ORIGINAL PAPER

A randomised, double-blinded study comparing giving

etoricoxib vs. placebo to female patients with
fibromyalgia
H. Mahagna,1,2 D. Amital,2,3 H. Amital1,2

SUMMARY

Whats known

Objectives: Current therapeutic approaches to fibromyalgia syndrome (FMS) do

not provide satisfactory pain control to a high percentage of patients. This unmet
need constantly fuels the pursuit for new modalities for pain relief. This randomised, double-blind, controlled study assessed the efficacy and safety of adding
etoricoxib vs. placebo to the current therapeutic regimen of female patients with
FMS. Methods: In this double-blind, placebo-controlled study, female patients
were randomised to receive either 90 mg etoricoxib once daily or placebo for
6 weeks. Several physical and mental parameters were assessed throughout the
study. The primary end-point was the response to treatment, defined as 30%
reduction in the average Brief Pain Inventory score. Secondary outcomes were
changes in the Fibromyalgia Impact Questionnaire, SF-36 Quality of Life assessment questionnaire and Hamilton rating scales for anxiety and depression.
Results: Overall, 73 patients were recruited. Although many outcome measures
improved throughout the study, no difference was recorded between the etoricoxib- and placebo-treated groups. The Brief Pain Inventory, Fibromyalgia Impact
Questionnaire, The Hamilton Anxiety and Depression scores did not differ between
the two groups. Conclusions: This is the first randomised, double-blind study
assessing the effect of adding etoricoxib to pre-existing medications for female
patients with FMS. Although being mildly underpowered this study clearly has
shown that etoricoxib did not improve pain scores and did not lead to any beneficial mental or physical effects.

Introduction
Fibromyalgia syndrome (FMS) is a musculoskeletal
pain disorder with characteristic diffuse tenderness
and concomitant cognitive, sleep and mood impairments. FMS is significantly more common in women,
its prevalence is approximately 2 per cent of the adult
female population and increases with age (1).
Although defined classification criteria for the diagnosis of the FMS have been used for more than three
decades, they do not indicate the pathogenesis of the
disorder, which remains vague (24). It is wellacknowledged that an effective approach to these
patients must be multidisciplinary and individualised,
focusing on patient education and aerobic activity,
and providing psychological and cognitive support
along with concomitant medical therapy (57).
The best studied and currently used medications,
such as antidepressants and gabapentinoids, affect
2016 John Wiley & Sons Ltd
Int J Clin Pract, February 2016, 70, 2, 163170. doi: 10.1111/ijcp.12760

Non-steroidal anti-inflammatory drugs (NSAIDs) and

COX-2-selective agents are often used by patients
with FMS, usually for temporary relief of pain.
Nevertheless, solid data supporting this use are
absent.

Department of Medicine B,
Sheba Medical Center, Tel
Hashomer, Israel
2
Sackler Faculty of Medicine,
Tel Aviv University, Tel Aviv,
Israel
3
Ness Ziona Beer Yaacov
Mental Health Center, BeerYaacov, Israel

Whats new
This is the first randomised, double-blind, controlled
study to assess the effect of etoricoxib on patients
with FMS.
This study shows that etoricoxib did not confer any
beneficial mental or physical effects to female
patients with FMS.

Correspondence to:
Howard Amital, MD MHA,
Head of Department of
Medicine B, Sheba Medical
Center, Tel Hashomer 52621,
Israel
Tel.: + 972 3 530 2652
Fax: + 972 3 535 4796
Email: howard.amital@sheba.
health.gov.il
Disclosures
The authors have no relevant
disclosures nor were there any
issues of conflict that emerged
while conducting this study
First two authors share equal
contribution.

the central nervous system. Agents that increase

synaptic levels of monoaminergic neurotransmitters
play a role in treating the disorder. Tricyclic antidepressants have been shown to be effective; however,
these agents are associated with a relatively high rate
of safety issues (8). Selective serotonin reuptake inhibitors (SSRIs) are generally better-tolerated than tricyclic antidepressants; yet, they appear to have only
minor therapeutic effects (8). The serotonin noradrenaline reuptake inhibitors (SNRIs) duloxetine and
milnacipran are currently approved and used to provide pain control for FMS (912). Recently, the use
of quetiapine fumarate, an antidepressant and atypical antipsychotic agent, with serotonergic, noradrenergic and dopaminergic effects, was shown to
provide beneficial outcomes in patients (13). Pregabalin binds with high affinity to the a2d subunit at
voltage-gated calcium channels. This mediates its
analgesic action, probably via the reduction of

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Adding etoricoxib to FMS therapy

calcium ion influx into hyper-excited neurons, which

leads to the decreased release of neurotransmitters
that play a role in pain processing, such as substance
P and glutamate (14). Several studies have corroborated the efficacy, safety profile, and tolerability of
pregabalin treatment in FMS and similar findings
were recently repeated with a once daily controlledrelease form (1519).
Non-steroidal anti-inflammatory drugs (NSAIDs),
COX-2-selective agents and acetaminophen are used
by many FMS patients, mostly for immediate pain
relief (20). However, studies aimed to confirm such
efficacy are poorly-designed and of low quality
(21,22).
In this study, we challenged the prevailing concept
that only medications affecting the central nervous
system are able to confer relief from diffuse musculoskeletal pain. Our hypothesis was that by conducting a clinical study with the capacity to ensure high
adherence and compliance rates, we would be able to
add an analgesic effect that will attenuate the
chronic, diffuse pain perceived by patients with FMS
and perhaps improve their cognitive and mental
endurance.
The study design was based on adding daily
90 mg etoricoxib, a COX-2 selective inhibitor or placebo, to the ongoing therapeutic regimens of patients
with FMS, for 6 weeks. Pain, overall quality of life,
disability, anxiety and depression were measured
throughout the study.

Patients and methods

This randomised, double-blind, controlled study
compared the addition of 90 mg etoricoxib vs. placebo to the therapeutic regimen of female patients
with FMS. All women met the 1990 American College of Rheumatology classification criteria for
fibromyalgia. Their ages ranged from 18 to 75 years.
All women provided signed informed consent.
The patients were randomised to receive either
90 mg of etoricoxib or placebo daily. Pre-existing
background antidepressants and/or pregabalin were
continued. The duration of the study was 6 weeks.
There were four office visits throughout this period.
Blinding was carried out by MSD-Israel and codes
were opened at the end of the entire study period,
i.e. after the last patient recruited, concluded the 6week study. Both patients and caregivers were
blinded to the study medication.
Women with the following criteria were excluded:
those with confirmed pregnancy or breast feeding,
with active or previous coronary artery disease, congestive heart failure, coexisting neoplastic conditions
(not including basal cell carcinoma), coexisting rheu-

matic conditions, active or previous gastrointestinal

bleeding, renal failure, comorbid conditions causing
significant disability and those with uncontrolled
hypertension. Use of NSAIDS or other coxibs were
not permitted and at least 2 weeks were required
from the last NSAID dose to enrolment. Modifications of concurrent pharmacologic treatment regimen were not permitted during the study.
Monitoring of adherence to the study medication
or placebo was carried out throughout the study by
counting pills taken by each subject at each office
visit. Assessment of adverse effects was conducted by
actively addressing this issue with each patient at
each encounter.
Local ethics committee approval was obtained in
the two centres in Israel where the study was conducted: Meir Medical Center in Kfar Saba and Sheba
Medical Center in Tel Hashomer. The study was registered at the clinical studies site and granted the following code NCT00755521.
All patients completed the following rheumatic
and psychiatric scales:
Brief pain inventory (BPI) Pain severity as measured by the self-reported BPI (short form) average
pain severity score (23), which assesses average pain
severity during the past 24 h (010 scale, where
0 = no pain and 10 = pain as bad as one can imagine). The primary end-point was the response to
treatment defined as 30% reduction in the BPI
average pain severity score. Decreases of 10%, 20%
and 50% were recorded as secondary end-points.
SF-36 Quality of life assessment A translated and
validated Hebrew version of the SF-36 scale was used
to measure quality of life. The SF-36 contains eight
subscales: physical functioning (PF), social functioning (SF), role limitations attributable to physical and
emotional problems, mental health, vitality, bodily
pain and general health. Each scale was scored from
0 to 100, with a high score indicating better health
and less bodily pain (24).
Fibromyalgia impact questionnaire (FIQ) This
scale commonly performed on patients with FMS is
regarded to be reliable and valid. The FIQ is less
affected than other scores by temporary alterations
and fluctuations of disease severity (25).
Hamilton Anxiety Rating Scale (HAM-A) and
Hamilton Rating Scale for Depression (HRSD). These
two scales are widely used to gauge the severity of
anxiety and depression (26,27). The HAM-A consists
of 14 items designed to assess the severity of a
patients anxiety. Each of the 14 items contains a
number of symptoms, and each group of symptoms
is rated on a scale of 04, with 4 being the most severe (26). The HRSD is a 17-item scale that measures
the presence and severity of depression. The HRSD
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Adding etoricoxib to FMS therapy

is a reliable gauge of the degree of symptom severity

in depressed patients (27).

Statistical analysis
The number of patients enrolled in the study was
determined on the following assumptions; an initial
expected average BPI value of about 6.5 with the
change showing a normal distribution in both groups
with a standard deviation of 1.3 in both groups. In
the etoricoxib-treated group it was expected that
average change would be 30% of baseline, whereas in
the placebo group the average expected change
would be 15% of baseline. Defining success as a
decrease of 30% from baseline BPI, and using the
normal distribution, the expected success rates in the
two groups would be 50% and 23%, respectively.
Sample sizes of 41 or 39 in each group would provide a power of 0.75 or 0.7, respectively with for significance level 0.05. Given the feasibility of the study
as a single-centre study, 40 patients could be
recruited to each arm.
The two groups were compared for patient demographic characteristics using the MannWhitney test for
ordinal or interval level variables and the chi-squared
test or the Fishers exact test for categorical variables, as
dictated by sample size and number of categories.
For continuous variables, significance between and
within arms over the study was established by a
repeated-measures ANOVA, using baseline measurement as a covariate. Contrast t-tests were used for pairwise comparisons between arms at specific time points.
The treatment allocation of individual patients
remained blinded throughout the entire study. The
analysis regarding missing data of patients who
dropped out was based on the principle of the last
observation carried forward.

Results
Patients
Overall, 73 patients were recruited and 59 completed
the study. Drop-outs were because of the withdrawal
of consent or adverse events. As mentioned, the analysis was based on last observation carried forward, so
most of the tables contain data concerning 64 patients.
No serious adverse events were recorded during the
study. Figure 1 presents the disposition of patients.
The compliance rate was very high (> 95%)
because of the continuous and direct contact
between the study coordinator and the patients.
As shown in Figure 1, six patients withdrew consent at different phases of the study and six in the
placebo group. Three patients in the study dropped
out because of adverse events, one each because of
parasthesia, urinary tract infection or weakness.
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Int J Clin Pract, February 2016, 70, 2, 163170

Table 1 shows the demographic parameters of the

two study groups. No significant differences were
demonstrated between the two groups except for the
number of children.

Brief pain inventory (BPI)

The BPI was used to measure patients subjective
pain severity. Table 2 presents the primary endpoint, the reduction of 30% in the BPI average
pain severity score. Decreases of 10%, 20% and 50%
were recorded as secondary end-points. None of
these parameters decreased differently between
patients treated with etoricoxib or placebo.
We found no major differences in BPI scores
between the two groups throughout the study. While
the initial pain severity score of the etoricoxib-treated group was 6.4  1.7 vs. 6.4  1.8 in the placebo,
after 6 weeks of therapy the pain severity score
decreased to 5.9  2.3 and 5.6  2.7, respectively
(P = 0.6 between the groups). A similar finding was
observed regarding the BPI pain interference scores,
initially 6.7  1.9 in the etoricoxib-treated group vs.
6.6  1.7 in the placebo-treated group. After
6 weeks, the results were 5.9  2.5 versus 5.4  3.1,
respectively (p = 0.5 between the groups). A significant general improvement over time was demonstrated in both groups (P < 0.5).

Fibromyalgia impact questionnaire (FIQ)

Both groups FIQ improved during the 6 weeks of
the study; however, no significant changes were
noted between groups throughout the study. The initial scores were 63.0  12.1 and 65.4  9.7 in the
etoricoxib and placebo-treated groups, respectively,
which declined to 56.5  19.1 and 56.5  17.7 after
6 weeks (P = 0.6).

SF-36 quality of life assessment and disability

The two groups did not differ in physical and mental
dimensions of quality of life as demonstrated by the
SF-36 questionnaire (Table 3). Interestingly, both
groups showed a significant improvement in both
scores throughout the study.
The disability scores as measured by the Sheehan
disability scale did not differ between the two groups
at any time point. In contrast to other parameters,
no improvement was recorded in this measure
throughout the study (data not presented).

Depression and anxiety assessment

The study medication had no effect on the depression or anxiety status based on the Hamilton scores
for depression and anxiety (Table 3). One can
observe constant and significant improvement over
time as reflected by these parameters regardless of

165

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Adding etoricoxib to FMS therapy

Enrollment

Assessed for eligibility (n = 73)

Excluded (n = 9)
Not meeting inclusion criteria (n = 0)
Declined to participate (n = 6)
Other reasons (n = 3)

Randomized (n = 64)

Etoricoxib

Placebo

Allocation
Allocated to intervention (n = 32)
Received allocated intervention (n = 32)

Allocated to intervention (n = 32)

Received allocated intervention (n = 32)

Did not receive allocated intervention

(withdrawal of consent) (n = 0)

Did not receive allocated intervention (give

reasons) (n = 0)

Follow-Up
Lost to follow-up (give reasons) (n = 0)

Lost to follow-up (give reasons) (n = 0)

Discontinued intervention (n = 3) (adverse

events = 2, withdrawal of consent n = 1)

Discontinued intervention (n = 2) (withdrawal of

consent = 0, adverse events = 0)

Analysis

Analysed (n = 32)
Excluded from analysis (give reasons) (n = 0)

Analysed (n = 32)
Excluded from analysis (give reasons) (n = 0)

Last observation carried forward

Last observation carried forward

Figure 1 Patient disposition

whether the patents were treated with etoricoxib or

placebo.

Adverse events
No serious adverse events were recorded. Similar
rates adverse events were reported in the two groups;
all were nonspecific and seemed to be unrelated to
the medication, but rather to the fibromyalgia
(Table 4).

Discussion
The FMS construct raises much controversy, lack of
acceptance and sometimes even reluctance to
acknowledge its mere existence, which extends to the
patients who suffer from it (28). It is challenging to

successfully treat such patients and experienced medical care providers need to address the patients mental and physical distress and complexity.
Over the last few decades, much emphasis has
been directed towards the central pain perception of
chronic pain syndromes such as FMS. Accordingly,
major therapeutic studies have primarily focused on
agents that affect central nervous system networking
and perception.
Clinicians have become increasingly acquainted
with the term central sensitisation and its presentation as diffuse pain along with other centrally associated symptoms such as fatigue, sleep disturbances,
memory impairment and depression. Therefore, it is
not surprising that traditional pain therapies have
not been given proper attention and research.
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Adding etoricoxib to FMS therapy

Table 1 Demographic parameters of the etoricoxib and placebo-treated groups

Etoricoxib (n = 32)
Parameter

Category

(Mean  SD)

(Mean  SD)

Single
Married
Divorced
Widow
All
1
2
3
4
5
8
All
Israel
Other
All
Elementary
Secondary
Higher
Academic
All
Employed
Unemployed
Retired
All
High
Medium
Low
Very low
All
Antidepressants
Antiepileptics
Opiates
All

31
29
n
5
20
4
1
30
0
5
11
5
1
1
23
20
7
27
2
8
5
11
26
16
5
7
28
3
13
5
4
25
15
1
1
32

49.8  13.2
3.52  6.2
(%)
16.7
66.7
13.3
3.3
100
0
21.7
47.8
21.7
4.3
4.3
100
74.1
25.9
100
7.7
30.8
19.2
42.3
100
57.1
17.9
25
100
12
52
20
16
100
46
3
3
52%

32
25
n
4
19
3

26
3
11
5
2
2
0
23
17
6
23
1
9
4
12
26
17
8
2
27
7
13
3
1
24
14
2
0
32

51.0  9.7
5.16  6.6
(%)
15.4
73.1
11.5

100
13.0
47.8
21.7
8.7
8.7
0
100
73.9
26.1
100
3.8
34.6
15.4
46.1
100
63.0
29.6
7.4
100
29.2
54.2
12.5
4.2
100
44
6
0
50%

Age, years*
Years since diagnosis
Marital status, n (%)

Number of children, n (%)

Origin, n (%)

Schooling, n (%)

Occupational status, n (%)

Income status

Current pharmacologic treatment, n (%)

Placebo (n = 32)

Significance
between
arms (p-value)

0.78
0.13*
0.80

0.021*

0.72

0.81*

0.18

0.057*

0.8

*MannWhitney test. Fishers exact test. chi-square test.

NSAIDs are the most commonly used medications

for treating pain, primarily due their availability in
both prescription and over-the-counter preparations.
Despite the absence of solid evidence, these medications are often used by patients with FMS and are
commonly prescribed by physicians in addition to
antidepressants and anticonvulsants. Many patients
use NSAIDs on a daily basis rendering them vulnerable to their side effects.
The prevailing concept of the scientific community is that NSAIDs are ineffective for treating FMS,
although solid evidence supporting this position is
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lacking. On the other hand, studies underscoring

the efficacy of SNRIs and gabapentinoids present
modest, short-term clinical effects, which in daily
life are translated to low adherence rates and to
premature cessation of drug intake (2932). Therefore, additional therapeutic approaches to FMS
should be revisited; surely, commonly used analgesic
therapy should be properly evaluated to determine
whether they provide any added value to current
regimens.
Only two randomised trials that were carried out
nearly three decades ago evaluated that effect of

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Adding etoricoxib to FMS therapy

Table 2 Brief Pain Inventory (BPI) response rates

following 6 weeks of treatment (number and percentage

of subjects with a decrease of BPI Pain Severity score)
Decrease
in BPI
score

Etoricoxib
(n = 32)

Placebo
(n = 32)

Significance
between
arms (p-value)

>
>
>
>

9
14
13
4

9
14
12
6

0.93
0.91
0.71
0.73

30%
10%
20%
50%

(28.1%)
(44%)
(41%)
(12.5%)

(28.1%)
(44%)
(37.5%)
(18.75%)

Done with chi-squared test.

NSAIDS on patients with FMS. Goldenberg et al.

(21) conducted a study to underline the effect of
amitriptyline on FMS. In that double-blind study, 62
patients were enrolled and received either 25 mg of
amitriptyline at night, 500 mg of naproxen twice
daily, both medications or a placebo. Amitriptyline
was significantly beneficial in all the scores measuring
pain, sleep and fatigue, and in patient and physician

global assessments. No efficacy of naproxen when

used alone in any outcome parameter was shown.
Aiming to determine whether the two drugs were
better than either alone, the results indicated a
minor, non-significant synergistic effect of improved
pain in the combination therapy compared with
those who were treated with amitriptyline alone.
Le Gallez et al. (22) investigated whether ibuprofen potentiated the analgesic effect of meptazinol (an
opiod analgesic). They carried out a double-blind,
three-way crossover study of placebo, ibuprofen
(1600 mg/day) and ibuprofen (1600 mg/day) plus
meptazinol (400 mg/day) in 45 patients with soft tissue rheumatism. Soft tissue rheumatism was defined
as periarticular musculoskeletal pain condition
requiring treatment with an NSAID. Treatment order
was randomised and each regimen was given for
2 weeks, preceded by 1 week on paracetamol alone.
Assessments included pain parameters and verbal rating scales. Patients overall impression and final preference showed both active treatments to be better
than placebo and demonstrated a slight preference
for the combination.

Table 3 SF-36 scores (mean  SD) and Hamilton scores for depression and anxiety during 6 weeks of treatment

(physical and mental health dimension scores are presented separately and as sum)

Etoricoxib (n = 32)

Placebo (n = 32)

27.4  11.7
36.1  19.6
35.6  19.0
p < 0.01

0.79
0.38
0.95

throughout study

26.6  11.4
32.0  16.7
35.2  16.8
p < 0.02

36.7  16.1
46.0  20.1
48.4  19.0
p < 0.001

0.42
0.43
0.3

throughout study

40.1  17.1
45.1  20.5
46.5  21.0
p = 0.11

31.8  14.0
41.8  20.6
43.4  19.0
p < 0.001

0.45
0.22
0.48

throughout study

34.3  12.4
38.9  18.3
42.6  19.4
p < 0.05

13.3  6.9
10.7  6.4
9.9  6.2
p < 0.01

0.72
0.47
0.36

throughout study

12.8  4.8
11.2  6.5
10.6  6.0
p = 0.09

18.8  8.5
15.0  9.3
15.5  9.2
p < 0.05

0.39
0.73
0.8

throughout study

20.6  8.1
15.8  10.6
16.4  10.7
p < 0.01

Study week

Dimension A-Physical health

0
4
6
Overall changes (significance)
Dimension B-Mental health
0
4
6
Overall changes (significance)
Total SF-36 scores
0
4
6
Overall changes (significance)
Depression
0
4
6
Overall changes (significance)
Anxiety
0
4
6
Overall changes (significance)

Significance
between arms
(p-value)

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Adding etoricoxib to FMS therapy

Table 4 Distribution of adverse events in the two

groups

Adverse event

Etoricoxib
(n = 32)

Placebo
(n = 32)

Tiredness
Abdominal pain
Severe migraine
Irritability
Urinary tract infection
Parasthesia
Pruritus
Nightmares
Elevated blood pressure
Morning stiffness
Joint swelling
Total

1
3
1
1
2
2
0
0
0
0
0
10 (31.2%)

0
4
2
0
0
1
1
1
1
1
2
13 (40.6%)

These two studies did not focus on the added

value of NSAIDS on the outcome of patients with
FMS; both measured their contributions as possible
potentiators to other medications using parameters
which are currently not chosen as primary outcomes.
In contrast to our study, the use of NSAIDS had
more potentially adverse events given their gastrointestinal toxicity and particularly since addition of
proton pump inhibitors was not a common practice
then. In our study, we elected to use a coxib in order
to minimise the risk of gastrointestinal ulceration
and bleeding (3335). In addition, we enrolled a relatively larger group of patients compared with the
previously mentioned studies.

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Int J Clin Pract, February 2016, 70, 2, 163170

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None of the study objectives was met. We could

not demonstrate that adding etoricoxib provided any
benefit to patients pain, sleep, mood or disability
parameters.
The limitation of the study originates from the
fact that we did not assess the use of etoricoxib alone
vs. placebo, believing that such an attempt lacked a
proper and sound scientific basis. The study duration
was only 6 weeks; however, the mechanism of action
of NSAIDS does not mandate a long term to measure their clinical effect. It is likely that prolonging
the study would have increased the number of
adverse events that the patients would experience.
Another drawback of this study is its limited scale,
originating from the fact that it was conducted by a
single group. The study was designed to encompass
80 patients in total, whereas data of 64 subjects were
finally included in the analysis.
The results clearly show that even if the study was
appropriately powered it would not change the negative findings of the study.
In conclusion, this is the first randomised, doubleblind study to assess the effect of adding etoricoxib
to existing regimens in FMS. Despite being underpowered this study has clearly shown that etoricoxib
conferred no mental or physical beneficial effects to
female patients with FMS.

Acknowledgment
This project was supported by a research grant from
MSD.

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Paper received June 2015, accepted October 2015

2016 John Wiley & Sons Ltd

Int J Clin Pract, February 2016, 70, 2, 163170