Bushmakin 52,Fibromialgia ,cuestionario

7/27/2019 Bushmakin 52,Fibromialgia ,cuestionario

1/9

IMPORTANT

This document has been supplied underPfizers copyright licences.

It must not be used for promotional purposes.

This document is protected by copyright and it may not (even for internal

purposes) be further copied, stored or on-copied electronically without

permission, save as may be permitted by law.

The recipient may print out a single paper copy of any document

received electronically.


2/9

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


3/9

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


4/9

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



5/9

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.




6/9

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.




7/9

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.




8/9

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.




9/9

References

1 Wolfe F, Ross K, Anderson J et al. The prevalence

and characteristics of fibromyalgia in the general

population. Arthritis Rheum 1995; 38: 1928.

2 Wolfe F, Smythe HA, Yunus MB et al. The Ameri-

can College of Rheumatology 1990 Criteria for the

Classification of Fibromyalgia. Report of the Multi-

center Criteria Committee. Arthritis Rheum 1990;

33: 16072.

3 Arnold LM, Crofford LJ, Mease PJ et al. Patient

perspectives on the impact of fibromyalgia. Patient

Educ Couns 2008; 73: 11420.

4 Hoffman DL, Dukes E. The health status burden of

people with fibromyalgia: a review of studies that

assessed health status with the SF-36 or the SF-12.

Int J Clin Pract 2008; 62: 11526.

5 Choy E, Perrot S, Leon T et al. A patient survey of

the impact of fibromyalgia and the journey to diag-

nosis. BMC Health Serv Res 2010; 10: 102.

6 Fitzcharles MA, Yunus MB. The clinical concept of

fibromyalgia as a changing paradigm in the past

20 years. Pain Res Treat 2012; 2012: 184835. Epub

2011 Oct 29. Published online 2011 October 29.

doi: 10.1155/2012

184835.7 Wolfe F, Clauw DJ, Fitzcharles M-A et al. The

American College of Rheumatology preliminary

diagnostic criteria for fibromyalgia and measure-

ment of symptom severity. Arthritis Care Res 2010;

62: 60010.

8 Clauw DJ, Arnold LM, McCarberg BH, FibroCol-

laborative. The science of fibromyalgia. Mayo Clin

Proc 2011; 9: 90711.

9 Ceko M, Bushnell MC, Gracely R. Neurobiology

underlying fibromyalgia symptoms. Pain Res Treat

2012; 2012: 585419. Epub 2011 Oct 27. Published

online 2011 October 27. doi:10.1155/2012585419.

10 Carville SF, Arendt-Nielsen S, Bliddal H et al.

EULAR evidence based recommendations for the

management of fibromyalgia syndrome. Ann Rheum

Dis 2008; 67: 53641.

11 Pfizer Inc. Lyrica [Pregabalin] Capsules Prescribing

Information. New York, NY: Pfizer, Inc., 2011.

12 Eli Lilly and Company. Cymbalta [Duloxetine

Hydrochloride] Delayed Release Capsules Prescribing

Information. Indianapolis, IN: Eli Lilly and Com-

pany, 2011.

13 Forest Pharmaceutical. Savella [Milnacipran

Hydrochloride] Prescribing Information. St. Louis,MO: Forest Pharmaceuticals, 2009.

14 Field MJ, Cox PJ, Stott E et al. Identification of the

alpha2-delta-1 subunit of voltage-dependent cal-

cium channels as a molecular target for pain medi-

ating the analgesic actions of pregabalin. Proc Natl

Acad Sci USA 2006; 103: 1753742.

15 Errante LD, Petroff OA. Acute effects of gabapentin

and pregabalin on rat forebrain cellular GABA, glu-

tamate, and glutamine concentrations. Seizure 2003;

12: 3006.

16 Cunningham MO, Woodhall GL, Thompson SE

et al. Dual effects of gabapentin and pregabalin on

glutamate release at rat entorhinal synapses in vitro.

Eur J Neurosci 2004; 20: 156676.

17 Maneuf YP, Hughes J, McKnight AT. Gabapentin

inhibits the substance P-facilitated K(+)-evokedrelease of [(3)H]glutamate from rat caudial trigemi-

nal nucleus slices. Pain 2001; 93: 1916.

18 Crofford LJ, Rowbotham MC, Mease PJ et al. Pre-

gabalin for the treatment of fibromyalgia syndrome:

results of a randomized, double-blind, placebo-con-

trolled trial. Arthritis Rheum 2005; 52: 126473.

19 Arnold LM, Russell IJ, Diri EW et al. A 14-week,

randomized, double-blind, placebo-controlled

monotherapy trial of pregabalin in patients with

fibromyalgia. J Pain 2008; 9: 792805.

20 Mease PJ, Russell IJ, Arnold LM et al. A random-

ized, double-blind, placebo-controlled, phase III

trial of pregabalin in the treatment of patients with

fibromyalgia. J Rheumatol 2008; 35: 50214.

21 Boomershine CS. A comprehensive evaluation of

standardized assessment tools in the diagnosis of

fibromyalgia and in the assessment of fibromyalgia

severity. Pain Res Treat 2011; 2012: 653714. Epub

2011 Oct 10.

22 Burckhardt CS, Clark SR, Bennett RM. The fibrom-

yalgia impact questionnaire: development and vali-

dation. J Rheumatol 1991; 18: 72833.

23 Bennett RM, Bushmakin AG, Cappelleri JC et al.

Minimal clinically important difference in thefibromyalgia impact questionnaire. J Rheumatol

2009; 36: 130411.

24 Farrar JT, Young JP Jr, LaMoreaux L et al. Clinical

importance of changes in chronic pain intensity

measured on an 11-point numerical pain rating

scale. Pain 2001; 94: 14958.

25 Kleinbaum DG, Klein M. Survival Analysis. A Self-

Learning Text. 2nd edn. New York, NY: Springer

Science + Business Media, Inc., 2005.

26 Kaplan EL, Meier P. Nonparametric estimation

from incomplete observations. J Am Stat Assoc

1958; 53: 45781.

27 Lagakos SW. General right censoring and its impact

on the analysis of survival data. Biometrics 1979; 35:

139156.

28 Pfizer Inc. Lyrica [Pregabalin] Capsules PrescribingInformation. New York, NY: Pfizer, Inc., 2009.

29 Stacey BR, Barrett JA, Whalen E et al. Pregabalin

for postherpetic neuralgia: placebo-controlled trial

of fixed and flexible dosing regimens on allodynia

and time to onset of pain relief. J Pain 2008; 9:

100617.

30 Sharma U, Griesing T, Emir B, Young JP Jr. Time

to onset of neuropathic pain reduction: a retrospec-

tive analysis of data from nine controlled trials of

pregabalin for painful diabetic peripheral neuropa-

thy and postherpetic neuralgia. Am J Ther 2010; 17:

57785.

Paper received April 2012, accepted August 2012



Documents

Bushmakin 52,Fibromialgia ,cuestionario