgesics. One study37 focused on muscle
spasm and pain associated with lumbar and cervical osteoarthritis.
All 14 studies18, 21-22,24-25,30-37
had extractable data. Thirteen articles18, 21, 24-25,30-37
reported a global measure of symptom improvement. While articles reported
this outcome at various time points, only global improvement at the end of
the trials was present in a sufficient number of studies to be considered
reliable enough for this analysis. Nine24-25,30-31,33-37
of these ratings of improvement were physician rated, and 118
was patient rated.
Among the 10 studies18, 24-25,30-31,33-37
reporting global improvement in back pain at the end of the trial, the summary
OR for improvement by day 10 was 4.7 (Figure
1). There was evidence of heterogeneity between the different studies
(29 = 25.90; P = .002)
but no evidence of publication bias (Egger P = .37).
The pooled risk difference for these studies was 0.37 (95% CI, 0.24-0.50),
which calculates to 2.7 (95% CI, 2.0-4.2) individuals needing treatment for
1 to experience symptom improvement.
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Figure 1. Likelihood of experiencing overall
improvement in back pain by the end of the study among patients treated with
cyclobenzaprine hydrochloride compared with placebo. Squares represent the
sample size; horizontal lines, the respective 95% confidence intervals of
the odd ratios.
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In addition to a global rating of improvement, data were abstracted
for 5 continuous variables: local pain, muscle spasm, tenderness to palpation,
range of motion, and activities of daily living. These data were abstracted
at 3 points (days 1-4, 5-9, and >9) and were largely patient rated. The results
of analysis of each of these 5 continuous variables at each of the 3 points
are given in Table 2 and presented
graphically in Figure 2. At all
3 points, patients treated with cyclobenzaprine had significantly greater
improvement in all 5 variables reported. For 4 of the variables (muscle spasm,
tenderness to palpation, range of motion, and activities of daily living),
there was a greater difference between the placebo and cyclobenzaprine groups
in the first 3 days of treatment than at either 1 or 2 weeks. In the first
few days of treatment, patients had an average effect size of 0.52 (modest),
an effect that declined to 0.44 through the end of the trials. To put this
into context, an effect size of 0.2 is considered small; 0.5, moderate; and
0.8, large.38 While the differences at the
3 points were not significant, there was statistical evidence of a trend toward
decreasing effectiveness over time (P = .04). There
was no evidence of statistical heterogeneity for any of the continuous points
abstracted.
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Table 2. Standardized Mean Differences Between Treatment With Placebo
and Cyclobenzaprine*
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Figure 2. Standardized mean differences
in patient response to cyclobenzaprine hydrochloride compared with placebo
on 5 different domains of back pain. Squares represent the sample size; horizontal
lines, the respective 95% confidence intervals of the effect size.
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For the global improvement outcome and for the first few days among
4 of the continuous outcomes (local pain, muscle spasm, tenderness to palpation,
and range of motion), there was statistical evidence for publication bias
(Table 2). Because of this possibility,
we conducted a file drawer test to see how many unpublished studies with negative
findings would have to be filed away somewhere to negate our findings. We
found that there would have to be 947 studies finding no global improvement
with the use of cyclobenzaprine and between 201 and 786 studies (Table 2) finding no benefit in our 5 specific
back pain measures to negate our results.
A sensitivity analysis was also performed to assess the effects of study
quality, year of publication, duration of treatment, type of back pain, and
whether Merck, Sharpe and Dohme sponsored the study. There was no effect of
any of these on our data. We also explored the effect of dropping individual
studies from our meta-analysis, also without significant effect on our summary
OR.
Patients treated with cyclobenzaprine were significantly more likely
to experience adverse effects (Table 3).
Fifty-three percent of the patients receiving cyclobenzaprine experienced
at least one adverse effect, compared with 28% receiving placebo. The most
common adverse effects included drowsiness, dry mouth, and dizziness.
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Table 3. Comparison of Adverse Effects Between Cyclobenzaprine and
Placebo*
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COMMENT
Our meta-analysis suggests that cyclobenzaprine may be useful in the
management of back pain. Patients given cyclobenzaprine were nearly 5 times
more likely to improve, and only 3 patients needed to be treated for 1 to
improve. In the 5 domains of back pain and disability (local pain, muscle
spasm, tenderness to palpation, range of motion, and activities of daily living),
the magnitude of improvement was modest, with an average effect size of 0.5.
There was evidence of a trend toward decreasing efficacy over time, with the
greatest effect in the first few days of treatment. This improvement was accompanied
by adverse effects: more than half of the patients experienced at least one,
with drowsiness being the most common.
The AHCPR clinical practice guidelines,11
released in 1994, recommend acetaminophen as the first choice for treating
back pain. Nonsteroidal anti-inflammatory drugs, while deemed effective, were
considered less optimal secondary to adverse effects. The AHCPR further recommended
that muscle relaxants not be used. The AHCPR's qualitative review was based
on 0 studies specifically examining acetaminophen and back pain, on 4 randomized
controlled trials of NSAIDs, and on 12 randomized controlled trials evaluating
muscle relaxants, although only 2 evaluated cyclobenzaprine. Our search found
14 randomized placebo-controlled trials of cyclobenzaprine, most (11 of the
14) not indexed in MEDLINE, the search engine the AHCPR panel used.11
Another systematic review39 that looked
at muscle relaxants as a class included studies of tizanidine hydrochloride,
dantrolene sodium, carisoprodol, methocarbamol, baclofen, orphenadrine citrate,
chlormezanone, diazepam, and tetrazepam, although only one study evaluated
cyclobenzaprine. Among these 14 trials, 11 found benefit and 3 did not, although
only 8 were placebo controlled. The review concluded that there was strong
evidence for the benefit of muscle relaxants and that the different types
of muscle relaxants were equally effective in treating acute back pain.
There are several other common treatment modalities for acute low back
pain. While they are the most commonly used medicine in low back pain, evidence
for the effectiveness of NSAIDs is modest. The AHCPR low back pain NSAID recommendations11 are based on 4 randomized placebo-controlled trials40-43 that
looked at diclofenac, piroxicam, naproxen sodium, and diflunisal. Two of these
studies41, 43 were placebo controlled,
and 142 compared diflunisal alone with diflunisal
in combination with cyclobenzaprine and placebo. The fourth study40 compared diclofenac to manipulation, physical therapy,
bed rest, back school, and placebo (topical gel). The results were mixed:
one43 found NSAIDs superior to placebo at all
time points, another41 found benefit only at
day 3 of treatment, and another42 found that
the combination of an NSAID and cyclobenzaprine helped only at day 4. A recent
systematic review39 of back pain treatment
retrieved 19 randomized controlled trials evaluating NSAIDs. Eleven studies
of acute back pain found no benefit, 7 found benefit, and 1 was unclear. The
researchers concluded that while NSAIDs were better than placebo, they might
not be better than other analgesic agents.
The AHCPR panel also concluded that the evidence could not support a
recommendation for using muscle relaxants in combination with NSAIDs vs using
NSAIDs or acetaminophen alone. This is based on one 4-armed study21 (n = 175) that compared diflunisal, cyclobenzaprine,
diflunisal combined with cyclobenzaprine, and placebo, finding that the combination
of diflunisal and cyclobenzaprine was better at only one point, day 4, compared
with either drug alone or placebo. Another small (n = 40) non–placebo-controlled
study20 evaluating the combination of naproxen
and cyclobenzaprine vs naproxen alone found the combination to be better than
either alone for the relief of muscle spasm and tenderness, with a greater
range of motion of the lower back (P<.05). Although
the available evidence for the use of a combination of muscle relaxants and
NSAIDs in the treatment of back pain is limited, it implies a positive role
for the combination.
The use of tricyclic antidepressants, which are chemically comparable
to cyclobenzaprine, in the management of back pain has been studied, with
mixed results. Some studies44-46
found benefit, particularly among patients with comorbid depression,47-48 and others49-51
found no benefit. A recent meta-analysis52
suggested no benefit for the use of tricyclic antidepressants in patients
with back pain, although the included studies focused on chronic back pain.
Since low back pain has been associated with a higher prevalence of mental
disorders and cyclobenzaprine is chemically similar to tricyclic antidepressants,
it is possible that the effect found may be a result of treating depression.
While most of our studies excluded mental disorders, no study used validated
instruments to screen or control for depressive symptoms in its analysis.
However, the low doses of cyclobenzaprine used, and the rapidity of improvement
in symptoms, argue against a treatment effect mediated by resolution of depressive
symptoms.
Other treatment modalities, including acupuncture and chiropractic care,
have also been reviewed. A Cochrane Collaboration meta-analysis53
of acupuncture, based on a review of 11 low-quality randomized controlled
trials, concluded that there was no evidence that acupuncture was more effective
than no treatment, trigger-point injection, or transcutaneous electrical nerve
stimulation. Similarly, a systematic review54
of the use of chiropractic care, based on 8 low-quality randomized controlled
trials, found no convincing evidence of superiority to placebo treatment.
While our results suggest a modest benefit from the use of cyclobenzaprine,
there are several important limitations to these findings. First, 10 of the
14 trials had evidence that blinding may not have been effective; patients
receiving cyclobenzaprine had more adverse effects than those treated with
placebo. The most common adverse effects were sedation, dry mouth, fatigue,
and dizziness (Table 3). Inadequate
blinding has been believed to be responsible for bias in previous trials suggesting
benefit from ascorbic acid55 and zinc56 for the common cold. Our results may be particularly
prone to this bias, since most outcomes are based on physician rather than
patient reports of symptom improvement. One of our studies18
that used patient ratings had results consistent with those based on physician
ratings. Another study30 explored the potential
biasing effect of higher rates of adverse effects by stratifying patient results
by the presence or absence of adverse effects. This study30
found the rate of improvement between both groups to be equal, and concluded
that the potential unmasking of treatment group by adverse effects had no
impact on patient outcomes.
A second problem was heterogeneity of our dichotomous outcome, global
improvement. We explored for the possible sources of this heterogeneity among
the trials. Three studies31-32,37
explored chronic rather than acute back pain, another37
focused on osteoarthritis, and study quality varied widely among trials. Drug
companies also sponsored some studies. None of these factors explained the
heterogeneity in our data. While 234, 36
of the trials had significantly greater treatment effects than the remaining
ones, deleting any single trial had no significant effect on the summary OR,
and even when both were simultaneously dropped, there was still evidence for
benefit (OR, 2.9; 95% CI, 2.3-3.7). There was no evidence of heterogeneity
among any of our continuous outcomes, perhaps because of the remarkable consistency
among the trials in reporting on all 5 outcomes (local pain, muscle spasm,
tenderness to palpation, range of motion, and activities of daily living)
and in using similar scales.
Another problem in our analysis was the presence of publication bias
among some of our 5 continuous outcomes. Publication bias looks for evidence
that small trials with negative findings may be missing from the analysis,
that they have been "filed away" rather than published. Publication bias posits
that trials showing effectiveness would probably be published, as would large
trials with negative findings. The concern is that there may be small trials
that may not be published if they have negative findings, since they would
meet considerable editorial obstacles on the issue of being "underpowered."
To see what effect such studies could have on our meta-analysis, a file drawer
test was conducted. This asks the following question: how many studies with
negative findings would there have to be, filed away somewhere, for the meta-analysis
to reach a wrong conclusion? In this analysis, the results are comfortably
large. It seems unlikely that several hundred trials with negative findings
could exist, filed away somewhere. We searched exhaustively for unpublished
studies, including searching the National Institutes of Health's database
of funded research and asking pharmaceutical companies. The many studies with
negative results needed to negate our findings is not evidence that cyclobenzaprine
is effective. This determination should be based on the quality of the underlying
trials and on the quality of the meta-analysis. In this case, we found a 5-fold
increase in the likelihood of reporting at least modest improvement in symptoms.
A large file drawer test result is reassuring that the analysis is not likely
to be wrong because of missing small unpublished trials, but is not itself
evidence of treatment efficacy.
A fourth problem is that it is impossible to say what the optimum duration
of treatment is. In the first 4 days of treatment, patients experienced moderate
degrees of improvement. After day 4, the degree of improvement declined from
moderate (>0.5 effect size) to small (>0.2 effect size).38
There was evidence of a trend toward declining effectiveness over time. While
this suggests that the optimum duration of treatment may be short, on the
order of a few days, it is unclear what the optimum treatment duration is,
since even at 14 days there was evidence of improvement with treatment.
A final limitation is that, in the real world, clinicians are not limited
to just 1 treatment option. National Ambulatory Medical Care Survey data suggest
that patients presenting with low back pain are commonly given more than 1
treatment.12 Often, acetaminophen is combined
with an NSAID or a muscle relaxant. Less commonly, patients are given a narcotic
for the first few days of pain. To our knowledge, no studies have been done
to determine the optimum combination of treatment modalities. Since many of
these treatments may be operating on different aspects of back pain, there
may be an additive effect. On the other hand, overmedication is a common problem
among patients, and more may not be better. Studies to look at back pain management
with a combination of common therapies are needed. Some clinicians, well versed
with the sedative effects of cyclobenzaprine, prescribe it for the short term
as a nighttime medicine. The trials in our analysis all used a 2 or 3 times
daily dose. Whether similar benefits will accrue with a single nighttime dose
is uncertain.
We conclude that cyclobenzaprine is significantly better at relieving
back pain than placebo at all times measured. Patients can expect about a
5-fold increase in the odds of experiencing improvement by 14 days and up
to 2 SDs of improvement, a moderate effect size. Clinicians will need to treat
3 patients to improve the symptoms of 1. Adverse effects will be common, experienced
in more than half of the patients, with 20% experiencing drowsiness. The treatment
effect is greatest early, suggesting that a short course may be preferable,
although even at 2 weeks patients given cyclobenzaprine had slightly better
results on all 5 domains of back pain. Studies to determine the optimum combination
and duration of treatment in the management of acute back pain are needed.
AUTHOR INFORMATION
Accepted for publication December 5, 2000.
The opinions or assertions contained herein are the private views of
the authors and are not to be construed as official or as reflecting those
of the Department of the Army or the Department of Defense.
Corresponding author and reprints: Robert Browning, MD, 974 Paulsboro
Dr, Rockville, MD 20850 (e-mail: browning_robert{at}hotmail.com).
From the Departments of Medicine, National Naval Medical Center (Dr
Browning), and Uniformed Services University of the Health Sciences (Drs Jackson
and O'Malley), Bethesda, Md; and the Department of Medicine, Walter Reed Army
Medical Center, Washington, DC (Drs Jackson and O'Malley).
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