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Evaluation of the fibromyalgia impact questionnaireat baseline as a predictor for time to pain improvementin two clinical trials of pregabalin
A. G. Bushmakin,1 J. C. Cappelleri,1 A. B. Chandran,2 G. Zlateva2
Introduction
Fibromyalgia (FM) is a chronic condition that may
occur in individuals regardless of age or gender, but
disproportionately affects women in an approximate
ratio of 7 : 1 (1). Although FM has been convention-
ally characterised by chronic widespread pain, fatigue
and multiple tender points (2), the frequent presence
of a constellation of comorbid symptoms contribute
to the reduced function and quality of life reported
by patients with FM (35). These symptoms include
sleep disturbances, headaches, irritable bowel, cogni-
tive dysfunction, anxiety and depression, all of which
are associated with significant impact on daily func-
tioning. It is now recognised that these symptoms
are part of the clinical presentation of FM (6) and
have been incorporated into clinical guidance (7).
The aetiology and pathogenesis of FM have yet to
be fully elucidated. Nevertheless, re-evaluation of the
clinical concept of FM, incorporating results of neu-
roimaging studies, support a dysfunction in central
pain processing and other alterations in neurotrans-
mitters as integral to the pathways underlying the
multidimensional nature of this disease (8,9).
Recent evidence-based recommendations for the
management of FM suggest the use of non-pharma-
cologic and pharmacologic therapies (10), with the
latter consisting of agents from diverse therapeutic
classes. Although these classes include analgesics,
antidepressants, anticonvulsants, muscle relaxants
S U M M A R Y
Background: The Fibromyalgia Impact Questionnaire (FIQ) is a patient-reported
outcome that evaluates the impact of fibromyalgia (FM) on daily life. This study
evaluated the relationships between the functional status of FM patients, measured
with the FIQ at baseline, and median time to a clinically relevant pain reduction.
Methods: Data were derived from two randomised, placebo-controlled trials that
evaluated pregabalin 300, 450 and 600 mg
day for the treatment of FM. TheKaplanMeier (nonparametric) method was applied to estimate median times to
transient and stable events. The transient event was defined as a 27.9%
improvement on an 11-point daily pain diary scale (0 = no pain, 10 = worst pos-
sible pain), and the stable event was defined as the mean of the daily improve-
ments 27.9% relative to baseline over the subsequent study duration starting on
the day of the transient event. A parametric model using time-to-event analysis
was developed for evaluating the relationship between baseline FIQ score and the
median time to these events. Results: Median time was longer among patients
treated with placebo relative to pregabalin for the transient events (1112 days
vs. 57 days) and stable events (86 days vs. 1329 days). A significant association
was observed between baseline FIQ scores and median time to transient and sta-
ble events (p < 0.001). Median times to events were similar between the studies.
For transient pain reduction events, median times ranged from 3.0 to 4.5 days for
baseline FIQ scores of 10, and 9.19.6 days for FIQ scores of 100; for stable pain
reduction events, the median time ranged from 11.0 to 13.0 days and from 27.0
to 28.5 days for baseline FIQ scores of 10 and 100 respectively. Conclu-
sions: Time to a clinically relevant reduction in pain was significantly associated
with FM severity at baseline as measured by the FIQ. Such an analysis can inform
patient and physician expectations in clinical practice.
Whats knownCategorisation of fibromyalgia as a
multidimensional condition has enabled
development of patient-reported outcome measures
that have successfully evaluated the disease and its
treatment within the context of pain (with a
numeric rating scale, NRS) and, separately, patient
function and disease severity surrounding theimpact of fibromyalgia on daily life (with the
Fibromyalgia Impact Questionnaire, FIQ).
Whats newAmong subjects with fibromyalgia, longer median
times to pain reduction (as measured by NRS), both
transient and stable reduction, after pregabalin
treatment were associated with higher levels of
baseline fibromyalgia severity (as measured by the
FIQ). Determining the time to clinical efficacy and
its relationship with baseline disease severity is a
useful approach for enhancing management
strategies by informing patients and physicians
regarding clinically realistic expectations of
pregabalin treatment.
1Pfizer Inc., Statistics, Groton,
CT, USA2Pfizer Inc., Outcomes
Research, New York, NY, USA
Correspondence to:
Joseph C. Cappelleri, Pfizer Inc.,
445 Eastern Point Road (MS
8260-2502), Groton, CT 06340,
USA
Tel.: +1 860 441 8033
Fax: +1 860 686 5139
Email: joseph.c.cappelleri@
pfizer.com
Disclosures
Andrew G. Bushmakin, Joseph
C. Cappelleri, Arthi B.
Chandran, and Gergana Zlateva
are employees and stockholders
of Pfizer Inc, the sponsor of
this study.
OR I GI NA L P A P E R
2012 Blackwell Publishing Ltd52 Int J Clin Pract, January 2013, 67, 1, 5259. doi: 10.1111/ijcp.12035
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and sedativeshypnotics, only three drugs have been
specifically approved for the treatment of FM: pre-
gabalin (11), duloxetine (12) and milnacipran (13).
In contrast with the antidepressants duloxetine
and milnacipran, pregabalin is an anticonvulsant that
is a high affinity ligand of alpha2-delta subunits of
voltage-gated calcium channels (14). Pregabalin has
been shown to reduce the release of neurotransmit-ter, including glutamate (15,16) and substance P
(17). Pregabalin was the first pharmacologic therapy
approved in the US for the treatment of FM, and
has also been approved at doses up to 450 mg daily
for FM in 24 countries, including Canada, Russia,
Israel, and several Asian, Middle Eastern and Latin
American countries. Its approval was based on dem-
onstration of statistically and clinically significant
reductions in pain relative to placebo as well as
improvements in other patient-reported outcomes
(PROs) (1820).
Although pain remains a primary outcome mea-
sure in FM, the categorisation of FM, as a multidi-
mensional condition, has enabled development of
PROs that evaluate FM within a broader context of
patient functioning and categorisation of disease
severity (21). In particular, the Fibromyalgia Impact
Questionnaire (FIQ) was developed and validated as
a PRO for evaluating the impact of FM on daily life
(22). Cutoff scores for defining severity levels on the
FIQ have been established, as has a clinically relevant
difference on the FIQ (23).
In clinical trials, PROs, such as the FIQ, are gener-
ally analysed in the form of the differences between
treatment arms. However, time-to-event modelling(i.e. survival analysis) can provide an additional
perspective of treatment effects that includes initial
improvement and stable improvement. Such a per-
spective may enhance our knowledge of the relevant
events that may be expected during treatment in a
clinical setting, including time to improvement and
an understanding of why patients switch medica-
tions, especially if a surrogate marker is identified
that can be used to estimate the time to response.
The purpose of the current investigation is to evalu-
ate the relationship between functional impairment
in patients with FM, measured by FIQ scores at
baseline, and the median time-to-improvement for
clinically meaningful reductions in pain for different
doses of pregabalin and placebo.
Methods
Data used for modelling in the current analysis were
derived from two similarly designed randomised, pla-
cebo-controlled trials that evaluated three doses of
pregabalin (300, 450 and 600 mgday) for the treat-
ment of FM (19,20). It should be noted that
600 mgday is not an approved or a recommended
dose for FM. All patients, including patients rando-
mised to 600 mgday, were included in this second-
ary analysis to be consistent with the two main
efficacy publications emanating from the two studies
(19,20).
In one study (Study 1), 745 patients were rando-mised to 14 weeks of double-blind treatment (19),
and in the other study (Study 2), 748 patients were
randomised to 13 weeks of treatment (20). Both
studies were conducted in accordance with the Dec-
laration of Helsinki, approved by the appropriate
institutional review boards or independent ethics
committees, and patients provided written informed
consent prior to participation.
Details of the subjects, methodology and results of
the trials have been previously published (19,20).
Two types of events were considered in this analy-
sis, a transient event and a stable event. The tran-
sient pain reduction event was defined as an
improvement by 27.9% on an 11-point daily pain
diary numerical rating scale (0 = no pain, 10 = worst
possible pain); this percent reduction in pain has
been previously determined to be a clinically impor-
tant difference (24). The stable pain reduction event
was defined as having the mean of the daily
improvements be 27.9% relative to baseline over
the subsequent study duration starting on the day of
the transient event.
Two different methods of time-to-event analysis
were used to provide distinct sets of results (25). In
the first time-to-event analysis, KaplanMeier (non-parametric) methodology (26) was applied to esti-
mate median time to events stratified by treatment
arm. In the second analysis, parametric models were
fit to evaluate the relationship between baseline FIQ
scores and the median time to event for patients
treated with pregabalin. The models included time to
event as the outcome accounting for censoring, and
baseline FIQ as the predictor. Time to event was
taken to follow a gamma distribution, and thus the
gamma model provides the parametric survival esti-
mate. The model included an intercept parameter,
the coefficient parameter for baseline FIQ, and scale
and shape parameters. On the basis of the model,
the times to transient and stable events were pre-
dicted for deciles of baseline FIQ values. Scoring of
the FIQ is on a 0100 scale, with higher scores indi-
cating a greater impact of FM.
Using the same types of model, a secondary analy-
sis was performed that evaluated baseline pain as a
predictor of time to event, with the times to tran-
sient and stable events predicted for each baseline
pain severity score from 4 to 10; a minimum score
Time to meaningful pain reduction 53
2012 Blackwell Publishing LtdInt J Clin Pract, January 2013, 67, 1, 5259
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of 4 was required for entry into the clinical trials. All
analyses were conducted using sas version 9.2 (SAS
Institute Inc., Cary, NC, USA).
Results
Subject demographics in both studies were similar,
well-balanced across treatment groups, and consis-tent with what may be expected for an FM popula-
tion (Table 1). The overall population was
predominantly female (94.4%) and white (90.6%),
with a mean age of 49.4 (standard deviation 11.2)
years.
On the basis of KaplanMeier estimation, median
times to the transient event of clinically meaningful
pain reduction were similar in both studies
(Table 2), and were longer among patients treated
with placebo (1112 days) relative to pregabalin
(57 days). Median times to stable pain reduction
events were also similar between the studies; pregab-
alin resulted in a shorter median time relative to pla-
cebo, with a median time for placebo subjects in
study 1 that was beyond the study duration.Although the pregabalin 300 mg dose generally
resulted in a longer median time to event, there was
a general lack of significance in the median time to
transient and stable events across active treatment
dose groups, enabling the doses to be pooled in each
study for the predictive modelling using a parametric
approach. In addition, the proportions of patients
Table 1 Demographic and clinical characteristics of the study populations
Variable
Placebo Pregabalin 300 mg Pregabalin 450 mg Pregabalin 600 mg
Study 1(n = 184)
Study 2(n = 190)
Study 1(n = 183)
Study 2(n = 185)
Study 1(n = 190)
Study 2(n = 183)
Study 1(n = 188)
Study 2(n = 190)
Sex, n (%)
Female 169 (91.8) 183 (96.3) 173 (94.5) 174 (94.1) 183 (96.3) 169 (92.3) 179 (95.2) 180 (94.7)
Male 15 (8.2) 7 (3.7) 10 (5.5) 11 (5.9) 7 (3.7) 14 (7.7) 9 (4.8) 10 (5.3)
Age, years, mean (SD) 49 (11.4) 48.6 (11.3) 49.1 (11.2) 50.1 (10.4) 50.8 (11.8) 47.7 (10.8) 50.9 (11.1) 48.7 (11.2)
Race, n (%)
White 169 (91.8) 167 (87.9) 164 (89.6) 169 (91.4) 171 (90.0) 169 (92.3) 174 (92.6) 170 (89.5)
Black 7 (3.8) 10 (5.3) 9 (4.9) 10 (5.4) 12 (6.3) 7 (3.8) 5 (2.7) 8 (4.2)
Other 8 (4.3) 13 (6.8) 10 (5.5) 6 (3.2) 7 (3.7) 7 (3.8) 9 (4.8) 12 (6.3)
FM duration, years, mean (SD) 10.3 (9.0) 8.8 (6.9) 9.6 (7.0) 9.6 (8.6) 10.3 (7.7) 9.6 (8.5) 9.9 (8.3) 9.3 (7.6)
Baseline pain score, mean (SD) 6.6 (1.3) 7.2 (1.2) 6.7 (1.3) 7.1 (1.4) 6.6 (1.4) 7.1 (1.4) 6.7 (1.4) 7.0 (1.1)
Baseline FIQ score, mean (SD) 58.7 (15.6) 65.1 (13.7)* 61.1 (15.7) 65.8 (13.4)* 59.6 (15.1) 63.6 (13.9)* 59.5 (16.2) 62.7 (13.2)*
*Calculated separately as they were not reported in the study publication.
Table 2 Median time to events based on KaplanMeier estimation
Study
Median time to event, days (percent responders) p*
Placebo Pregabalin 300 mg Pregabalin 450 mg Pregab alin 600 mg All subjects Pregabal in subjects
Transient event
Study 1 12 (75.3) 7 (83.5) 6 (85.7) 6 (86.5) 0.0001 0.6818
Study 2 11 (75.5) 7 (79.4) 6 (87.8) 5 (84.7) < 0.0001 0.0271
Stable event
Study 1 (42.3) 23 (61.5) 14 (63.0) 15 (58.9) < 0.0001 0.725
Study 2 86 (46.8) 29 (59.4) 18 (62.8) 13 (60.3) 0.0029 0.7005
*On the basis of the log-rank test of equality among distributions of the treatment groups examined; p-values for all subjects indicate that at least one intervention
group was different from at least another intervention group, and p-values for pregabalin subjects indicates that at least one pregabalin group was different from at
least one other pregabalin group for transient event in study 2.
Transient event defined as a 27.9% improvement on an 11-point daily pain diary numerical rating scale (0 = no pain, 10 = worst possible pain).
Stable event defined as the mean of the daily improvements being maintained at a level 27.9% relative to baseline over the study duration starting on the day
of the transient event.
54 Time to meaningful pain reduction
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who were transient and stable responders were con-
sistently higher with pregabalin (Table 2), and these
proportions were similar between the two studies.
For the pooled doses of pregabalin in the paramet-
ric model, a clear relationship was observed in both
studies between baseline FIQ scores and median time
to improvement for the transient event of pain
reduction (Figure 1A, C) and the stable event of painreduction (Figure 1B, D). These graphs show that
longer median times to improvement were associated
with higher (less favourable) FIQ scores at baseline,
and these relationships were statistically significant
(p < 0.001).
On the basis of this model, the median times to
the transient event of pain reduction across deciles of
baseline FIQ scores were generally consistent between
Study 1 and Study 2 (Table 3), and increased from
4.5 [95% confidence interval (CI) 3.4, 6.0] and 3.0
(95% CI 2.1, 4.3) days for baseline FIQ scores of 10
in Study 1 and 2, respectively, to 9.1 (95% CI 7.2,
11.5) and 9.6 (95% CI 7.5, 12.4), respectively, for
baseline scores of 100. Similarly, the median times to
stable events were also consistent between the studies
and were approximately three times higher than the
median to transient events, regardless of the FIQ
score. For the stable event, the estimated median
time for subjects with baseline FIQ scores of 10 was
13.0 (95% CI 8.6, 19.7) and 11.0 (95% CI 6.6, 18.3)
in Studies 1 and 2, respectively, and this increased to
28.5 (95% CI 19.5, 41.5) and 27.0 (95% CI 18.1,
40.4), respectively, for subjects with baseline FIQ
scores of 100.Clear relationships were also observed between
baseline NRS pain score and time to transient and
stable events (Figure 2). Estimation of median time
to events was consistent between the two studies for
each level of pain severity (Table 4), and there was a
moderate correlation between baseline pain and base-
line FIQ; Pearson r = 0.52 and 0.51 in Study 1 and
Study 2 respectively (p < 0.0001 for both studies).
Discussion
Although the results reported in this study were
derived from clinical trials, they are relevant to the
clinical setting by providing data that can inform
physicians and patients regarding treatment expecta-
tions, such as the length of time to onset of efficacy.
Figure 1 Parametric model demonstrating the relationship between baseline score on the Fibromyalgia Impact
Questionnaire (FIQ) and predicted median time to events. Black circles represent predicted median time to event and the
shading represents the 95% confidence interval. Transient event in Study 1 (A) and Study 2 (C) defined as a 27.9%
improvement on an 11-point daily pain diary numerical rating scale (0 = no pain, 10 = worst possible pain). Stable event
in Study 1 (B) and Study 2 (D) defined as the mean of the daily improvements being maintained at a level 27.9%
relative to baseline over the study duration starting on the day of the transient event.
Time to meaningful pain reduction 55
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Table 3 Predicted median and 95% confidence intervals (95% CI) for time to event in active treatment arms in
Studies 1 and 2 as a function of baseline scores of the Fibromyalgia Impact Questionnaire (FIQ).
Baseline
FIQ score
Median (95% CI) time to event, days
Transient event* Stable event
Study 1 Study 2 Study 1 Study 2
10 4.5 (3.4, 6.0) 3.0 (2.1, 4.3) 13.0 (8.6, 19.7) 11.0 (6.6, 18.3)
20 4.9 (3.8, 6.2) 3.4 (2.6, 4.6) 14.2 (9.9, 20.5) 12.2 (7.9, 18.9)
30 5.2 (4.3, 6.4) 3.9 (3.1, 5.0) 15.5 (11.2, 21.5) 13.5 (9.3, 19.5)
40 5.7 (4.9, 6.6) 4.4 (3.7, 5.3) 16.9 (12.6, 22.7) 14.9 (10.9, 20.4)
50 6.1 (5.4, 7.0) 5.1 (4.4, 5.8) 18.4 (14.1, 24.2) 16.4 (12.5, 21.5)
60 6.6 (5.9, 7.4) 5.8 (5.2, 6.4) 20.1 (15.4, 26.2) 18.1 (14.1, 23.3)
70 7.2 (6.3, 8.1) 6.5 (5.8, 7.3) 21.9 (16.7, 28.9) 20.0 (15.5, 25.9)
80 7.8 (6.7, 9.1) 7.4 (6.4, 8.6) 23.9 (17.7, 32.3) 22.2 (16.6, 29.6)
90 8.4 (6.9, 10.2) 8.5 (7.0, 10.3) 26.1 (18.7, 36.4) 24.5 (17.4, 34.3)
100 9.1 (7.2, 11.5) 9.6 (7.5, 12.4) 28.5 (19.5, 41.5) 27.0 (18.1, 40.4)
*Transient event defined as a 27.9% improvement on an 11-point daily pain diary numerical rating scale (0 = no pain, 10 = worst
possible pain).
Stable event defined as having the mean of the daily improvements be 27.9% relative to baseline over the subsequent study dura-
tion starting on the day of the transient event.
Figure 2 Parametric model demonstrating the relationship between baseline pain Numerical Rating Scale (NRS; 0 = no
pain, 10 = worst possible pain) score and predicted median time to events. Black circles represent predicted median time
to event and the shading represents the 95% confidence interval. Transient event in Study 1 (A) and Study 2 (C) defined
as a 27.9% improvement on the NRS. Stable event in Study 1 (B) and Study 2 (D) defined as the mean of the daily
improvements being maintained at a level 27.9% relative to baseline over the study duration starting on the day of the
transient event.
56 Time to meaningful pain reduction
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These results show that there is a direct and signifi-
cant relationship between FM severity, assessed using
the FIQ, and the time to a clinically significant
reduction in pain with pregabalin; a longer time to
pain reduction was observed at greater levels of FM
severity. Furthermore, the magnitude of both the
relationship and the reduction can be quantified in a
meaningful, practical and comprehensive manner.
The results of these analyses, with respect to both
responder rates and response times, were consistent
across both studies, demonstrating stability and
repeatability. In particular, the substantial rates ofresponse with pregabalin suggest that the median time
to event is unlikely to be influenced by patients who
failed to achieve the study endpoint. Importantly,
both models (FIQ- and pain-based) resulted in pre-
dictions that were similar. Furthermore, the models
based on different studies also gave close results, pro-
viding further support of the models stability.
Patients who have not (yet) experienced the event
are said to be censored. Censored data contribute
valuable information and they should not be omitted
from the analysis. It would also be wrong to treat
the observed time (at censoring) as the survival time.
In our study, we used a specialised set of statistical
methods that have been developed for handling such
data. These methods use all information up to the
time of censoring and do not throw away informa-
tion. The censored observations contribute to the
total number at risk up to the time that they ceased
to be followed. If more than 50% of the observations
are censored, estimates may not be reliable (27). In
our study, less than 50% of the subjects (about 40%)
did not experience a stable event (and hence were
censored) and, therefore, we expect the estimates
produced to be reliable. If the subjects were to expe-
rience a stable event, it would be after their censored
time and the analysis makes use of this information.
Approximately 75% of patients on placebo were
responders in the transient time-to-event analysis.
This high percentage is suggestive of a large placebo
effect for a transient response and underscores the
importance of also conducting an analysis where
responders are to have a stable event, which invokes
a more rigorous standard. In the stable time-to-event
analysis, the percentage of subjects on placebo whoresponded falls substantively to 42% in one study
and 47% in another. In supplementing the transient
analysis, the stable event analysis therefore adds fair
balance to the overall analysis.
As indicated by the general lack of significance
across active treatment dose groups in the time-to-
event curves for transient and stable events, the dose
of pregabalin was consistently observed to be a statis-
tically insignificant factor in the onset and mainte-
nance of efficacy. Pregabalin 300 mgday resulted in
a longer numerical estimate of median time to event
relative to the other doses [450 mgday is the maxi-
mum recommended dose for the treatment of FM
(28)], which suggests a possible doseresponse rela-
tionship. Across all doses of pregabalin, subjects with
mild FM (FIQ score < 39) had a median time to ini-
tial efficacy of approximately 45 days, whereas those
with moderate (FIQ score 39 to < 59) and severe
FM (FIQ score 59) had median times of approxi-
mately 6 days and 79 days respectively. Pooling the
three doses of pregabalin increased the stability of
the results.
Table 4 Predicted median and 95% confidence intervals (95% CI) for time to event in active treatment arms in
Studies 1 and 2 as a function of baseline pain scores on a Numerical Rating Scale (NRS).
Baseline NRS
pain score
Median (95% CI) time to event, days
Transient event* Stable event
Study 1 Study 2 Study 1 Study 2
4 4.6 (3.7, 5.6) 3.5 (2.8, 4.2) 14.8 (10.7, 20.7) 13.0 (9.2, 18.2)
5 5.3 (4.5, 6.1) 4.2 (3.6, 4.9) 16.6 (12.4, 22.2) 14.6 (10.9, 19.6)
6 6.0 (5.3, 6.8) 5.0 (4.4, 5.6) 18.6 (14.2, 24.3) 16.5 (12.7, 21.5)
7 6.9 (6.2, 7.7) 6.0 (5.4, 6.6) 20.7 (15.9, 27.1) 18.7 (14.5, 24.0)
8 7.9 (6.9, 9.1) 7.1 (6.3, 8.0) 23.2 (17.4, 30.9) 21.0 (16.2, 27.3)
9 9.0 (7.5, 10.8) 8.5 (7.3, 10.0) 25.9 (18.8, 35.8) 23.8 (17.7, 31.8)
10 10.4 (8.2, 13.1) 10.2 (8.4, 12.5) 29.0 (20.0, 42.1) 26.8 (19.1, 37.5)
*Transient event defined as a 27.9% improvement on an 11-point daily pain diary numerical rating scale (0 = no pain, 10 = worst
possible pain).
Stable event defined as having the mean of the daily improvements be 27.9% relative to baseline over the subsequent study dura-
tion starting on the day of the transient event.
Time to meaningful pain reduction 57
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Although a short time to onset of efficacy after
initiation of therapy is of great benefit, the ability to
maintain a stable level of improvement during treat-
ment is an equally important attribute that contrib-
utes to patterns of dosing, adherence and switching.
In the current analysis, the median time to stable
improvement was approximately three times longer
than the time to onset, regardless of baseline FMseverity (as measured by FIQ) or pain severity (as
measured by NRS Pain).
Two previous studies of pregabalin estimated the
time to onset of pain relief (29,30). In these studies,
however, the type of population and the definition
of pain reduction differed from the ones presented
in the current study. Patients in the previous two
studies had postherpetic neuralgia or painful diabetic
neuropathy; moreover, pain relief was defined as a
1-point reduction in pain relative to baseline for
those patients who had clinically meaningful pain
reduction (> 30%) at end point (29,30). One of
these studies reported a median time to pain reduc-
tion of 1.5 days for fixed-dose pregabalin in patients
with postherpetic neuralgia (29), and the other
reported pain reductions by 2 days after initiating
treatment (30). However, in contrast with those
studies, which considered a statistically significant
reduction in pain, the current analysis used a clini-
cally significant reduction in pain as the marker for
efficacy and evaluated the entire pregabalin cohort
regardless of response. Therefore, both the median
time to transient event and the median time to stable
event may represent more realistic and relevant esti-
mates of what may be expected in clinical practice.An important limitation of this study is that it was
based on clinical trial populations, which may be dif-
ferent from that of the clinical setting in that they may
reflect patients who are more motivated or adherent
to therapy. Thus, in clinical practice, it is possible that
the time to achieve significant and consistent
improvements may take longer than reported herein,
especially since time for titration of dose to therapeu-
tic levels may vary among treating physicians.
Another potential limitation is that the predictive
model for baseline pain only covered the NRS range of
410, whereas for the FIQ, the full-scale range was used.
However, a minimum pain score of 4 was part of the
entry criteria for the clinical trials but there was no min-
imum FIQ score. It should also be noted that although
pain is a primary characteristic of FM and remains a
key objective of therapy, the FIQ provides a more com-
prehensive and clinically relevant perspective by assess-
ing FM and categorising its severity as a condition. The
moderate correlation between baseline FIQ and pain
scores further supports the concept of FM as a condi-
tion that is characterised by factors in addition to pain.
This study could also potentially be criticised for
not evaluating the time to withdrawal because of
adverse events. Among the patients treated with pre-
gabalin in both studies, adverse events and withdraw-
als because of adverse events, which occurred in up
to 32.6% of patients, were dose-dependent, with diz-
ziness and somnolence the adverse events that most
frequently led to withdrawal (19,20). However, itshould be considered that while a patient may or
may not discontinue therapy upon occurrence of an
adverse event, in the absence of knowledge of when
efficacy is likely to occur, patients may discontinue
prior to its onset. Thus, informing patient and physi-
cian expectations of the timing of treatment benefits
may be more clinically relevant for maintaining per-
sistence with therapy than occurrence of adverse
events. As such, this study focused on determining
efficacy onset and whether time to clinically mean-
ingful reductions in pain are associated with, and
can be predicted by pain and functional impairment
at baseline; similar evaluations for adverse events
may be worth pursuing in a subsequent analysis.
Despite these limitations, this study represents a
new approach to evaluating clinical trial data that
may have direct application to clinical practice.
Conclusions
This study demonstrated how techniques for time-to-
event analysis can be used to explore relationships
between baseline values of a surrogate measure and
efficacy outcomes. In particular, for patients with FM,
baseline FIQ scores were predictive of the time to effi-cacy in a clinically meaningful and quantifiable man-
ner. Such an understanding has practical applications
by informing patients and physicians regarding the
clinical expectations of therapy and enhancing man-
agement strategies. This relationship may also provide
a metric for comparative analysis of expected out-
comes and, in addition, a methodological framework
for evaluating changes in other outcomes as a
function of a baseline surrogate measure.
Acknowledgements
This study was funded by Pfizer Inc. Editorial assis-
tance was provided by E. Jay Bienen and was funded
by Pfizer, Inc.
Author contributions
All authors contributed to the study design, statistical
analysis plan, results interpretation and review of the
draft manuscript; the final manuscript was read and
approved by all authors.
58 Time to meaningful pain reduction
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Time to meaningful pain reduction 59
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