ORIGINAL ARTICLE

Costs and Health Resources

Utilization Following Switching to

Pregabalin in Individuals with

Gabapentin-Refractory

Neuropathic Pain: A post hoc

Analysis

Ana Navarro, MD*; Marıa T. Saldana, MD†; Concepcion Perez, MD‡;

Xavier Masramon, MSc§; Javier Rejas, MD¶

*Primary Care Health Centre Puerta del Angel, Madrid, Spain; †Primary Care Health CentreRaıces, Castrillon, Asturias, Spain; ‡Pain Clinic, University Hospital La Princesa, Madrid,

Spain; §European Biometrics Institute, Barcelona, Spain; ¶Health Outcomes ResearchDepartment, Pfizer S.L.U., Alcobendas, Madrid, Spain

n Abstract

Purpose: To analyze the changes in pain severity and asso-

ciated costs resulting from resource utilization and reduced

productivity in patients with gabapentin-refractory periph-

eral neuropathic pain who switched to pregabalin therapy

in primary care settings in Spain.

Patients and Methods: This is a post hoc analysis of a 12-

week, multicentre, noninterventional cost-of-illness study.

Patients were included in the study if they were over

18 years of age and had a diagnosis of chronic, treatment-

refractory peripheral neuropathic pain. The analysis

included all pregabalin-naıve patients who had previously

shown an inadequate response to gabapentin and switched

to pregabalin. Severity of pain before and after treatment

with pregabalin, alone or as an add-on therapy, was

assessed using the Short-Form McGill Pain Questionnaire

(SF-MPQ) and its related visual analogue scale (VA). Health-

care resource utilization, productivity (including lost-work-

day equivalents [LWDE]), and related costs were assessed at

baseline and after pregabalin treatment.

Results: A total of 174 patients switched to pregabalin

had significant and clinically relevant reductions in pain

severity (mean [SD] change on SF-MPQ VA scale, )31.9

[22.1]; P < 0.05 vs. baseline; effect size, 1.87). Reduction in

pain was similar with both pregabalin monotherapy and

add-on therapy. Significant reductions in healthcare

resource utilization (concomitant drug use [in pregabalin

add-on group], ancillary tests, and unscheduled medical vis-

its) were observed at the end of trial. Additionally, there

were substantial improvements in productivity, including a

reduction in the number of LWDE following pregabalin

Address correspondence and reprint requests to: Ana Navarro, MD,Centro de Salud de Atencion Primaria ‘‘Puerta del Angel’’, Paseo deExtremadura 113-115, 28022 Madrid, Spain. E-mail: navarrosiguero@eresmas.com

Submitted: June 1, 2011; Revision accepted: September 8, 2011DOI. 10.1111/j.1533-2500.2011.00515.x

� 2011 The Authors

Pain Practice � 2011 World Institute of Pain, 1530-7085/11/$15.00

Pain Practice, Volume ••, Issue •, 2011 ••–••

treatment ()18.9 [26.0]; P < 0.0001). These changes corre-

lated with substantial reductions in both direct

()652.9 ± 1622.4 €; P < 0.0001) and indirect healthcare costs

()851.6 [1259.6] €; P < 0.0001).

Conclusions: The cost of care in patients with gabapentin-

refractory peripheral neuropathic pain appeared to be sig-

nificantly reduced after switching to pregabalin treatment,

alone or in combination with other analgesic drugs, in a

real-life setting.n

Key Words: neuropathic pain, pregabalin, gabapentin,

healthcare resource utilization, productivity, cost, burden of

illness

INTRODUCTION

Neuropathic pain, defined as ‘‘pain arising as a direct

consequence of a lesion or disease affecting the somato-

sensory system,’’1 is estimated to affect up to 3% of

the population2 and is responsible for substantial levels

of disability and impaired quality of life in affected

individuals.3–8 As a consequence, it represents a sub-

stantial societal burden in terms of both healthcare

resource consumption and reduced productivity.8–10

The management of neuropathic pain offers many

challenges for the practitioner as many patients fail to

respond to initial treatment. Many affected individuals

continue to live with inadequately controlled symp-

toms.11,12 Available treatment options include topical

lidocaine, opiates, antidepressants, and anticonvul-

sants.13,14 Among the anticonvulsants, gabapentin and

pregabalin are considered first-line options for the

treatment of peripheral neuropathic pain.14–16 They

act through similar pathways via binding to N-type

calcium channels,17 and they have both been shown in

randomized clinical trials to be effective for the treat-

ment of peripheral neuropathic pain.13,14 The linear

pharmacokinetics of pregabalin offers a simpler dosing

regime than gabapentin, even though the two drugs

have similar safety profiles.14

A few studies have directly addressed the cost-effec-

tiveness of pregabalin treatment for peripheral neuro-

pathic pain and, while some indirect analyses have

indicated that pregabalin therapy is slightly more cost-

effective than gabapentin,18,19 others predicted that

the availability of generic gabapentin would yield a

more favorable cost–benefit relationship than seen

with pregabalin.20 Recent data analyses of data from

routine clinical practice have suggested that, despite

the cost of pregabalin, the overall costs associated with

neuropathic pain are substantially reduced with

pregabalin therapy.9,21 To date, however, no studies

have specifically addressed the costs and health

resource utilization outcomes of pregabalin therapy in

patients with gabapentin-refractory neuropathic pain

in a real-life setting.

The LIDO study was a large, multicenter, observa-

tional study to assess the costs associated with manag-

ing treatment-refractory peripheral neuropathic pain as

part of routine practice in a primary care setting.22 In

this study, we present the results of a post hoc analysis

to determine health resource utilization and the corre-

sponding cost of treatment with pregabalin, alone and

in combination with other analgesics, in patients with

gabapentin-refractory peripheral neuropathic pain.

Despite the acquisition cost of pregabalin, patients

who switched to this drug in a real-world context

experienced a significant and clinically relevant reduc-

tion in pain intensity that is associated with a substan-

tial reduction in both healthcare costs and indirect

costs because of reduced productivity.

PATIENTS AND METHODS

Study Design

This was a post hoc analysis of the LIDO study (a pro-

spective 12-week, multicenter, observational cohort

study to assess the cost of treating refractory neuro-

pathic pain under real-life conditions in primary care

settings). A description of methods and main results of

the original study have been published elsewhere.22 In

brief, the study involved primary care physicians

weighted by density of population from all regions of

Spain. The study was conducted between September

2005 and April 2006. This was a noninterventional

study in which the choice of analgesic therapy was the

responsibility of the treating physician and current

treatments could be replaced with one or more drugs,

or a new drug could be added to the existing therapy.

The study was approved by the Ethics Committee for

Clinical Research at Hospital de la Princesa in Madrid,

Spain, and was conducted in accordance with the prin-

ciples of the Declaration of Helsinki for studies in

human subjects. The aim of this post hoc analysis was

to analyze the effects of switching to pregabalin treat-

ment, alone or in combination with other analgesic

drugs. During the baseline visit, we analyzed the

effects that the pregabalin treatment would have on

healthcare resource utilization, productivity, and asso-

2 • NAVARRO ET AL.

ciated costs in a subgroup of patients with gabapentin-

refractory peripheral neuropathic pain.

Study Population

The original study included both male and female

patients who were at least 18 years of age with a diag-

nosis of neuropathic pain because of diabetic neuropa-

thy, postherpetic neuralgia, or trigeminal neuralgia.

Patients were included if they were refractory to previ-

ous analgesic therapy with at least one drug and had

suffered chronic pain for at least 6 months. Patients

were required to have a score of at least 4 on the Span-

ish version of Douleur Neuropathique 4 (DN4) ques-

tionnaire23 and a level of education appropriate to

complete written health questionnaires in Spanish.

Patients also had to provide informed consent for their

data to be recorded in a database for subsequent anal-

ysis. In addition to fulfilling these selection criteria,

patients included in this post hoc analysis had previ-

ously received gabapentin and had not received pre-

gabalin treatment before study initiation. The overall

sample size of the LIDO study was defined according

to the primary study endpoint, and therefore, no sam-

ple size was predetermined for the secondary analysis

presented here.

Variables Recorded

For the purposes of this study and during the 12-week

follow-up, patients were assessed at baseline and at the

final study visit. At the baseline visit, the Spanish ver-

sion of the DN4 diagnostic questionnaire was com-

pleted23 and inclusion criteria were assessed. Data were

collected on sociodemographic variables, disease char-

acteristics, treatment duration, and retrospectively, the

use of healthcare and nonhealthcare resources during

the 12 weeks prior to study initiation. Patients com-

pleted the Short-Form McGill Pain Questionnaire (SF-

MPQ) at baseline and at the 12-week follow-up visit.

Patients also completed a diary throughout the study

period in which they recorded weekly pain intensity in

the visual analogue (VA) scale included in the SF-MPQ.

Healthcare Resource Utilization and Work Productivity

Utilization of healthcare resources (medical visits,

pharmacological and nonpharmacological treatment,

ancillary tests, and pain-related hospital admissions)

over the 3 months prior to both baseline and final vis-

its were obtained from patient records. Work produc-

tivity and the number of workdays lost because of

pain were reported by each patient in a face-to-face

interview during mentioned baseline and final study

visits. The following questions/variables were

recorded:

• Are you employed at this time (are you working

for pay)?

• Number of workdays lost because of pain,

• Number of days normal daily activities were hin-

dered by pain,

• Number of days pain did not disrupt normal daily

activities

For patients who were employed, a self-perceived

productivity rate on a scale from 0% to 100% was

assessed. These data were used to calculate the lost-

workday equivalents (LWDE) because of pain during

the previous 3 months according to the following

equation: LWDE = W1 + W2 (1 ) P), where W1 is the

number of days within the previous 3 months that the

patient was unable to work or carry out normal daily

activities, W2 is the number of days within the previ-

ous 3 months that the patient was able to work despite

suffering pain, (1 ) P) is the percentage of work dis-

ability, and P is the percentage of work effectiveness.

Estimation of Costs

The total cost per patient including direct healthcare

costs and indirect costs derived from LWDE was calcu-

lated. The cost of pharmacological treatments was

obtained from the Pharmacy Association Catalogue,

2006.24 The costs of nonpharmacological treatments,

medical visits, hospitalizations, and ancillary tests

(Table 1) were obtained from the Oblikue healthcare

costs database 2006.25 Finally, the cost for each

LWDE was determined by applying the human capital

method to data from the Spanish National Statistics

Institute (http://www.ine.es/) for the first quarter of

2006. To obtain an estimate of daily costs, the full

worker’s monthly salary costs were divided by

30 days.

Statistical Analysis

For statistical analyses, patients were divided into two

groups according to the treatment initiated at the

baseline visit: those who received pregabalin alone as a

substitute for the previous therapy (pregabalin

Pregabalin in Gabapentin-Refractory Neuropathic Pain • 3

monotherapy group) and those who received pregaba-

lin in addition to the previous regimen (pregabalin

add-on group). Baseline characteristics were described

as means and standard deviations for quantitative vari-

ables and as absolute and relative frequencies for qual-

itative variables. The Kolmogorov–Smirnov test was

used to confirm that quantitative variables were nor-

mally distributed. Analysis of variance (ANOVA),

Kruskall–Wallis test, chi-square test, or Fisher’s exact

test were used to assess homogeneity of baseline vari-

ables in the two patient groups. The percentage of

patients with a reduction of at least 50% in pain inten-

sity as rated by the VA scale of the SF-MPQ question-

naire was calculated, and these patients were defined

as responders. The cumulative number of days with no

pain or only mild pain (< 40 mm in the VA scale) was

calculated, and the changes from baseline in other

measures were used as outcome variables. Pearson

moment coefficients of correlation (r) between baseline

and end-of-trial visit changes in pain intensity (VA),

health resource utilization, and related cost variables

were also calculated. Between-group comparisons of

baseline values and mean values at follow-up visits

were done by Student’s t test for quantitative variables

or chi-square test for qualitative variables. The statisti-

cal significance of change from baseline visit to follow-

up was determined by Student’s t test for paired data.

The statistical significance of between-group differ-

ences in the change from baseline of quantitative vari-

ables was calculated by analysis of covariance

(ANCOVA) adjusted for baseline value. Analyses of

data collected at baseline and 12-week follow-up

included only patients who completed the follow-up

period for which the change in baseline variables could

be calculated. Last observation carried forward meth-

odology was used for variables in which data were col-

lected weekly (VA scale of SF-MPQ) for patients who

withdrew before the end of the 12-week follow-up. All

statistical tests were two-tailed, and the cutoff for sta-

tistical significance was set at P < 0.05.

To evaluate the clinical relevance of changes in

SF-MPQ scores, the effect size was calculated using

the difference of means before and after treatment

divided by the combined standard deviation of the

measure before treatment. An effect size of between

‡ 0.20 and < 0.50 was considered to be a small effect,

‡ 0.50 to < 0.80 a moderate effect, and ‡ 0.80 a large

effect.26

RESULTS

Patients

The LIDO study included 1703 patients. Prior to study

initiation, 238 patients had received gabapentin, and of

those, 174 were prescribed pregabalin during the study.

These patients were included in this post hoc analysis.

A total of 13 (7.5%) patients withdrew from the study

before the end-of-trial visit: seven were lost to follow-

up, four withdrew upon patient request, and the

remaining two withdrew because of adverse effects.

A comparison of baseline demographic and clinical

characteristics is shown in Table 2. The mean age of

the patients was 57.8 (12.7) years and 54.4% were

women. The mean length of treatment with gabapentin

prior to the study was over a year, except in the pre-

gabalin add-on group (8.7 months), with and average

dose of 1,172 (671) mg/day. Significant differences

were observed in mean daily dose of gabapentin

Table 1. Unit Cost of Healthcare Resources

Resource Unit Cost (€)

Nonpharmacological therapiesPhysical therapy1 9.96Transcutaneous electrical nerve stimulation2 22.95Infiltrations3 146.34Electrotherapy3 7.36Nerve block2 87.83Iontophoresis3 9.91Spinal cord stimulation implants2 6,886.21Drug inject able Pumps4 8,212.71Hydrotherapy1 5.91Short-wave diathermy1 6.24Magnetotherapy1 4.87Acupuncture5 35.00

Unscheduled medical visits (outpatient)Primary care1 19.81Specialist Pain unit1 51.23Specialized care1 56.41Emergency room1 111.89Hospitalization (one day in a general ward)1 300.52

Diagnostic proceduresCT scan1 145.28MRI scan1 343.66Electromyography1 126.51Echo-Doppler1 131.18Thermography1 133.27Radiological study 17.26Clinical biochemistry1 23.48Gammagraphy1 133.25

ProductivityCost of a workday lost6 51.27

CT, computed tomography; MRI, magnetic resonance imaging; TENS: transcutaneouselectrical nerve stimulation.1FREMAP, Mutua de Accidentes de Trabajo y Enfermedades Profesionales de laSeguridad Social numero 61; 2008.2Hospital de la Princesa, Madrid, Spain.3Oblikue, 2008. eSALUD. SOIKOS.25

4SED, Spanish Pain Society.5APTN, Spanish Federation of Natural Therapies and Unconventional Therapies.6Spanish National Statistics Institute (http://www.ine.es/).

4 • NAVARRO ET AL.

between groups analyzed in this work; 1,310 (733) in

the pregabalin monotherapy vs. 977 (517) mg/day in

the pregabalin add-on groups (Table 2). At baseline,

most patients (70.1%) were receiving one or more

analgesics in combination with gabapentin, and the

mean number of concomitant treatments was signifi-

cantly larger in the pregabalin add-on group (Table 2).

A trend toward statistical significance was observed in

the mean pain score in the VA scale of the SF-MPQ;

68.4 (17.3) vs. 73.3 (16.6), P = 0.069 in the pregabalin

add-on group.

In both groups of patients treated with pregabalin,

there was a statistically significant reduction in pain

according to all five scores on the SF-MPQ question-

naire (Table 3). The magnitude of this effect was

large (‡ 0.80) in all pain dimensions except for affec-

tive pain in the monotherapy group and pregabalin

treatment overall. The mean change in VA scale was

highly clinically relevant (magnitude > 1.80 in all

three groups), and the mean percentage change was

substantially larger in the pregabalin monotherapy

group than in the add-on therapy group, although the

between-group difference for this variable was not

statistically significant. The proportion of patients

who were classed as responders (‡ 50% reduction in

pain intensity from baseline) was also notably larger

in the pregabalin monotherapy group than in patients

receiving pregabalin as add-on therapy (48.5% vs.

34.3%); however, the difference between the groups

was not statistically significant (P = 0.068). The

cumulative number of days without pain, or with only

mild pain, was significantly greater in the pregabalin

monotherapy group than in the pregabalin add-on

group; 29.5 (29.4) vs. 20.7 (23.5), P = 0.039. Com-

parison of the rate of change in pain intensity on the

VA scale revealed no differences between the groups

(Figure 1).

Drug Treatment During the Study

Patients in the pregabalin monotherapy group received

a mean dose (SD) of 219 (108) mg/day vs. 222 (132)

Table 2. Demographic and Clinical Characteristics at Baseline

Patient characteristicPGB Overall(N = 174)1

PGB Monotherapy(N = 100)1

PGB Add-on(N = 74)1 P2

Sex (female), n (%) 81 (54.4%) 47 (53.4%) 34 (55.7%) 0.7808Age, mean (SD) 57.8 (12.7) 55.8 (12.1) 60.5 (13.1) 0.0167Body mass index (kg/m2), mean (SD) 26.6 (4.2) 26.9 (4.2) 26.2 (4.3) 0.3549Civil status (married or civil partnered), n (%) 110 (65.5%) 61 (63.5%) 49 (68.1%) 0.5290Occupational status, n (%)

Retired 57 (32.9%) 32 (32.0%) 25 (34.2%) 0.5191Active 44 (25.4%) 29 (29.0%) 15 (20.5%)Homemaker 21 (12.1%) 10 (10.0%) 11 (15.1%)Occupational disability 21 (12.1%) 7 (7.0%) 14 (19.2%)Not active 20 (11.6%) 16 (16.0%) 4 (5.5%)Unemployed 10 (5.8%) 6 (6.0%) 4 (5.5%)

Years since diagnosis of neuropathic paincondition, mean (SD)

2.2 (3.4) 2.1 (3.4) 2.3 (3.4) 0.7738

DN4 Questionnaire, mean (SD) 6.5 (1.8) 6.2 (1.7) 6.9 (1.7) 0.0056SF-MPQ, mean (SD)

Sensory 15.0 (6.4) 13.9 (6.0) 16.5 (6.7) 0.0105Affective 4.9 (3.6) 4.0 (3.2) 6.1 (3.8) 0.0002Total 19.9 (9.3) 17.9 (8.6) 22.5 (9.7) 0.0014PPI (0 to 5) 2.7 (1.0) 2.6 (1.0) 2.9 (1.0) 0.1494VAS (0 to 100) 70.4 (17.1) 68.4 (17.3) 73.3 (16.6) 0.0689

Concomitant analgesics at baseline visitMean number (SD) 2.4 (1.4) 1.9 (1.0) 3.1 (1.4) < 0.0001Number of drugs, n (%)

1 52 (29.9%) 45 (45.0%) 7 (9.5%)2 51 (29.3%) 33 (33.0%) 18 (24.3%)3 38 (21.8%) 13 (13.0%) 25 (33.8%)4 22 (12.6%) 7 (7.0%) 15 (20.3%)> 4 11 (6.4%) 2 (2.0%) 9 (12.1%)

Duration of gabapentin treatment (months),mean (SD)

13.4 (24.0) 16.5 (27.5) 8.7 (16.3) 0.0575

Mean dose of gabapentin (mg/day), mean (SD) 1,172 (671) 1,310 (733) 977 (517) 0.002

DN4, Doleur Neuropathique four questionnaire; PGB, pregabalin; PPI, present pain intensity; SF-MPQ, Short-Form McGill Pain Questionnaire.1Total number of analyzed patients—some patients did not report all requested data.2P value between groups.

Pregabalin in Gabapentin-Refractory Neuropathic Pain • 5

mg/day in the pregabalin add-on group, P = 0.884.

Table 4 depicts utilization of concomitant analgesic

drugs during the study. Because of the design of the

analysis, drug utilization comparison between baseline

and end-of-trial visits was carried in the pregabalin

add-on group only. However, we also compared drug

use at the baseline visit between the two pregabalin

groups. The mean number of pharmacological treat-

ments was significantly higher in the pregabalin add-

on group at baseline. Significant differences between

the groups at end of treatment and between baseline

and end of treatment were attributable to the shift

from polytherapy to monotherapy in the pregabalin

monotherapy group by definition. The frequency of

patients using concomitant analgesics overall was also

substantially reduced after 12 weeks of therapy with

the consumption of many classes of drug reduced by

50% or more in the pregabalin add-on group. Statisti-

cal comparisons vs. baseline were not undertaken for

the overall group, given the a priori reduction in con-

comitant analgesics in the pregabalin monotherapy

group as mentioned. In the pregabalin add-on group,

significant reductions in concomitant analgesics were

for NSAIDs (because of the significant reduction in

diclofenac use), amitriptyline and vitamins. No signifi-

cant differences were observed in the dose of concomi-

tant analgesics at 12 weeks of follow-up compared

with baseline (data not shown).

Resource Utilization and Productivity

Table 4 shows also the healthcare resource utilization

in terms of nonpharmacological treatments and ancil-

lary tests. In terms of nonpharmacological treatment,

the percentage of patients who received electrotherapy

or local infiltrations of analgesic drugs at baseline was

significantly higher in the pregabalin add-on group.

Compared with baseline, the proportion of patients

who received physiotherapy or transcutaneous electri-

cal nerve stimulation was significantly reduced after

12 weeks of pregabalin therapy in both groups, and

the percentage of patients receiving infiltrations was

significantly reduced compared with baseline in the

pregabalin add-on group. When all patients receiving

pregabalin therapy were considered together, there

were significant reductions in the use of all nonphar-

macological treatments compared with baseline. At

baseline, the proportion of patients who required

ancillary tests was higher in the pregabalin add-on

0 1 2 3 4 5 6 7 8 9 10 11 12

-40

-35

-30

-25

-20

-15

-10

-5

0

All patientsPGB monotherapyPGB add-on

Study week

Mea

n ch

ange

in p

ain

seve

rity

No sta s cally significant differences were observed between the groups at any me point.

Abbrevia on: PGB, pregabalin.

Figure 1. Mean change in pain intensity according to the McGillShort-Form Pain Questionnaire visual analogue scale. No statis-tically significant differences were observed between thegroups at any time point. PGB, pregabalin.

Table 3. Adjusted Mean Change of the Different Pain Attributes Measured Using the Short-Form McGill PainQuestionnaire

OutcomesPGB Overall(N = 174)1

PGB Monotherapy(N = 100)1

PGB Add-on(N = 74)1 P2

SF-MPQ, mean (SD)Sensory )7.1 (4.7)* [1.11] )6.9 (4.8)* [1.15] )7.4 (4.5)* [1.10] 0.2937Affective )2.8 (2.7)* [0.78] )2.4 (2.5)* [0.75] )3.4 (3.0)* [0.89] 0.5419Total )9.9 (6.8)* [1.06] )9.3 (6.7)* [1.08] )10.8 (6.8)* [1.11] 0.4025PPI (0 to 5) )1.3 (1.0)* [1.30] )1.4 (0.9)* [1.40] )1.3 (1.1)* [1.30] 0.0509

SF-MPQ (VAS), mean (SD)Mean change, mm )31.9 (22.1)† [1.87] )32.6 (21.2)† [1.88] )31.0 (23.3)† [1.87] 0.6461Mean percentage change )46.2 (23.7)† )48.8 (23.2)† )42.5 (24.1)† 0.0955

Responders3, % 42.5 48.5 34.3 0.0683Cumulative days without pain or withmild pain (VAS < 40 mm), mean (SD)

25.8 (27.4) 29.5 (29.4) 20.7 (23.5) 0.0389

VAS, visual analogue scale; PGB, pregabalin; PPI, present pain intensity; SF-MPQ, Short-Form McGill Pain Questionnaire.1Total number of analyzed patients—some patients did not report all requested data.2P value between groups.3Patients with a reduction of at least 50% of the baseline pain intensity according to the SF-MPQ VAS.*P < 0.0001 and †P < 0.05 vs. baseline.

6 • NAVARRO ET AL.

group in all cases where significant differences were

observed between the groups (computed tomography,

magnetic resonance imaging, electromyography, radi-

ography, and blood tests). Overall, significant reduc-

tions were observed in all ancillary tests except for

thermography. Likewise, significant reductions in the

use of ancillary tests compared with baseline were

observed in the individual treatment groups, except for

Doppler scanning in the add-on therapy group and

scintigraphy in both treatment groups considered indi-

vidually. However, no significant correlation was

observed between mean baseline-final variation of pain

intensity and mean changes in ancillary test utilization

(r = 0.09, P = 0.245).

Table 5 shows the quarterly number of medical vis-

its and hospital admissions along with productivity

measures for the different groups at baseline and fol-

lowing pregabalin therapy. At baseline, the total num-

ber of medical visits and the number of specialist

referrals and visits to the emergency room were signifi-

cantly larger in the pregabalin add-on group, whereas

primary care visits were significantly more frequent in

the pregabalin monotherapy group. Hospital admis-

sions were also significantly more frequent in the pre-

gabalin add-on group at baseline. Compared with

baseline, there were significant reductions in the num-

ber of medical visits and hospital admissions after

12 weeks of pregabalin treatment in all cases except

for the number of hospital admissions in the pregaba-

lin monotherapy group. Reduction in mean number of

all-type medical visits was significantly correlated with

mean baseline-final variation of pain intensity

Table 4. Healthcare Resource Use (Drugs, Nonpharmacological Treatments, and Ancillary Tests) at Baseline andDuring Treatment

Resource

PGB Overall (N = 174)1PGB Monotherapy

(N = 100)1 PGB Add-on (N = 74)1 P2

Baseline EOT Baseline EOT Baseline EOT Baseline EOT

Pharmacological treatmentMean number (SD) 2.4 (1) 1.7 (1.0)* 1.9 (1.0) – 3.1 (1.4) 2.7 (0.9)§ < 0.001 < 0.0011 drugs, n (%) 52 (30) 100 (58) 45 (45) – 7 (10) 0 (0) < 0.001 NA2 drugs, n (%) 51 (29) 38 (22) 33 (33) – 18 (24) 38 (51)3 drugs, n (%) 38 (22) 25 (14) 13 (13) – 25 (34) 25 (34)4 drugs, n (%) 22 (13) 8 (5) 7 (7) – 15 (20) 8 (11)> 4 drugs, n (%) 11 (6) 3 (2) 2 (2) – 9 (12) 3 (4)

Concomitant analgesics, n (%)Nonopioid analgesics 74 (42.5) 41 (23.6) 36 (36.0) – 47 (63.5) 41 (55.4) < 0.001 NA

Acetaminophen 52 (29.9) 30 (17.2) 20 (20.0) – 32 (43.2) 30 (40.5) 0.002Metamizol 31 (17.8) 11 (6.3) 16 (16.0) – 15 (20.3) 11 (14.9) 0.598

NSAIDs 52 (29.9) 15 (8.6) 22 (22.0) – 30 (40.5) 15 (20.3)§ 0.013Diclofenac 23 (13.2) 5 (2.9) 9 (9.0) – 14 (18.9) 5 (6.8)‡ 0.092Ibuprofen 19 (10.9) 8 (4.6) 8 (8.0) – 11 (14.9) 8 (10.8) 0.234

Amitriptyline 25 (14.4) 11 (6.3) 5 (5.0) – 20 (27.0) 11 (14.9)§ < 0.001Opioids 32 (18.4) 20 (11.5) 7 (7%) – 25 (33.8) 20 (27.0) < 0.001

Tramadol 23 (13.2) 16 (9.2) 6 (6.0) – 17 (23.0) 16 (21.6) 0.002Benzodiazepines 12 (6.7) 5 (2.9) 6 (6.0) – 6 (8.1) 5 (6.8) 0.810Vitamins 13 (7.5) 0 (0.0) 0 (0.0) – 13 (17.6) 0 (0.0)† < 0.001

Nonpharmacological treatment, n (%)Physiotherapy 41 (29) 15 (11)* 19 (23) 9 (11)§ 22 (37) 6 (10)† 0.069 0.416TENS 16 (12) 5 (4)† 7 (9) 1 (1)§ 9 (16) 4 (7)§ 0.195 0.195Infiltrations3 13 (10) 2 (2)‡ 4 (5) 1 (1) 9 (16) 1 (2)§ 0.029 0.916Electrotherapy 11 (8) 2 (1)‡ 2 (3) 0 (0) 9 (15) 2 (3) 0.006 0.240Ancillary tests, n (%)CT 41 (24) 9 (5)* 18 (18) 2 (2)† 23 (31) 7 (10)† 0.045 0.060MRI 60 (35) 12 (7)* 27 (27) 3 (3)* 33 (45) 9 (12)* 0.016 0.038Electromyography 56 (32) 11 (6)* 21 (21) 3 (3)* 35 (47) 8 (11)* 0.001 0.246Doppler scan 12 (7) 3 (2)§ 5 (5) 0 (0)§ 7 (10) 3 (4) 0.254 0.038Thermography 1 (1) 1 (1) 1 (1) 0 (0) 0 (0) 1 (1) 0.391 0.249Radiography 82 (47) 22 (13)* 39 (39) 8 (8)* 43 (58) 14 (19)* 0.012 0.120Blood test4 119 (68) 52 (30)* 61 (61) 23 (23)* 58 (78) 29 (39)* 0.015 0.078Scintigraphy 11 (6) 3 (2)§ 5 (5) 1 (1) 6 (8) 2 (3) 0.408 0.381

CT, computed tomography; EOT, end of trial; MRI, magnetic resonance imaging; NSAID, nonsteroidal anti-inflammatory drug; TENS, transcutaneous electrical nerve stimulation;NA, not applicable.1Total number of analyzed patients; some patients did not report all requested data.2P value between groups.3Local infiltrations of analgesic drugs.4Includes blood count and biochemistry.*P < 0.0001, †P < 0.001, ‡P < 0.01 and §P < 0.05 vs. baseline.

Pregabalin in Gabapentin-Refractory Neuropathic Pain • 7

(r = 0.17, P = 0.031) and particularly with primary

care visits decreased (r = 0.24, P = 0.002).

At baseline, the number of days worked with

pain and the number of LWDE were higher in the

pregabalin add-on group, while the work productiv-

ity was lower in that group. All groups showed sig-

nificant improvements in productivity after 12 weeks

of pregabalin therapy, which were significantly cor-

related with mean change of pain intensity; work

productivity significantly and negatively correlated

with pain reduction (r = )0.33, P < 0.0001). Also,

LWDE and days worked with pain reductions were

significantly correlated with pain intensity improve-

ment, r = 0.19 (P = 0.020) and r = 0.20 (P = 0.019),

respectively.

Costs

Table 6 shows the total and itemized mean adjusted

quarterly costs associated with healthcare resource uti-

lization and indirect costs attributable to LWDE. At

baseline, total healthcare costs were significantly

higher in the pregabalin add-on group. Comparison of

the itemized healthcare costs at baseline showed that

the cost of medical visits and hospital admissions, and

of ancillary tests, was significantly higher in the pre-

gabalin add-on group, whereas no significant differ-

ences were observed between the groups for drug

treatments or nonpharmacological therapies. Indirect

costs were also higher in the pregabalin add-on group

at baseline, as were the total adjusted quarterly costs

Table 5. Quarterly Medical Visits, Hospitalizations, and Work Productivity at Baseline and During Treatment withPregabalin

Resource

PGB Overall (N = 174)1PGB Monotherapy

(N = 100)1 PGB Add-on (N = 74)1 P2

Baseline Change Baseline Change Baseline Change Baseline Change

No. of unscheduled medical visitsTotal 9.4 (6.7) )4.5 (5.5)* 8.2 (6.4) )4.0 (5.7)* 11.1 (6.8) )5.2 (5.2)* 0.0047 0.0956Primary care 6.5 (4.6) )2.6 (3.9)* 5.9 (4.7) )2.4 (4.1)* 7.4 (4.3) )2.8 (3.7)* 0.0367 0.1193Pain clinic 0.9 (2.0) )0.6 (1.9)† 0.8 (2.1) )0.6 (2.0)§ 0.9 (1.8) )0.5 (1.7)§ 0.7874 0.2473Specialist referrals 1.2 (1.3) )0.5 (1.3)* 1.0 (1.0) )0.4 (1.1)‡ 1.5 (1.5) )0.7 (1.6)† 0.0168 0.9990Emergency room 1.3 (1.9) )0.9 (1.4)* 0.8 (1.4) )0.6 (1.2)† 1.8 (2.2) )1.3 (1.6)* 0.0036 0.7558

Hospitalizations, n (%) 10 (6.6) )9 ()5.9)‡ 1 (1.1) )1 ()1.1) 9 (13.8) )8 ()12.3)§ 0.0016 0.2082Productivity

Lost workdays because of pain3 20.6 (25.9) )10.0 (20.0)* 17.3 (25.2) )7.0 (19.7)‡ 25.1 (26.3) )14.2 (19.8)* 0.0728 0.1733Days worked with pain 40.4 (31.9) )19.1 (29.0)* 35.4 (32.4) )15.6 (30.0)* 47.4 (30.2) )24.2 (27.1)* 0.0266 0.6089Work productivity, % 49.0 (23.0) 18.8 (21.3)* 53.7 (24.0) 21.4 (21.7)* 43.1 (20.5) 15.5 (21.1)* 0.0042 0.0416LWDE 36.6 (29.9) )18.9 (26.0)* 31.0 (29.8) )14.9 (25.2)* 44.2 (28.4) )24.3 (26.3)* 0.0086 0.4935

LWDE, lost workdays equivalents; PGB, pregabalin.1Total number of analyzed patients; some patients did not report all requested data.2P value between groups.3Calculated on active population only.*P < 0.0001, †P < 0.001, ‡P < 0.01, and §P < 0.05 vs. baseline. Values are shown are means (SD), except where otherwise indicated; change is adjusted for baseline values.

Table 6. Total and itemized mean adjusted quarterly costs in Euros by study groups and overall

Costs (€)

PGB overall (N = 174)1 PGB monotherapy (N = 100)1 PGB add-on (N = 74)1 P2

Baseline Change Baseline Change Baseline Change Baseline Change

Drugs3 173.4 (122.6) 121.4 (120.4)* 175.0 (117.5) 113.9 (111.1)* 171.3 (130.1) 131.4 (132.1)* 0.8455 0.3394Nonpharmacologicaltherapies

300.8 (1200.8) )271.2 (1166.1)‡ 155.7 (769.2) )131.4 (769.4) 496.9 (1596.0) )460.1 (1535.3)§ 0.0637 0.8998

Medical visits andhospitalizations

468.8 (995.6) )320.9 (945.5)* 289.7 (698.8) )178.9 (674.5)§ 710.9 (1258.2) )512.9 (1198.6)† 0.0055 0.0473

Ancillary tests 235.9 (246.6) )182.1 (257.3)* 181.1 (232.3) )156.0 (243.4)* 309.9 (247.6) )217.5 (272.7)* 0.0006 0.0089Healthcare costs 1179.0 (1744.9) )652.9 (1622.4)* 801.5 (1134.6) )352.4 (1099)‡ 1689.0 (2238.5) )1059.1 (2075.2)* 0.0008 0.0272Indirect costs (LWDE) 1624.5 (1523.2) )851.6 (1259.6)* 1341.5 (1489.7) )647.3 (1197.5)* 2006.9 (1493.5) )1127.8 (1296.5)* 0.0041 0.3909Total costs 2803.5 (2624.8) )1504.6 (2190.1)* 2143.1 (2068.5) )999.7 (1789.8)* 3695.9 (3019.8) )2186.9 (2490.4)* 0.0001 0.6814

LWDE, lost workdays equivalents; PGB, pregabalin.1Total number of analyzed patients; some patients did not report all requested data.2P value between groups.3Prices of drugs extracted from Pharmacy Association Catalogue year 2006.*P < 0.0001, †P < 0.001, ‡P < 0.01, and §P < 0.05 vs. baseline. Values are shown are means (SD); change is adjusted for baseline values.

8 • NAVARRO ET AL.

for this group. After 12 weeks of pregabalin treatment,

statistically significant reductions in costs were

observed for all categories and in all groups compared

with baseline, except for the cost of nonpharmacologi-

cal therapies in the pregabalin monotherapy group.

Significant differences between the groups were

observed for the reductions from baseline in the costs

of medical visits and hospital admissions, ancillary

tests, and for overall healthcare costs. In all three

cases, the largest reductions were observed in the pre-

gabalin add-on group. Reduction in total cost was cor-

related significantly with mean change of pain

intensity (r = 0.21, P = 0.006), mainly due to signifi-

cant correlation with indirect costs variation; r = 0.20,

P = 0.008, because correlation with healthcare cost

changes showed a trend toward statistical significance;

r = 0.13 (P = 0.097).

DISCUSSION

In this post hoc analysis of the LIDO study, patients

with gabapentin-refractory neuropathic pain because

of diabetic neuropathy, postherpetic neuralgia, or tri-

geminal neuralgia showed significant and clinically rel-

evant reductions in pain intensity after 12 weeks of

treatment with pregabalin. This reduction in pain cor-

related with significant reductions in the use of health-

care resources and improvements in productivity that

together resulted in substantial, statistically significant

reductions in costs incurred because of health expendi-

ture and loss of productivity. Thus, despite the cost of

pregabalin treatment, its use in patients with gabapen-

tin-refractory neuropathic pain would appear to have

substantial pharmacoeconomic benefits.

Overall, patients treated with pregabalin displayed

a very substantial reduction in VA scale of the SF-

MPQ (effect size = 1.87), with similar effects in both

treatment groups. Interestingly, the percentage of

responders appeared to be higher in the pregabalin

monotherapy group than in patients who received pre-

gabalin as an add-on treatment (48.5% vs. 34.3%),

although the difference was not statistically significant,

and the cumulative number of days without pain was

significantly greater in the pregabalin monotherapy

group. However, as this was an observational study

undertaken in a routine clinical practice setting, it is

difficult to draw specific conclusions regarding any

possible differences in the efficacy of pregabalin mono-

therapy vs. add-on therapy. For instance, comparison

of baseline characteristics suggests that those who were

prescribed add-on therapy had more refractory pain at

baseline, as they had significantly higher scores on the

sensory, affective, and total scores from the SF-MPQ,

as well as a significantly larger number of medical vis-

its and hospital admissions in the 3 months prior to

the baseline visit. In contrast, the mean duration of

gabapentin treatment appeared to be substantially

longer in the monotherapy group (although the differ-

ence was not statistically significant). However, aver-

age gabapentin dose (below the recommended

therapeutic doses) was significantly higher in patients

in the pregabalin monotherapy group compared with

add-on group. Also, the mean number of analgesic

drugs prescribed at baseline was significantly higher in

the pregabalin add-on group. Taken together, these

observations suggest that, in routine clinical practice,

the choice of pregabalin add-on therapy vs. monother-

apy is likely to depend on a number of factors, includ-

ing pain intensity, existing use of polytherapy, and,

possibly, duration and average dose of prior gabapen-

tin therapy, showing that pregabalin add-on group is a

sicker patient population, as based on their baseline

data, than subjects receiving pregabalin as a monother-

apy.

The observational nature of the study may also

mean that patient-reported outcomes were influenced

by patient expectations of treatment benefit. Conse-

quently, it is possible that the magnitude of the treat-

ment effect in terms of pain reduction could have been

underestimated in patients with more refractory pain

and that this could hinder comparisons between the

groups. Nevertheless, taken together, our results

clearly show that patients with gabapentin-refractory

neuropathic pain report substantial, clinically relevant,

and statistically significant reductions in pain intensity

and corresponding increases in the number of days

without pain following 12 weeks of pregabalin ther-

apy, irrespective of the treatment regimen used.

As might be expected, the reduction in pain

observed with pregabalin therapy was associated with

a reduction in the use of healthcare resources. This

finding is consistent with the results of other recent

analyses of the outcome of pregabalin therapy in

patients with treatment-refractory neuropathic

pain.9,22,27 In another post hoc analysis of the LIDO

study designed to compare the outcome and cost of

pregabalin and gabapentin therapy, the cost reductions

achieved with pregabalin were similar to those with

gabapentin, despite evidence of greater reductions in

pain intensity in the pregabalin group.21 In that study,

Pregabalin in Gabapentin-Refractory Neuropathic Pain • 9

the greater cost of pregabalin therapy may have offset

some of the other cost reductions obtained as a result

of achieving effective pain control. Nevertheless, as in

our study, substantial reductions in total costs, due

both to reduced healthcare costs and increased produc-

tivity, were still observed in patients who received pre-

gabalin. Our results thus provide further evidence that

pregabalin treatment is cost-effective in patients with

treatment-refractory neuropathic pain and, further-

more, show that similar or even greater cost reductions

are obtained despite patients having failed to respond

to a similar first-line therapy.

Overall, there were significant reductions in the use

of nonpharmacological treatments compared with

baseline, and the number of ancillary tests required

was reduced significantly in all cases except thermogra-

phy (only requested in one patient from each of the

treatment groups). There were also significant reduc-

tions in the percentage of patients receiving concomi-

tant analgesic drugs, particularly amitriptyline,

NSAIDs, and vitamins used for neuropathic pain, in

the subgroup receiving pregabalin as an add-on ther-

apy. This is supported also by the observation that, on

the whole, reductions in the number of patients receiv-

ing other specific analgesics were apparent in the add-

on therapy group, although without reaching statistical

significance. This is likely due to the reduced sample

size of this group. As this was a noninterventional

study in primary care settings, conclusions regarding

the decision to choose add-on therapy rather than pre-

gabalin monotherapy are difficult to draw. Neverthe-

less, the lack of an apparent advantage of add-on

therapy in terms of pain alleviation suggests that expec-

tations of additional benefit may not have been accu-

rate. Future studies should focus on achieving a clear

consensus on the most appropriate treatment option in

this patient group, as it is conceivable that even further

improvements in cost reductions could be achieved.

Significant reductions in the number of medical vis-

its and hospital admissions were observed in all groups

compared to baseline, with the exception of hospital

admissions in the monotherapy group (only one admis-

sion prior to baseline). Although, with the exception

of visits to the pain clinic, the number of medical visits

was significantly higher in the add-on therapy group at

baseline, similar reductions were observed following

12 weeks of pregabalin therapy, with no significant

differences between the groups. Thus, taken together

with the observed reduction in pharmacological and

nonpharmacological treatments, and in the use of

ancillary tests, our results clearly show a reduction in

healthcare resource use in patients with gabapentin-

refractory neuropathic pain who receive pregabalin

treatment in routine clinical practice. Not surprisingly,

this reduction went hand in hand with a substantial,

statistically significant reduction in healthcare costs in

all groups. Interestingly, the greatest reduction in

health costs was seen in the pregabalin add-on group,

with significantly larger reductions in overall costs and

in the costs of medical visits/hospital admissions and

ancillary tests. These substantial reductions may be

due in part to the notably larger number of hospital

admissions in the add-on group at baseline, consistent

with the possibility that patients in this group generally

had worse, more treatment-refractory pain. Thus, irre-

spective of any potential differences between the out-

comes of monotherapy vs. add-on therapy with

pregabalin in this patient group, the overall reduction

in health expenditure was substantial and may have

led to particular reductions in the cost of treating the

most severely affected patients.

An important aspect of this analysis was the consid-

eration of indirect costs in terms of the number of

LWDE. Neuropathic pain is known to be a substantial

societal burden not only in terms of the direct cost of

treatment but also as a result of the reduced productiv-

ity of patients because of absenteeism and generally

lower effectiveness in the workplace as a result of

chronic pain.3,4,28,29 Despite evidence of lower produc-

tivity in the pregabalin add-on group at baseline, simi-

lar improvements were observed following pregabalin

therapy, with no significant difference in indirect costs

because of LWDE between the groups.

In summary, the results of our study in routine med-

ical practice seem to show that pain intensity and asso-

ciated costs because of consumption of healthcare

resources and loss of productivity were likely reduced

in patients with gabapentin-refractory neuropathic

pain after 12 weeks of treatment with pregabalin,

either alone or in combination with other analgesic

drugs. The magnitude of changes from baseline to

week 12 were, perhaps, more substantial in direct

healthcare cost in group receiving pregabalin as add-

on therapy, meaning that these subjects could have a

better response, at least from an economics perspec-

tive. Finally, despite the greater acquisition cost of pre-

gabalin treatment, then, the overall economic benefits

of controlling neuropathic pain with this first-line

treatment appear to be substantial even in patients

with gabapentin-refractory pain.

10 • NAVARRO ET AL.

AUTHOR CONTRIBUTIONS

This was a collaborative work, and the authors

worked closely each other. MTS, CP, AN, and JR par-

ticipated in the design of the original study and in the

interpretation of data and drafting the manuscript.

XM participated in the analysis and interpretation of

data and in the preparation of the manuscript. All

authors were responsible for literature review and

extraction of references.

FUNDING SOURCE

Data collection and analysis were funded by Pfizer

Spain. All authors had complete access to the data,

participated in the analysis and/or interpretation of

results, and drafted the manuscript.

CONFLICT OF INTERESTS

Javier Rejas is an employee of Pfizer Spain. Xavier

Masramon is an employee of European Biometric

Institute (EBI), a specialized consultancy from Quin-

tiles Iberia, SA, a Consultancy Agency engaged by Pfiz-

er Spain for this work. All other authors declare no

conflict of interests.

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