Pharmacoeconomic outcomes for pregabalin: a systematic review in neuropathic pain, generalized anxiety disorder, and epilepsy from a Spanish perspective.

Adv Ther (2014) 31:1–29 DOI 10.1007/s12325-013-0088-2

REVIEW

Pharmacoeconomic Outcomes for Pregabalin: A Systematic Review in Neuropathic Pain, Generalized Anxiety Disorder, and Epilepsy from a Spanish Perspective ´ lvarez Josep Darba` • Lisette Kaskens • Concepcioń Pe´rez • Enrique A

•

Ruth Navarro-Artieda • Antoni Sicras-Mainar

To view enhanced content go to www.advancesintherapy.com Received: October 7, 2013 / Published online: January 4, 2014 Ó Springer Healthcare 2014

ABSTRACT

conduct a systematic review to evaluate the

Introduction: Pregabalin is an anticonvulsant

cost-effectiveness of pregabalin associated with the treatment of its labeled indications from a

approved in Europe for the treatment of

societal perspective in Spain.

neuropathic pain, as an adjunct therapy for epileptic seizures, and recently for generalized

Methods: Data from the MEDLINE database were searched using algorithms to identify

anxiety disorder. The aim of this study was to

relevant economic evaluations published in English or Spanish on pregabalin for the

Electronic supplementary material The online version of this article (doi:10.1007/s12325-013-0088-2) contains supplementary material, which is available to authorized users.

management of neuropathic pain, generalized

J. Darba` (&) Department of Economics, Universidad de Barcelona, Barcelona, Spain e-mail: [email protected]

anxiety disorder (GAD), and epilepsy in Spanish patients over the last 10 years. Results: In

total,

52

potentially

relevant

abstracts were identified from the MEDLINE database.

Twenty

manuscripts

met

the

inclusion criteria. The majority of the selected L. Kaskens BCN Health Economics and Outcomes Research, Barcelona, Spain C. Pe´rez Pain Clinic, Hospital Universitario La Princesa, Madrid, Spain ´ lvarez E. A Department of Psychiatry, Hospital de la Santa Creu i San Pau, Barcelona, Spain R. Navarro-Artieda Medical Information Department, Hospital Germans Trias i Pujol, Badalona (Barcelona), Spain A. Sicras-Mainar Directorate of Planning, Badalona Serveis Assistencials SA, Badalona (Barcelona), Spain

papers

(14/20)

evaluated

pregabalin

for

neuropathic pain from a societal perspective in Spain vs.

(5

economic

gabapentin,

4

models economic

of pregabalin analyses

of

pregabalin in comparison with usual care, 4 economic evaluations comparing pregabalin monotherapy with add-on strategies, and one that evaluated different times of initiating pregabalin therapy). Five studies analyzed the use of pregabalin in Spain for the management of GAD (one cost-effectiveness model that compared

pregabalin

with

venlafaxine,

Adv Ther (2014) 31:1–29

2

2

secondary

analyses

in

benzodiazepine-

refractory patients, and 2 studies evaluating pregabalin vs. usual care in patients refractory to standard regimens). The last manuscript described a cost-effectiveness model that compared pregabalin versus levetiracetam use for the treatment of refractory partial epilepsy. Conclusion: The majority of published evidence supports the possibility that pregabalin could be a cost-effective and/or cost-saving alternative for the treatment of refractory epilepsy, GAD, and neuropathic pain, in both treatment-naı¨ve patients and in those who have demonstrated inadequate response or intolerance to previous therapy. Keywords: Cost-effectiveness analysis; Direct costs; Economic evaluation; Epilepsy; Generalized productivity

anxiety costs;

disorder; Indirect/ Neuropathic pain;

Pregabalin; Spain; Usual care

Within

these

pregabalin-prescribed

disorders, neuropathic pain—continuous or episodic—is a very common condition in European countries [4] and is a direct consequence of damage to the somatosensory system that results in dysesthesia and pain from normally non-painful stimuli [5]. Up to 5% of the European population suffers from severe painful neuropathies [6]. Similarly, anxiety disorders are the most prevalent psychiatric disorders in Western countries, with GAD being the most common form in primary care settings [7]. Furthermore, GAD has shown to be the most severe and disabling [8]. Despite the fact that the 1-year prevalence of GAD in the general population is relatively low (2%) [9], the lifetime risk of suffering from GAD (up until 75 years old) is considerably higher (9%) [7]. Finally, epilepsy is a serious and common neurological alteration characterized by recurring seizures [10]. Epileptic crises are a direct consequence of excessive, or hypersynchronous, neuronal activity in the

INTRODUCTION Chronic neuropsychiatric disorders are prevalent in the Western society, representing a considerable burden for the quality of life of patients resulting in a significant negative impact on work productivity for society and on consumption of resources from the national healthcare services [1]. Pregabalin is a thirdgeneration anticonvulsant drug that potently and selectively binds to the a-2-delta subunit of

brain [11] and its incidence in developed societies ranges from 26 to 70 cases per 100,000 people/year [12]. The average costs of treating these illnesses, under routine medical practice in Spain, have been evaluated previously and the annual per patient costs have been reported as €4,356 for neuropathic pain (2006 prices), €5,139 for GAD (2004 prices), and €6,838 for epilepsy (2005 prices) [13–15]. A relatively broad selection of therapeutic options have become available over the last

‘‘hyper-excited’’ voltage-gated calcium channels, thus reducing calcium influx at the nerve

20 years to ameliorate these neurological afflictions, although the frequently vague and

terminals [2]. Pregabalin has proven efficacy in

changing symptomatology—combined with a broad range of associated co-morbid

different neurological conditions and has been licensed in Europe for the treatment of

conditions

of

other

mental

and

somatic

neuropathic pain syndromes, as an adjuvant therapy for epilepsy, and more recently for

disorders—poses a range of diagnostic and therapeutic challenges [16–18]. Moreover, it

generalized anxiety disorder (GAD) [3].

typically takes years after onset before GAD,

Adv Ther (2014) 31:1–29

3

are

might show to what extent pregabalin is a cost-

accurately diagnosed and treated with the

effective, or cost-saving, alternative relative to

appropriate first-line treatments. The complex etiology and diagnostic patterns compromise

other common options prescribed regularly to treat patients with the same approved

efficient therapeutic and clinical management; thus this raises the direct and productivity

indications of use as pregabalin. The fact that there are no official national guidelines in Spain

costs of the illnesses and significantly impacts

that

national healthcare systems. Neuropathic pain is a difficult-to-treat disease that commonly

pregabalin for its current indications is one of the elements that justifies the need for the

does not respond to analgesics [19]. Currently, anticonvulsants like gabapentin and

review we have raised. The objective of this systematic review is to review the impact of

pregabalin

epileptic,

or

painful

neuropathies

consider

the

cost-effectiveness

of

first-choice

pregabalin on healthcare and productivity costs

therapies for peripheral neuropathic pain in Spain, together with secondary tricyclic

(societal perspective) of patients using it for its licensed indications (epilepsy, GAD, or

antidepressants and the dual serotonin and norepinephrine reuptake inhibitor duloxetine

neuropathic pain) in Spain.

in

METHODS

painful

are

established

diabetic

as

neuropathy

[20,

21].

Similarly, pregabalin has proven to be an effective and well-tolerated therapeutic approach for adult patients with GAD [22] and consequently is considered to be one of the first-choice therapies by current European guidelines [23]. Finally, a considerable percentage of epileptic patients who develop drug resistance to anti-epileptics [24] have responded to last-generation drugs, with pregabalin and levetiracetam being the most common therapeutic options [25, 26]. Although the acquisition costs for pregabalin are higher than that for other alternative treatments recommended as first line to these indications in Spain, the clinical benefit of pregabalin in treating the symptomatology of these chronic neurological and psychiatric disorders may reduce and/or offset healthcareassociated and/or productivity costs with also an important effect on the economic burden borne by national healthcare systems. Due to

The inclusion process of the manuscripts in the study and the subsequent data extraction were performed, in a duplicate manner, by two of the co-authors. Inclusion criteria of the reviewed studies covered all the manuscripts with economic results on the use of pregabalin in Spain as a treatment for the three currently approved indications (neuropathic pain, GAD, and epilepsy), independently of the comparator used, the kind of economic evaluation performed, or perspective of the analysis. This is because payers and bodies funding healthcare resources in Spain, particularly at regional levels, may be interested in both evaluation of costs and effectiveness simultaneously, but also assessment of healthcare costs only. The authors conducted their review in MEDLINE using search algorithms to identify relevant economic publications in English or Spanish

this, economic evaluations of this molecule are

for pregabalin use in treating neuropathic pain, anxiety, and epilepsy. The review was

needed according to its use to better establish its role and level of recommendation in routine

conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews

medical practice. Such economic evaluations

and Meta-Analyses) guidelines for reporting

Adv Ther (2014) 31:1–29

4

systematic reviews to assess the benefits and

publications

specific

harms of a healthcare intervention [27] and the

anxiety,

epilepsy.

recommended flow diagram is summarized in Fig. 1. The search was performed in July 2013

search, ‘‘gray’’ literature of Spanish monographs and reports was also examined to

and identified publications with the main keyword ‘‘pregabalin’’. The authors used

identify material such as publications that can be referenced, but were not published in peer-

also

other

reviewed, indexed medical journals, or not yet

pharmacoeconomic keywords to identify economic outcomes: ‘‘cost’’, ‘‘expenditure’’,

published manuscripts. This gray literature also included searching for possible publications in

‘‘productivity’’, ‘‘health economics’’, ‘‘pharmacoeconomic’’, ‘‘indirect costs’’, and ‘‘work loss’’. Articles were required to feature

local journals not indexed in MEDLINE that could contain publications on economic ã). evaluations of pregabalin (e.g., SciELO Espan

keywords in the title, abstract, and/or full-text publications pertaining to humans and

As shown in Fig. 1, the search in MEDLINE identified 52 potentially relevant citations.

published within the last decade (2004–2013). Abstracts were manually reviewed to select

After removing 6 duplicates identified by the keyword combination, a total of 46 unique

the

next

extensive

Fig. 1 Study search scheme

list

of

or

to To

neuropathic supplement

pain, our

Adv Ther (2014) 31:1–29

5

citations remained for review at the abstract

incremental

level. Of the 46 abstracts, 34 articles were

Spain: €30,000 per quality-adjusted life-year

selected for further review in full text and 12 were excluded for not being specifically focused

(QALY) gained [28]. Finally, an evaluation of the quality of the included studies was assessed using

on pregabalin. The remaining 34 articles were assessed for eligibility by determining

the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist recently

inclusion

terms:

published as a guideline for reporting economic

‘‘pregabalin’’ ? ‘‘pharmacoeconomic term’’ ? ‘‘disease (anxiety, epilepsy, or pain)’’ or

evaluations of health interventions [29]. Since the CHEERS checklist focuses on economic models,

‘‘pregabalin’’ ? ‘‘disease’’. In addition, the remaining abstracts were required to fulfill the

some of the items in the list are not applicable to studies of retrospective cost analysis or economic

following statements: the study pertained to

evaluations for time periods under 1-year

humans with anxiety, epilepsy, or pain in which relevant economic end points were

extension. For this reason, we have adapted the CHEERS list of items (24) as a percentage of the

evaluated. After all criteria were assessed, 18 articles were included for systematic review.

total items that apply to the particular reviewed study. Also, details of items not fulfilled in a

Only the articles that met the following criteria

particular study are also identified and listed in a

were selected: studies performed with/about Spanish subjects and reporting economic

table. The CHEERS guideline evaluation of each of the included manuscripts was performed by an

outcomes for patients treated with pregabalin. The review of ‘‘gray’’ literature was focused on

author, independently of the two authors responsible for the manuscript inclusion and

the latest information (year 2013) pertaining to economic outcomes (cost) for Spanish patients

data extraction procedures. This systematic review is based on previously

treated with pregabalin in anxiety, epilepsy, or

conducted studies and does not involve any

pain. Two citations were identified for inclusion. One of them, related to a cost analysis of patients

new studies of human or animal subjects performed by any of the authors.

with diabetic peripheral neuropathy, has not been published yet, but is pending final acceptance for

RESULTS

of

the

following

search

cost-effectiveness

threshold

for

publication. The second, which has been recently submitted for publication, is related to GAD patients treated with pregabalin after poor response to selective-serotonin reuptake inhibitors (SSRIs) in routine medical practice. Economic

attractiveness

judgments

were

based on the estimates for pregabalin in the identified economic evaluations for each condition/disease. Most of the estimates within a study concluded that pregabalin was cost-

During the last 10 years (January 2004–July 2013), 20 studies have examined the economic outcomes associated with pregabalin in Spanish patients with epilepsy, anxiety, or neuropathic pain. The field with the most identified references, 14 of the 20 articles, referred to the economic outcomes of Spanish patients with neuropathic pain (Table 1). Five studies were centered on

saving, cost-neutral but with better health

pharmacoeconomic outcomes of Spanish GAD patients (Table 2). Finally, only one of the

outcomes, or alternatively showed an incremental cost-effectiveness ratio (ICER) equal

manuscripts focused on epilepsy outcomes in Spain (Table 3). In all analyzed diseases, most

to or below the usually accepted healthcare

publications

were

treatment-associated

cost

Costing year

2006

2006

2006

Study (year) [reference]

Rodrı´guez et al. (2007) [31]

Pe´rez et al. (2010) [32]

Sicras-Mainar et al. (2011) [35]

Patients with peripheral neuropathic pain

Patients with refractory chronic peripheral neuropathic pain secondary to diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, or radiculopathy at axial rotation

Hypothetic cohort of 1,000 patients with neuropathic pain due to painful diabetic polyneuropathy or postherpetic neuralgia

Population

Comparative cost analysis, 3rd payer perspective, 2 years

Cost– consequences analysis, NHS and societal perspectives, 12 weeks

Costeffectiveness model, NHS perspective, 12 weeks

Type of economic analysis, perspective, time horizon

Gabapentin

Gabapentin

Gabapentin

Comparator

Table 1 Economic analysis of pregabalin in patients with neuropathic pain

Analysis of a retrospective cohort study using univariate linear models with covariates

Matched nested case–control analysis using univariate linear models with covariates

Markov Monte Carlo simulation model

DecisionAnalytical model

A significant higher drug cost change was associated with PGB in comparison with GBP (€168 vs. €92). This difference was offset by a greater reduction in productivity costs compared with GBP (-€964 vs. -€680), yielding similar overall cost reductions (-€1,254 vs. -€1,384, respectively) PGB-treated patients showed lower adjusted total costs in comparison with GBP (€2,514 vs. €3,214), due to less sick leave (€1,067 vs. €1,633) and lower healthcare costs (€1,447 vs. €1,609). The higher acquisition cost of PGB (€351 vs. €191) was compensated with lower costs in medical visits, physiotherapy, hospital stays and concomitant analgesics

Probabilistic 95% confidence interval using bootstrapping techniques for differences in costs

Total health costs of therapies were €1,049 for PGB and €951 for GBP, respectively. ICER for PGB versus GBP had a mean of €12 per additional day with no or mild pain, €431 per additional patients with no or mild pain, and €20,535 per QALY gained

Economic outcomes

95% confidence interval estimation for differences in costs and consequences

Multiple probabilistic sensitivity analysis

Handling of uncertainty

Total healthcare costs were lower for those patients initiated with PGB therapy, despite of the higher treatment acquisition cost that was compensated by lower costs in other healthcare components

Although there were no significant differences in global costs, PGB was associated with a greater reduction of medical visits and of lost workdays, offsetting the higher pharmacological costs

PGB was more cost-effective than generic GBP in patients with neuropathic pain due to diabetic polyneuropathy and/ or post-herpetic neuralgia

Conclusions

6 Adv Ther (2014) 31:1–29

Costing year

2010

2010

2007



Sicras et al. (2013) [37]

Flo´rez-Garcıá et al. (2011) [39]

Table 1 continued

Patients with refractory neck pain as a result of cervical or lumbar radiculopathy

Patients with painful diabetic peripheral neuropathy starting treatment with either PGB or GBP for the first time

Patients with painful axial radiculopathy starting treatment with either PGB or GBP for the first time

Population

Cost– consequences analysis, perspective not specified, 12 weeks

Comparative cost analysis, 3rd payer perspective, 1 year

Comparative cost analysis, 3rd payer perspective, 1 year


UC

Gabapentin

Gabapentin

Comparator

Analysis of a prospective cohorts study using ANCOVA models








Adding PGB was associated with significant reductions in the indirect healthcare costs (-€1,041 vs. -€457). The higher change in treatment cost for PGB (€310 vs. €26) was offset by higher reductions in other components, producing similar direct (-€67 vs. -€144) and overall (-€1,108 vs. -€601) cost reductions in both groups

Mean total costs per patient were significantly lower in the PGB group (€2,003 vs. €3,127), mainly due to lower adjusted healthcare costs (primary healthcare: €973 vs. €1,165; specialized care: €339 vs. €510) and lower costs associated with productivity losses (€691 vs. €1,451)

Total costs per patient were significantly lower in patients initiating PGB in comparison with GBP: €2,472 vs. €3,346. This observation was mainly derived from lower absenteeism costs (€1,012 vs. €1,595) and lower adjusted healthcare costs (primary healthcare: €1,109 vs. €1,320; specialized care: €351 vs. €430)

Economic outcomes

PGB was associated with a higher reduction in LWDE, which in turn results in greater reduction of indirect costs while maintaining similar total costs despite its higher drug price

In comparison with GBP, adding PGB to existing painful diabetic peripheral neuropathy therapy resulted in lower total healthcare costs and lower resources utilization

PGB treatment of patients with painful axial radiculopathy was less costly for the healthcare system than treatment with GBP in routine medical practice

Conclusions

Adv Ther (2014) 31:1–29 7

Costing year

2007

2006

2006


MoreraDomıńguez et al. (2010) [40]

De SalasCansado et al. (2012) [41]


Table 1 continued

PGB-naı¨ve outpatients with refractory painful diabetic peripheral neuropathy treated under routine medical practice in primary care settings

PGB-naı¨ve outpatients with refractory neuropathic pain treated under routine medical practice in primary care settings

Patients with refractory low back pain as a result of lumbosacral radiculopathy

Population

Costeffectiveness model, NHS and societal perspectives, 12 weeks

Costeffectiveness model, NHS and societal perspective, 12 weeks

Cost– consequences analysis, perspective not specified, 12 weeks


UC

UC

UC

Comparator

Decision tree model with estimation of ICER using bootstrapping techniques

Decision tree model with estimation of ICER using bootstrapping techniques



Probabilistic sensitivity analysis and univariate sensitivity analysis

Probabilistic sensitivity analysis and univariate sensitivity analysis



PGB was associated with higher QALY gain in a period of 12 weeks. Overall total costs (€1,368 vs. €1,258) and healthcare costs (€628 vs. €469) were similar for both PGB and UC. ICERs for PGB varied from €5,302 for total costs to €14,381 for healthcare costs. 79–84% of ICERs were below the threshold of €30,000/QALY.

Drug acquisition costs were higher for PGB (€251 vs. €104). Direct healthcare costs and total costs were similar in both groups: €529 vs. €560, and €1,387 vs. €1,335, respectively, yielding a dominant ICER for both total and healthcare costs per QALY gain in the base case scenario

Compared with UC, PGB resulted in fewer lostworkday-equivalents, which produced more significant reductions in indirect costs (-€962 vs. -€626). The drug costs (€304 vs. €37), were offset by reductions in other components that lead to higher significant reductions for PGB in total healthcare costs (-€992 vs. -€579)

Economic outcomes

PGB may be cost-effective in the treatment of refractory outpatients with painful diabetic peripheral neuropathy when compared with UC in the primary care setting

PGB may be cost-effective in the treatment of refractory neuropathic pain when compared with UC in routine medical practice

Despite its higher cost, adding PGB was associated with larger reduction in lost workdays and indirect costs, resulting in significant lower total costs

Conclusions

8 Adv Ther (2014) 31:1–29

Costing year

2006

2006

2006


Pe´rez et al. (2009) [43]

Saldanã et al. (2010) [44]

Navarro et al. (2011) [45]

Table 1 continued

PGB-naı¨ve patients with peripheral neuropathic pain treated under routine medical practice in primary care settings

Patients with painful cervical or lumbar radiculopathy under medical practice conditions in primary care settings

Patients with trigeminal neuralgia and PGB-naı¨ve under usual clinical practice in primary care setting

Population





UC

UC

PGB monotherapy vs. PGB addon

Comparator









Incremental drug costs (€35 for non-PGB, €161 for PGB-m, and € 155 for PGB add-on), were counterbalanced by higher significant reductions in all other components of healthcare costs, yielding a greater direct (-€438, -€322, -€493) and LWDE (-€608, -€991, -€1,073) cost reductions in all 3 groups, as well as for the total costs (-€1,045, -€1,313, -€1,566)

The additional costs of drugs in PGB subgroups (€15 nonPGB, €149 PGB-mono, and €146 PGB add-on), were offset by greater reduction of all other components of healthcare and nonhealthcare costs, resulting in a substantial reduction of total costs: -€1,203, -€1,423, -€1,429, respectively)

PGB significantly reduces the use of healthcare resources in terms of ancillary tests (-€211) and unscheduled medical visits (-€324). Additional costs of PGB treatment (€174) is compensated for by a reduction in both healthcare costs (-€621) and indirect costs (-€1,210)

Economic outcomes

Treatment with PGB, both in monotherapy and in combination with other medications, results in a significant reduction in overall healthcare costs during the 12 weeks of the study

The incremental cost of the acquisition price of PGB was compensated by reductions in other components of healthcare costs, and by a significant reduction in LWDE

Despite the increase in the cost of pharmacological treatment, PGB was associated with a reduction in the use of healthcare resources, absenteeism and loss of productivity in trigeminal neuralgia patients

Conclusions

Adv Ther (2014) 31:1–29 9

2006

2006


Pe´rez et al. (2013) [47]

PGB-naı¨ve patients with refractory chronic peripheral neuropathic pain (secondary to diabetic neuropathy, postherpetic neuralgia, or trigeminal neuralgia) who initiated therapy with PGB

PGB-naı¨ve patients with GBP-refractory peripheral neuropathic pain who switched to PGB therapy

Population

Cost of illness, NHS and societal perspective, 12 weeks

Cost– consequences analysis, NHS and societal perspective, 12 weeks


PGB initiation at different times from diagnosis (\6, 6–12, and [12 months)

Gabapentin

Comparator

Multivariate linear regression model

Analysis of a prospective cohort study using ANCOVA models


Estimation of 95% confidence interval of standard error



Mean total costs 12 weeks before the baseline visit were significantly lower when PGB was initiated early (\6 months) in comparison with later initiation (6–12 and [12 months) after diagnosis: €2,439 vs. €3,011 vs. €2,945, respectively. Lower healthcare costs (€746 vs. €996 vs. €1,182) and fewer LWDE (€1,692 vs. €2,015 vs. €1,763) with early initiation of PGB were the main factors contributing to its lower total costs

Significant reductions in healthcare resource utilization were observed in patients switching to PGB (nonpharmacological treatment -€271, ancillary tests -€182, medical visits and hospitalizations -€321), as well as in LWDE costs. These changes imply substantial reductions in both direct (-€653) and indirect (-€852) healthcare costs

Economic outcomes

Early initiation of PGB treatment after diagnosis in patients with refractory chronic peripheral neuropathic pain results in substantial cost savings from a societal perspective in daily practice

Healthcare costs in patients with GBP-refractory peripheral neuropathic pain were significantly reduced after switching to PGB, alone or in combination with other analgesics

Conclusions

ANCOVA analysis of covariance, GBP gabapentin, ICER incremental cost-effectiveness ratio, LWDE lost-workdays-equivalent, NHS national health system, PGB pregabalin, QALY quality-adjusted-life-year, SNRI serotonin–norepinephrine reuptake inhibitor, SSRI selective-serotonin reuptake inhibitor, ST standard therapy, UC usual care

Costing year


Table 1 continued

10 Adv Ther (2014) 31:1–29

Adv Ther (2014) 31:1–29

11

analyses (economic models or real-life post hoc

pregabalin in Spanish neuropathic patients

studies; Fig. 2) performed with the objective of

have been identified. These publications vary

comparing pregabalin with standard medical practice, or with their current common drug

in terms of the comparator to pregabalin, the type of economic evaluation, the time horizon

counterparts: gabapentin (neuropathic pain), venlafaxine and SSRIs/serotonin–

considered, the costing year used for the economic analysis, and the etiological cause of

norepinephrine

neurological pain (Table 1).

reuptake

inhibitors

(SNRIs;

GAD), and levetiracetam (epilepsy). Among them, seven publications included typical cost-

Pregabalin versus Gabapentin

effectiveness analysis: three in neuropathic pain, another three in GAD, and one in epilepsy. The

Gabapentin is a gamma-aminobutyric acid analog currently used to relieve neuropathic pain [30].

decision-analytical modeling and handling of

Five economic analyses of pregabalin versus gabapentin for the treatment of neuropathic

uncertainty are also recorded in the tables. All the studies included in this review had the same sponsor (Pfizer S.L.U., Alcobendas, Spain; Pfizer Inc., NYC, USA; or both). A

methodological

evaluation

of

each

included study is included in Table 4 based on a detailed checklist of the CHEERS guideline

pain have been performed in Spain, including one specific cost-effectiveness model [31]. This study analyzed a hypothetical cohort of 1,000 patients with diabetic neuropathy or postherpetic neuralgia and compared their healthcare-associated costs when treated with

items recommended for the publication of drug economic studies. Relevance and limitations of

pregabalin or gabapentin over a total period of 12 weeks. The economic outcomes of this cost-

each economic study are also displayed in Table 4. All costing models and estimates are

effectiveness analysis resulted in similar total healthcare costs of both treatments (€1,049 for

described according to the original publications

pregabalin vs. €951 for gabapentin). The mean

by its authors. Cost analyses indicate that the use of pregabalin resulted in higher drug

calculated ICER for pregabalin versus gabapentin was €12 per additional day with no or mild pain,

purchase costs compared to usual care or other treatments. On the other hand, healthcare costs

€431 per additional patient with no or mild pain, and €20,535 per QALY gained. Significant

and costs due to productivity losses associated

additional clinical benefits of pregabalin, in

with pregabalin were usually lower in terms of medical visits, hospitalization, impact on

comparison with gabapentin, were also proven for the number of days with no or mild pain and

productivity, and work absenteeism. As a result, cost usually accommodated the higher

the number of days with a reduction in pain intensity.

pregabalin acquisition costs, yielding to a

A similar time extension analysis (12 weeks)

higher economic benefit from pregabalin in GAD, epilepsy, and neuropathic pain under a

was used in a post hoc cost–consequences study [32] that took into account data from two

societal perspective in Spain.

multicenter, observational studies conducted to determine the cost of neuropathic pain in

Neuropathic Pain

primary care settings under usual clinical practice in Spain [33, 34]. The analysis was based

A considerable amount of published studies (14)

on a nested case–control approach with two

concerning pharmacoeconomic evaluations of

controls (pregabalin) per case (gabapentin) and

PGB was €25,304 (86% of

sensitivity analysis

bootstrapping techniques

6 months

costs univariate

6 months

percentage of patients under benzodiazepine therapy

although 6 months costs were not significantly different in PGB and SSRIs/SNRIs groups (€977 vs.

with covariates

SNRI

€822)

healthcare costs and with less

benzodiazepine resistance, linear models

with an SSRI/

with PGB or

significant reduction in total

PGB (-€289, P = 0.003) after differences in

using

[50]

patients was associated with

utilization costs decreased with estimation for

cohort study

perspective,

started therapy

(2013)

NHS

patients who

et al.

benzodiazepine-refractory GAD

Compared with SSRIs/SNRIs, mean total healthcare resource

SNRIs

interval

SSRIs/

threshold)

prospective

Comparative cost analysis,

Benzodiazepine-

refractory GAD

2009

Perera

Carrasco-

SSRI/SNRI

PGB or to an

[49]

Initiating treatment with PGB in

healthcare settings ICER per QALY gained with

univariate

ICER using

perspective,

switched to

(2012)

95% confidence

patients treated in mental

healthcare (€1,014 vs. €846) and drug costs (€376 vs. €220). The

analysis and

estimation of

model, NHS

patients who

et al.

Analysis of a

benzodiazepine-refractory GAD

presented increased 6-months

sensitivity

resamples below €30,000

comparison with SSRI/SNRIs in

Compared with SSRI/SNRI, PGB

Probabilistic

SNRIs

model with

effectiveness

Cost-

refractory GAD

Cansado

De Salas-

PGB is cost-effective in

simulations Decision tree

Monte Carlo

SSRIs/

incremental ratios decline to €70 and €23,909, respectively

second-order

1 year

Benzodiazepine-

and €32,832 per QALY gained. When considering indirect costs,

first- and

perspective,

GAD

(2010)

2008

with moderate to severe GAD

additional week with no anxiety

analysis with

model

model, NHS

[48]

term perspective for patients

(vs. VEN) were €96 per

sensitivity

simulation

effectiveness

PGB is cost-effective in a long-

The incremental drug costs of PGB

patients with

Probabilistic

Conclusions

Economic outcomes

cohort of 1000

Markov

Venlafaxine

Cost-

Handle of uncertainty

et al.

Hypothetic

2007

Vera-

Decisionanalytical model

Comparator


Llonch

Population

Costing year


Table 2 Economic analysis of pregabalin in patients with generalized anxiety disorder

12 Adv Ther (2014) 31:1–29

partial response to SSRIs may be cost-effective in comparison with UC

both cohorts: -€478 (PGB) and -€446 (UC), yielding to similar 6-months costs (€1,565 vs. €1,406, respectively)

estimation for differences in costs and consequences

cohort study using univariate linear models

analysis, NHS perspective, 6 months

response to

SSRIs in routine

medical practice

(2013)

[52]

GAD generalized anxiety disorder, ICER incremental cost-effectiveness ratio, PGB pregabalin, QALY quality-adjusted-life-year, SNRI serotonin–norepinephrine reuptake inhibitor, SSRI selective-serotonin reuptake inhibitor, ST standard therapy, UC usual care, VEN venlafaxine

covariates

with

treatment of GAD patients with

Including adjunctive PGB in the

costs were significantly reduced in

Mean total healthcare utilization

interval

95% confidence

prospective

Analysis of a

consequences

with poor

UC

threshold)

et al.

GAD patients

6 months

Cost–

with PGB was €15,804 (94% of

analysis

techniques

2009

healthcare settings

The ICER per QALY gained

sensitivity

bootstrapping

6 months

anxiolytics other

[51]

Carrasco

comparison with UC in mental

and drug costs (€525 vs. €219).

univariate

ICER using

perspective,

regimen of

(2013)

resamples below €30,000

GAD may be cost-effective in

healthcare (€1,272 vs. €1,070)

analysis and

estimation of

model, NHS

standard dose

et al.

than PGB, over

refractory outpatients with

Including PGB in the treatment of

presented increased 6-months

sensitivity

model with

Compared with UC, PGB

Probabilistic

Decision tree

UC

effectiveness

Cost-

Conclusions

Economic outcomes

Handle of uncertainty

refractory to

GAD patients

2008

De Salas-


Comparator


Cansado

Population

Costing year


Table 2 continued

Adv Ther (2014) 31:1–29 13

Adv Ther (2014) 31:1–29

NHS national health system, ICER incremental cost-effectiveness ratio, LEV levetiracetam, PGB pregabalin, QALY quality-adjusted-life-year, ST standard therapy

ST had the lowest treatment In comparison with cost per year: €897 vs. €3,018 ST, PGB has better (LEV) and €1,843 (PGB). cost-effectiveness Incremental cost per QALY than LEV when gained was €23,881 (PGB) vs. considering both €95,904 (LEV). ICER of PGB QALY gained and per day free of crisis was €22 day without crisis vs. €95 (LEV) Multiple probabilistic sensitivity analysis Markov simulation model CostLevetiracetam effectiveness and ST model, NHS perspective, 1 year Hypothetic cohort of 1000 patients with refractory partial epilepsy 2007 Dıáz et al. (2007) [54]

Comparator Type of economic analysis, perspective, time horizon Population Study Costing (year) year [reference]

Table 3 Economic analysis of pregabalin in epileptic patients


Conclusions Economic outcomes Handle of uncertainty

14

included

subjects

with

refractory

chronic

peripheral neuropathic pain due to diabetic neuropathy, post-herpetic neuralgia, trigeminal neuralgia, or radiculopathy at axial rotation. A significantly higher drug cost change was associated with pregabalin after 12 weeks of treatment (€168 vs. €92; P\0.001), but this was offset by a greater reduction in costs linked to productivity losses (-€964 vs. -€680; P = 0.163). This scenario reductions in pregabalin

and

found similar overall cost both groups: -€1,254 for -€1,384

for

gabapentin,

respectively (P = 0.593), while pregabalin treatment appeared to be associated with greater reduction in mean weekly intensity of pain. The remaining three manuscripts comparing pregabalin with gabapentin [35–37] were all focused on data collected retrospectively from several primary care health centers in a specific region of Spain (Badalona, Barcelona) instead of a well-balanced population, representative of all Spanish territories. One of these studies [35] included all subjects requiring care for peripheral neuropathic pain from January 2006 to December 2008 who initiated treatment with either pregabalin or gabapentin. In communitytreated patients with peripheral neuropathic pain, the observed higher acquisition cost of pregabalin with respect to gabapentin (€351 vs. €191; P\0.001) was compensated by lower costs in medical visits (€247 vs. €325; P\0.001), physiotherapy (€227 vs. €237; P\0.05), hospital stays (€18 vs. €59; P\0.05), and concomitant drugs (€221 vs. €383; P\0.001) in those patients initiated with pregabalin. Pregabalin-treated patients showed lower adjusted total costs when compared with gabapentin (€2,514 vs. €3,241; P\0.005), mainly due to a reduction in sick leaves costs (€1,067 vs. €1,633; P\0.05) and lower healthcare costs (€1,447 vs. €1,609; P\0.01). The remaining two studies, with a time frame horizon of 1 year, used 2010 as a

Adv Ther (2014) 31:1–29

15

Fig. 2 Real-life economic studies and models included in the present literature review of pregabalin in Spain. GAD generalized anxiety disorder costing year for the economic analysis from a

€1,165; P = 0.01) and specialized care (€339 vs.

third-payer perspective [36, 37]. Both papers

€510; P = 0.001). When sensitivity analysis was

aimed at comparing the costs of introducing pregabalin or gabapentin in the therapeutic

performed, outpatient costs remained higher (P = 0.063) despite reductions in the costs of

management of patients under routine medical practice: first in those with painful axial

gabapentin (-45%) and pregabalin (-7.5%), to match the current prices of these two drugs,

radiculopathy [36] and second in those with

leading to significantly higher healthcare costs of

painful diabetic peripheral neuropathy [37]. The 1-year adjusted total cost per patient with axial

gabapentin-treated patients compared with pregabalin-treated patients (€1,552 vs. €1,296;

radiculopathy was significantly lower in those starting pregabalin treatment compared to

P = 0.001).

gabapentin (€2,472 vs. €3,346; P = 0.005). This

Pregabalin versus Usual Care In Spain, four economic studies were identified

observation predominantly arose from lower costs, due to a reduction in absenteeism (€1,012

that compared pregabalin with usual care in

vs. €1,595; P\0.05) and from lower adjusted healthcare costs (€1,460 vs. €1,750; P = 0.001).

patients with chronic neuropathic pain. Usual care was considered as any drugs labeled for

Similar findings were found in subjects with a painful diabetic neuropathy; significantly lower

neuropathic pain in Spain, prescribed at their recommended doses that did not include

mean total adjusted costs per patient were

pregabalin.

observed in those starting treatment with pregabalin compared to gabapentin (€2,003 vs.

consequence analysis during a time horizon of 12 weeks. The first two real-life studies were

€3,127; P\0.001). This difference was found to be due to significantly lower costs, due to reduced

published in 2010 as a secondary analysis of the RADIO study of costs and consequences of

absenteeism (€691 vs. €1,451; P\0.05) as well as

refractory

lower healthcare costs (€1,312 vs. €1,675; P\0.001), both in primary healthcare (€973 vs.

analyzed the cost of treating pain, derived from radiculopathies, using 2007 as a year for

All

axial

studies

pain

simulated

[38].

Both

a

cost–

studies

Items not applicable

9 (discount rate) and 21 (characterizing heterogeneity)

9 (discount rate), 12 (measurement of preferences), 15 (choice of model) and 16 (model assumptions)

9 (discount rate), 10 (choice of health outcomes), 11 (measurement of effectiveness), 12 (measurement of preference based outcomes), 15 (choice of model)

9 (discount rate), 10 (choice of health outcomes), 11 (measurement of effectiveness), 12 (measurement of preference based outcomes) and 15 (choice of model)




Rodrı´guez et al. (2007) [31]

Pe´rez et al. (2010) [32]



Sicras et al. (2013) [37]

Flo´rez-Garcıá et al. (2011) [39]

6 (study perspective), 20a (characterizing uncertainty) and 21 (characterizing heterogeneity)

5 (setting and location), 16 (assumptions) and 21 (characterizing heterogeneity)

5 (setting and location) and 16 (assumptions)

5 (setting and location), 16 (assumptions) and 21 (characterizing heterogeneity)

20a (characterizing uncertainty) and 21 (characterizing heterogeneity)

5 (setting and location)

Items not considered in the economic evaluation

?

?

?

?

?

?

PGB economically attractive?

17/20 (85%)

16/19 (84%)

17/19 (89%)

16/19 (84%)

18/20 (90%)

21/22 (95%)

CHEERS checklist scorea

Cost–consequences analysis populated with data extracted from a real-world study supporting generalizability. Time horizon of 12 weeks appropriated for a neuropathic pain condition according to recommendations from the European Medicinal Agency to treat this health condition. Uncertainty limited to 95% confidence interval estimation of differences in costs and consequences. Differences in subgroups not reported

Cost analysis populated with data extracted from a real-world setting supporting generalizability to another setting in the country. Uncertainty handled with probabilistic resampling techniques and price sensitivity analysis. No assumptions included in the analysis and possibility for underreporting of costs due to the retrospective design of the cost analysis. Differences in subgroups not reported

Cost analysis populated with data extracted from a real-world setting supporting generalizability to another setting in the country. Uncertainty handled with probabilistic resampling techniques. Differences in subgroups reported. No assumptions included in the analysis and possibility for underreporting of costs due to the retrospective design of the cost analysis

Cost analysis populated with data extracted from a real-world setting supporting generalizability to another settings in the country. Uncertainty handled with probabilistic resampling techniques. No assumptions included in the analysis and possibility for underreporting of costs due to the retrospective design of the cost analysis. Differences in subgroups not reported

Cost–consequences analysis populated with data extracted from real-world studies supporting generalizability. Time horizon of 12 weeks appropriated for a neuropathic pain condition according to recommendations from the European Medicinal Agency to treat this health condition. Uncertainty limited to 95% confidence interval estimation for costs and consequences differences. Differences in subgroups not reported

Decision-analytical model appropriated. Time horizon of 12 weeks appropriated for a neuropathic pain condition according to recommendations from the European Medicinal Agency to treat this health condition. Model populated with data extracted from different RCT instead of a unique H2H RCT

Critical appraisal: relevance of the model and limitations of the economic evaluation

Table 4 Quality assessment of the economic analyses included in the systematic review using the CHEERS checklist

16 Adv Ther (2014) 31:1–29



9 (discount rate)

9 (discount rate)

9 (discount rate), 12 (measurement of preferences), 15 (choice of model) & 16 (model assumptions)



MoreraDomıńguez et al. (2010) [40]



Pe´rez et al. (2009) [43]

Saldanã et al. (2010) [44]

Table 4 continued

5 (setting and location), 6 (study perspective), 20a (characterizing uncertainty) and 21 (characterizing heterogeneity)

5 (setting and location), 6 (study perspective), 20a (characterizing uncertainty) & 21 (characterizing heterogeneity)

21 (characterizing heterogeneity)


6 (study perspective), 20a (characterizing uncertainty) and 21 (characterizing heterogeneity)


?

?

?

?

?


16/20 (80%)

16/20 (80%)

22/23 (96%)

22/23 (96%)

17/20 (85%)


Cost–consequences analysis populated with data extracted from a real-world study supporting generalizability, Time horizon of 12 weeks appropriated for a neuropathic pain condition according to recommendations from the European Medicinal Agency to treat this health condition. Uncertainty limited to 95% confidence interval estimation for costs and consequences differences. Differences in subgroups not reported. Societal perspective limited to lostworkdays-equivalents only. Differences in subgroups not reported

Cost–consequences analysis populated with data extracted from a real-world study supporting generalizability. Time horizon of 12 weeks appropriated for a neuropathic pain condition according to recommendations from the European Medicinal Agency to treat this health condition. Uncertainty limited to 95% confidence interval estimation for costs and consequences differences. Differences in subgroups not reported. Sample size limited. Consequences limited to only one outcome (pain). Societal perspective limited to lost-workdays-equivalents only. Differences in subgroups not reported

Decision-analytical model appropriated. Time horizon of 12 weeks appropriated for a neuropathic pain condition according with recommendations from European Medicinal Agency to treat this health condition. Model populated with data extracted from a real-world study. Societal perspective limited to lost-workdays-equivalents only. Differences in subgroups not reported

Decision-analytical model appropriated. Time horizon of 12 weeks appropriated for a neuropathic pain condition according to recommendations from European Medicinal Agency to treat this health condition. Model populated with data extracted from a real-world study. Societal perspective limited to lost-workdays-equivalents only. Differences in subgroups not reported

Cost–consequences analysis populated with data extracted from a real-world study supporting generalizability. Time horizon of 12 weeks appropriated for a neuropathic pain condition according to recommendations from the European Medicinal Agency to treat this health condition. Uncertainty limited to 95% confidence interval estimation of differences in costs and consequences. Differences in subgroups not reported. Differences in subgroups not reported


Adv Ther (2014) 31:1–29 17




9 (discount rate), 10 (choice of health outcomes), 11 (measurement of effectiveness), 12 (measurement of preference based outcomes), 15 (choice of model) and 16 (assumptions)

9 (discount rate)

9 (discount rate)




Pe´rez et al. (2013) [47]

Vera-Llonch et al. (2010) [48]


Table 4 continued



20b (characterizing uncertainty) and 21 (characterizing heterogeneity)




?

?

NA

?

?


22/23 (96%)

22/23 (96%)

16/18 (88%)

16/20 (80%)

16/20 (80%)


Decision-analytical model appropriated. Time horizon of 6 months appropriated for this health condition according to recommendations from the European Medicinal Agency. Model populated with data extracted from a prospective cohort real-world trial. Differences in subgroups not reported

Decision-analytical model appropriated. Time horizon of 1 year appropriated for this health condition according to recommendations from the European Medicinal Agency. Model populated with data extracted from a head to head clinical trial. Differences in subgroups not reported

Decision-analytical model appropriated. Time horizon of 12 weeks appropriated for a neuropathic pain condition according to recommendations from the European Medicinal Agency to treat this health condition. Model populated with data extracted from a real-world study. Uncertainty limited to 95% confidence interval estimation of the standard errors. Societal perspective limited to lostworkdays-equivalents only. Differences in subgroups not reported

Cost–consequences analysis populated with data extracted from a real-world study supporting generalizability, Time horizon of 12 weeks appropriated for a neuropathic pain condition according to recommendations from European Medicinal Agency to treat this health condition. Uncertainty limited to 95% confidence interval estimation for costs and consequences differences. Differences in subgroups not reported. Consequences limited to only one outcome (pain). Societal perspective limited to lostworkdays-equivalents only. Differences in subgroups not reported

Cost–consequences analysis populated with data extracted from a real-world study supporting generalizability, Time horizon of 12 weeks appropriated for a neuropathic pain condition according to recommendations from the European Medicinal Agency to treat this health condition. Uncertainty limited to 95% confidence interval estimation for costs and consequences differences. Differences in subgroups not reported. Societal perspective limited to lostworkdays-equivalents only. Differences in subgroups not reported


18 Adv Ther (2014) 31:1–29


9 (discount rate)

9 (discount rate), 10 (choice of health outcomes), 11 (measurement of effectiveness), 12 (measurement of preference based outcomes), and 15 (choice of model)

9 (discount rate)

CarrascoPerera et al. (2013) [50]


Carrasco et al. (2013) [52]

Dıáz et al. (2007) [54] 21 (characterizing heterogeneity)

16 (assumptions), 20a (characterizing uncertainty) and 21 (characterizing heterogeneity)


16 (assumptions), 20a (characterizing uncertainty) & 21 (characterizing heterogeneity)


?

?

?

?


22/23 (96%)

16/19 (84%)

22/23 (96%)

16/19 (84%)


Decision-analytical model appropriated. Differences in subgroups not reported

Cost and consequences analysis populated with data extracted from a real-world cohort study in the whole country. Time horizon of 6 months appropriated for this health condition according to recommendations from the European Medicinal Agency. Uncertainty limited to 95% confidence interval estimation of differences in costs and consequences. No assumptions included in the analysis. Differences in subgroups not reported

Decision-analytical model appropriated. Time horizon of 6 months appropriated for this health condition according to recommendations from European Medicinal Agency. Model populated with data extracted from a prospective cohort real-world trial. Differences in subgroups not reported

Cost analysis populated with data extracted from a real-world cohort study in the whole country. Time horizon of 6 months appropriated for this health condition according to recommendations from the European Medicinal Agency. Uncertainty limited to 95% confidence interval estimation of differences in costs. No assumptions included in the analysis. Differences in subgroups not reported


a

?, Economically attractive for PGB based on findings showing PGB as cost-saving, cost-neutral but with better health outcomes, or alternatively showing an ICER below the usually accepted healthcare incremental cost-effectiveness threshold for Spain (i.e., \€30,000 per QALY gained [28] Since the CHEERS checklist focuses on economic models for health economic evaluations, some of the items in the list are not applicable to all pharmacoeconomic studies. For this reason, this score was calculated as a percentage of fulfilled items from those that apply to the particular reviewed study instead of the original 24 total CHEERS items CHEERS Consolidated Health Economic Evaluation Reporting Standards, H2H head to head, ICER incremental cost-effectiveness ratio, NA not applicable, PGB pregabalin, QALY quality-adjusted-lifeyear, RCT randomized clinical trial



Table 4 continued

Adv Ther (2014) 31:1–29 19

Adv Ther (2014) 31:1–29

20

cost-comparative purposes [39, 40]. The first study focused its attention on patients with

in primary care settings [41, 42]. The first study selected matched pairs of pregabalin-naı¨ve

refractory neck pain as a result of cervical or lumbar radiculopathy under real-life conditions

patients with neuropathic pain receiving usual care or pregabalin, and refractory to previous

[39]. The results of this secondary analysis reflected that adding pregabalin was associated

treatment, in a 1:1 ratio [41]. Despite the significantly higher drug purchase costs for

with a higher reduction in pain severity in

pregabalin

comparison with usual care (P\0.001), which resulted in significant reductions in mean lost-

healthcare and total costs were similar in both groups: €529 vs. €560 (P = 0.628) and €1,387 vs.

workday-equivalents (-€20.1 vs. -€8.2; P = 0.014) and in significant lower cost due to

€1,335 (P = 0.587), respectively. This result yields a dominant ICER for both total and

productivity

losses:

vs.

(€251

vs.

€104;

P\0.001),

-€457

healthcare costs per QALY gain in the base

(P = 0.028). The higher treatment costs of pregabalin (€310 vs. €26; P\0.001) was offset

case scenario. The second paper with this specific framework was focused on refractory

by higher reductions in other components, yielding to similar reductions in direct costs

patients diagnosed with diabetic peripheral neuropathic pain [42]. Overall, the total costs,

(-€67 vs. -€144; P = 0.295) but higher when

including healthcare costs and costs due to

overall costs were considered (-€1,108 vs. -€601; P\0.01). The second manuscript

productivity losses (€1,368 vs. €1,258; P = 0.598), were similar for both pregabalin

completed the post hoc cost–consequence analysis in a subset of patients with chronic

and usual care patients. Healthcare costs were also similar: €628 vs. €469; P = 0.134. The ICERs

refractory lower back pain due to lumbosacral radiculopathy [40]. As was observed in the

for pregabalin for the management of community-based patients with refractory

previous paper, pregabalin was associated with

diabetic peripheral neuropathic pain varied

higher adjusted decline in severity of pain compared with usual care (P\0.001).

from €5,302 for total costs to €14,381 for healthcare costs. After probabilistic sensitivity

Consequently, pregabalin treatment resulted in fewer lost-workday-equivalents (27.8 vs.

analysis, the authors proved that 79–84% of ICERs were below the usually accepted

34.6;

threshold of €30,000/QALY [28].

P = 0.002)

-€1,041

and

significant

higher

reductions in corresponding costs when compared with usual care (-€962 vs. -€626;

Pregabalin Monotherapy in Comparison

P\0.005). Despite the higher cost associated with purchasing pregabalin (?€304 vs. ?€37;

with the Add-on Strategy Four cost–consequences

P\0.001), after 12 weeks larger reductions were

identified

observed for pregabalin in medical visits and hospitalizations (-€159 vs. ?€116; P = 0.001).

effectiveness of pregabalin in both monotherapy and in combination with other

The overall analysis of costs resulted in significant larger reductions in total healthcare

medications [43–46]. One of these economic analyses focused on pregabalin-naı¨ve patients

costs for pregabalin (-992€ vs. -€579; P\0.05).

diagnosed with trigeminal neuralgia under usual clinical practice in Spain and used 2006

Two cost-effectiveness studies were identified that compared pregabalin with usual care in Spanish patients with neuropathic pain

that

evaluations

demonstrated

the

were cost-

as the costing year [43]. Overall, and after 12 weeks, pregabalin significantly reduced the

Adv Ther (2014) 31:1–29

21

use of healthcare resources such as additional

monotherapy, and ?€155 for add-on therapy;

tests (-€211; P\0.0001) and unscheduled

P\0.001) were counterbalanced by higher

medical visits (-€324; P\0.0001). Globally, additional costs of therapies including

significant reductions in other components of healthcare costs, such as medical visits,

pregabalin (?€174) were compensated for by a reduction in both healthcare costs (-€621;

hospitalizations, and complementary tests. This trend translates into significant cost

P\0.0001)

of

reductions for all three groups in healthcare

productivity (-€1,210; P\0.0001). Another paper, also using 2006 as a costing year, was

costs (-€438, -€322, -€493, respectively; P\0.05) and productivity costs in terms

based on patients with refractory painful radiculopathy of cervical or lumbosacral origin

of lost-workdays-equivalents (-€608, -€991, -€1,073, respectively; P\0.001). This

in primary care settings. This paper, focused on

indicated significant differences in the reduction

the utilization of healthcare resources and days of sick leave, compared pregabalin

of overall healthcare costs during the 12 weeks of the study associated with the treatment

monotherapy with the add-on approach and non-pregabalin patients [44]. The additional costs of drugs in the pregabalin add-on

of peripheral neuropathic pain (-€1,045; -€1,313; -€1,566; respectively; P\0.05). The switch study included pregabalin-naı¨ve patients

subgroup (?€15 non-pregabalin, -€149 monotherapy, and ?€145 add-on, P\0.001)

with peripheral neuropathic pain who were previously unresponsive to gabapentin and

were offset by a greater reduction of both healthcare resources (-€449, -€425, -€364,

therefore switched to pregabalin [46]. The study concluded that healthcare costs in patients with

respectively; P\0.001) and days of sick leave (-€755, -€998, -€1,065, respectively;

gabapentin-refractory peripheral neuropathic pain were significantly reduced after switching

P = 0.001).

and

costs

Combined,

due

this

to

loss

a

to pregabalin alone or in combination with other

substantial reduction in total costs: -€1,203, -€1,423, -€1,429, respectively (P\0.001). The

resulted

in

analgesics. Consequently, significant reductions in components of healthcare resource utilization

third and fourth studies compared pregabalin monotherapy and add-on versus usual care not

were observed in patients switching to pregabalin including complementary tests (-€156

including pregabalin in refractory peripheral

monotherapy and -€218 add-on; P\0.001 in

neuropathic pain (under routine medical practice) and were both sub-analyses of the

both cases), medical visits, and hospitalizations (-€179 and -€513; P\0.05 and P\0.01,

previously described prospective 12-week study that used 2006 prices as a costing reference and pregabalin-naı¨ve patients [33]. One analysis was

respectively). These changes implied substantial reductions in both healthcare costs (-€352 and

focused on the cost–consequences of treating patients with peripheral neuropathic pain [45]

workdays-equivalents (-€647 and -€1,128, respectively; P\0.0001 in both cases).

and the other only considered gabapentinrefractory patients switching to pregabalin

The Time of Initiation of Pregabalin Therapy

therapy [46]. In the cost–consequences study, the authors identified that incremental changes in drug costs associated with pregabalin treatment (?€35 for non-pregabalin, ?€161 for

-€1,059; P\0.001) and costs due to lost-

The last economic evaluation on neuropathic pain was a cost-of-illness study that analyzed the most cost-saving time to initiate pregabalin therapy for the management of peripheral

Adv Ther (2014) 31:1–29

22

neuropathic pain [47]. The study focused on pregabalin-naı¨ve patients who started pregabalin

cost-effectiveness analysis and cost analysis

therapy at the first visit and with data available on the time since diagnosis. The analysis used

benzodiazepine-refractory GAD patients [49, 50]. Considering a time horizon of 1 year, the

prices from year 2006 for the calculation of healthcare costs and productivity cost loss due

probabilistic simulation model developed by Vera-Llonch et al. [48] had estimated a clinical

to lost-workdays-equivalents and subdivided

anxiety benefit for pregabalin (10.6 Hamilton

patients into three groups according to the time since diagnosis to pregabalin initiation (B6, 6–12,

Anxiety Rating Scale (HAM-A) score vs. 12.8 with venlafaxine), as well as a significant

[12 months). The aim of the study was to examine if early initiation of pregabalin after

increase in the number of weeks with no or minimal anxiety (HAM-A B9 in 13.5 vs.

diagnosis was associated with a lower economic

4.3 weeks, respectively). In addition, the cost-

burden compared to initiation at a later time point, for the management of refractory chronic

effectiveness analysis also highlighted the fact that drug acquisition costs were higher for

peripheral neuropathic pain in daily practice. The results showed that adjusted mean total

pregabalin over a 1-year period (€1,664 vs. €780 for venlafaxine), while the mean costs of

costs 12 weeks before the baseline visit were

medical care services were estimated to be

significantly lower when pregabalin was initiated early compared with intermediate

€2,207 for patients treated with pregabalin and €2,454 for patient treated with venlafaxine.

initiation after diagnosis (€2,439 vs. €3,011; P = 0.004) and with later initiation (€2,439 vs.

When considering healthcare and productivity costs simultaneously, incremental ratios

€2,945; P = 0.009). The main factors contributing to lower total costs with early initiation of

declined to only €70 per additional week and €23,909 per QALY gained, respectively, which is

pregabalin were the lower healthcare costs

below the common accepted threshold of

(€746 vs. €996 vs. €1,182) and fewer productivity costs measured as lost workday-

€30,000 accepted as willingness to pay [28]. Regarding the two studies comparing

equivalents (€1,692 vs. €2,015 vs. €1,763).

pregabalin and SSRIs/SNRIs therapy in benzodiazepine-refractory GAD patients, the

Generalized Anxiety Disorder

first

As

switched their drug therapy [49], while the second one only considered for analysis patients naı¨ve to pregabalin or SSRIs/SNRIs

summarized

in

Table 2,

five

different

economic analyses evaluated the costeffectiveness of pregabalin for patients with

of

[50].

pregabalin

one

The

was

versus

centered

SSRIs/SNRIs

on

cost-effectiveness

in

patients

results

who

show

GAD in Spain in comparison with SSRIs/SNRIs of usual care [48–52].

similar trends in both studies, but with some

Pregabalin versus SSRIs/SNRIs The first paper describes the cost-effectiveness of

reference costing year and demonstrated an increase in healthcare costs (€1,014 vs. €846;

treatment of GAD, from a Spanish healthcare perspective, with pregabalin versus venlafaxine

P = 0.166) and drug acquisition (€376 vs.

extended-release [48]. Two more manuscripts were centered on a post hoc comparative

remarkable differences. De Salas Cansado et al. [49] published their results using 2008 as a

€220; P\0.001) with pregabalin over the 6-month study period. The estimated ICER per

QALY

gained

was

€25,304,

and

its

Adv Ther (2014) 31:1–29

23

calculation

pregabalin vs. -€446 with usual care) after

exhibit a 86% of re-samples below €30,000 as

6 months. At the end of the 6-months period,

a threshold for pay value [28]. When focusing only on GAD patients naı¨ve to pregabalin and

healthcare costs were similar in both groups (€1,565 vs. €1,406; P = 0.777). The higher

SSRIs/SNRIs [50], the analysis used 2009 as a costing year. The mean total costs—after the

pregabalin acquisition costs (€534 vs. €241; P\0.001) were compensated by significant

6-month period—were higher for pregabalin

reductions in the number of medical visits

but not statistically significant (€977 vs. €822; P = 0.488). The only significantly different

(€474 vs. €580; P\0.013) and hospitalizations (€2 vs. €9; P = 0.056) in this group of patients

component was the drug acquisition costs (€354 for pregabalin vs. €213 for SSRIs/SNRIs;

when compared with usual care. However, patients significantly benefit more with

P\0.001). Interestingly, the mean total costs

pregabalin

decreased more intensely with pregabalin after 6 months (-€289 vs. -€194).

concomitant depressive symptom reductions were considered in comparison with usual care.

Pregabalin versus Usual Care

Also, patients receiving pregabalin showed a substantial better functioning on the World

bootstrapping

techniques

of

Two recent manuscripts were designed with the objective of comparing pregabalin cost-

Health

when

anxiety

Organization

symptoms

Disability

and

Assessment

effectiveness with usual care in GAD patients

Schedule 2.0 scale [53] than subjects treated with usual care.

refractory to previous standard anxiolytic therapies [51] or cost–consequences in subject

Pregabalin as Adjunctive Therapy

with partial response to SSRIs [52]. The studies used year 2008 and year 2009 prices,

for Epilepsy

respectively, for the estimation of GAD-related

The current literature search identified only one article that evaluated the economic

healthcare costs over 6 months. In comparison with usual care, refractory patients with

outcomes of pregabalin in Spanish epileptic

persistent symptoms of anxiety after standard regimen of anxiolytics other than pregabalin

patients (Table 3) [54]. The study was designed with the objective of evaluating the cost-

who switched to pregabalin presented increased

effectiveness of adjuvant treatment with pregabalin (300 mg/day) or levetiracetam

healthcare (€1,272 vs. €1,070; P = 0.069) and drug costs (€525 vs. €219; P\0.001). In turn,

(2,000 mg/day) in comparison with standard

this resulted in an ICER of €15,804 per QALY gained, with a total of 94% of re-samples from

therapy in Spanish patients with refractory partial epilepsy. The methodology of the

the bootstrapping analysis below the €30,000

study included a probabilistic and dynamic simulation model of a hypothetical cohort of

threshold per QALY [51]. The, as of yet, unpublished cost–consequences

1,000 patients with refractory partial epilepsy,

study by Carrasco et al. only considered SSRIsrefractory patients who start pregabalin therapy

evaluating the impact of adjuvant therapy on the frequency of days with crisis. The primary

or follow usual care (switch to another SSRIs/add another anxiolytic) [52]. Under this approach,

efficacy results of the model have shown that pregabalin provides an average of 43.3 ± 4.8

significant reductions in mean total healthcare

free-of-crisis days more than standard therapy,

costs were observed in both cohorts (-€478 with

in comparison with an average of 24.3 ± 6.2

Adv Ther (2014) 31:1–29

24

with levetiracetam. Standard therapy resulted

jeopardize an overall economic framework if we

in the lowest treatment cost per year: €897 vs.

consider the evolving drug prices, the changing

€3,018 with levetiracetam and €1,843 with pregabalin. Incremental costs per QALY

health payer schemes in recent years, and the introduction of new therapies. Besides this, the

gained with pregabalin and levetiracetam were €23,881 (95% CI 19,206–30,247) and

economic attractiveness of a therapeutic strategy was defined on the basis of well-

57,137–203,169),

established criteria of cost-saving and/or cost-

respectively. Similarly, the ICER per day free of crisis was €22 (95% CI 19–27) with

effectiveness approach for the healthcare management of patients in Spain [28].

pregabalin and €95 (95% CI 60–177) with levetiracetam. In conclusion, the study states

Similarly, the assessment of the quality of the included studies in this review by means of a

that, when compared with standard therapy,

score and a quality assessment review based on

pregabalin had better cost-effectiveness than levetiracetam as an add-on therapy in patients

the CHEERS checklist [29], suggested that all the 20 manuscripts reached a score of

with partial refractory epilepsy when considering both QALY gained and days

accomplishment of at least 80% of the required items from the CHEERS standards,

without crisis from the perspective of the

despite some observed limitations (see below).

Spanish National Healthcare System [54].

The cost-effectiveness of the use of pregabalin in neuropathic pain conditions was

DISCUSSION

also evaluated in previous studies in different countries [55, 56]. An American retrospective

This systematic literature review was carried out

cohort study evaluated the economic cost of initiating treatment with duloxetine or

€95,904

(95%

CI

with the objective of assessing current evidence regarding the impact of pregabalin on the economic

burden

associated

with

the

management of neuropathic pain, GAD, and epilepsy from the National Healthcare Systems and societal perspectives in Spain. In most economic studies, variability in analysis designs and assumptions, as well as differences in healthcare systems and costs of medical care, tended to hinder direct comparisons and synthesis of results. In contrast, the studies described herein have exhibited a relatively uniform analysis design and have been restricted to a target country, as a reference for evaluation (Spain). Thus, this yields a relatively significant consistency within the presented results and comparisons.

pregabalin

during

2006

in

patients

with

diabetic peripheral neuropathic pain [55]. The presented data favored duloxetine in terms of a slightly lower total healthcare costs over the 12-month period of the study compared to pregabalin-treated

patients

($34,146

vs.

$34,897, P\0.05). Interestingly, from the point of view of the data reviewed here, pregabalin treatment in Spanish patients with refractory neuropathic pain has shown to lead to a considerable lower total healthcare costs than that reported in this study, despite using the same costing year [41]. More recently, a cost–utility study adapted a simulation model to compare pregabalin—combined with usual care—to usual care alone when treating patients

However, the costing years used for reference, healthcare calculations, and the specific

with refractory neuropathic pain in a Swedish setting [56]. The model obtained an

subpopulations analyzed in each study could

incremental

cost-effectiveness

ratio

for

Adv Ther (2014) 31:1–29

25

pregabalin plus usual care treatment of €5,364

per QALY gained of €23,881 with pregabalin

(societal perspective) or €12,886 (National

treatment [54].

Healthcare Systems perspective). These are slightly higher than the costs obtained from

Several limitations have to be highlighted regarding the present systematic review on the

the economic model centered on Spanish patients with neuropathic pain (healthcare

economic burden associated with pregabalin for the treatment of its approved indications in

costs associated with pregabalin for 12 weeks:

Spain. Firstly, this study was restricted to the

€1,049) [31]. Otherwise, with the purpose of comparing

search of one individual database (MEDLINE), ã were although local databases as SciELO Espan

the Spanish results reviewed here, no other studies of economic evaluation of the use of

also evaluated. Despite that MEDLINE could be considered as the largest repository for highly

pregabalin

identified

reputable and indexed international scientific

elsewhere at the moment of this literature examination.

journals, some specific studies might be missed during the search mainly due to its publication

Besides, the evidence for the costeffectiveness of pregabalin in patients with

under local and/or not-indexed journals. Likewise, the performed systematic review

partial refractory epilepsy is still scarce. Along

evaluated here does not include the partial or

with the reviewed study in Spanish patients [54], only one other economic evaluation was

complete study results presented in meetings and congresses. Another limitation is that

available for comparison [57]. With the objective to mimic real world, Vera-Llonch

although the perspectives of the review were those of the national healthcare systems and the

et al. [57] developed a Markov simulation model to depict clinical outcomes and

societal one, none of the economic papers included costs paid by the patients themselves

economic costs over 1 year in a hypothetical

(the so-called out-of-pocket costs), because the

cohort of 1000 patients with refractory partial epilepsy assumed alternatively to receive add-

studies supporting the economic analyses did not record such expenses. Also, indirect costs

on therapy with pregabalin (300 mg/day) or no add-on therapy. The economic evaluation was

considered productivity loss due to lostworkdays-equivalents only. Besides, although

based on the average wholesale price and

one of the limitations of our study is that it

Medicare’s Resource-Based Relative Value Scale for services in 2006. The results showed that

includes simultaneously formal costeffectiveness analyses (a total of seven) and

add-on therapy with pregabalin allowed for a gain of 23.8 seizure-free days over 1 year; with

other types of partial or incomplete economic evaluations, the inclusion criteria of our study

an estimated additional cost of $678. The

were intended to include all the available

incremental cost per seizure-free day gained was $28.5 and the corresponding estimates of

economic data based on studies with pregabalin in Spain. This is justified by the

incremental cost per QALY gained were $52,893 [57]. These estimations are higher than those

observed claims from healthcare decision makers in our country, who might be more

obtained from the Spanish study reviewed in

interested in cost comparisons rather than in

this manuscript, which uses 2007 as a costing year and lead to an incremental cost per seizure-

observed incremental health benefits due to the current limited health budgets. The review

free day gained of €22 and an incremental cost

included

in

GAD

have

been

seven

cost-effectiveness

studies

Adv Ther (2014) 31:1–29

26

decision-

Spain. Also, this was derived from the fact that

analytical modeling and adequate sensitivity

the exact indications of these drugs in Spain are

analysis that effectively addressed uncertainty problems and scored high using the CHEERS

not always comparable with that of pregabalin. Despite these limitations, the present

checklist. Also, a total of eight other studies included cost–consequences analyses that,

systematic economic review of pregabalin in Spain has also demonstrated significant

although did not produce a typical integrated

advantages and scored relatively well in quality

cost-effectiveness ratio (and the management of uncertainty was limited), were considered

appraisal using the CHEERS checklist. It was focused on a specific country, also including its

complete economic evaluations assessing both costs and health outcomes at the same time [58].

national healthcare system perspective, and showed that usually healthcare schemes and

Other limitations of the reviewed studies were

procedures are different between countries and

the lack of description of the relevant aspects of the systems in which the decision needed to be

only comparable within the same national perspective: for example, a therapeutic option

made in most economic evaluations and the characterizing of heterogeneity (analysis of

could be cost-effective in a specific country, but not so in the neighboring one. Another

subgroups) that was also not presented in most

important consideration of this review is that

of the studies included in the review. On the other hand, the remaining five economic studies

all the studies considered for comparison incorporated the ‘‘social costs’’ in terms of

were simple cost analysis that may suffer from a non-properly handled uncertainty, and

productivity losses, an important component of ‘‘real costs’’ given the debilitating nature of

obviously cannot inform a possible incremental health benefit. Nevertheless, they may be useful

epilepsy, GAD, and chronic neuropathic pain.

for those payers more worried in facing

CONCLUSION

performed

with

an

appropriate

measurements constraints of their health budgets. Finally, it should be stated that transferability of cost-effectiveness data among indications, subpopulations of patients, and varying healthcare settings is usually difficult or statistically meaningless based on the fact that not only drug costs (and healthcare resources) may have huge variations among different countries, but the types of management of a particular

health

condition

in

terms

of

healthcare resources utilization may also vary substantially making them not comparable. Considering the identified publications in this systematic review, it is worth noting that non-

The recent available literature on the economic evaluation associated with pregabalin use in Spain for the management of labeled indications (neuropathic pain, GAD, epilepsy) consists of some models of hypothetic cohorts and a considerable amount of secondary analysis based on previous observational reports and results from clinical trials. In most of the studies analyzed, pregabalin appears to be a

financially

attractive

therapeutic

option

compared with usual care or with previously established therapeutic agents. From a societal

with

perspective in Spain, pregabalin is traditionally associated with initially higher acquisition drug

duloxetine (with indication for GAD and neuropathic pain) or amitryptiline (indicated

costs that are countered by significantly higher cutoffs in terms of healthcare costs, such as

for depression and GAD) were identified in

medical visits and hospitalizations, as well as by

study

comparisons

of

pregabalin

Adv Ther (2014) 31:1–29

27

lower costs due to productivity losses that

treatment of neuropathic pain, partial-onset seizures, and anxiety disorders. Clin Ther. 2007;29(1):26–48.

significantly affect the overall costs of treating such health conditions. 4.

Torrance N, Smith BH, Bennett MI, et al. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain. 2006;7(4):281–9.

5.

Portenoy RK. Painful polyneuropathy. Neurol Clin. 1989;7(2):265–88.

preparation of the tables, and for writing assistance. The authors wish to thank Emili Gonza´lez-Pe´rez (TFS Develop, Barcelona, Spain)

6.

Bouhassira D, Lanteri-Minet M, Attal N, et al. Prevalence of chronic pain with neuropathic characteristics in the general population. Pain. 2008;136(3):380–7.

for his assistance in writing this manuscript.

7.

Wittchen HU, Kessler RC, Beesdo K, et al. Generalized anxiety and depression in primary care: prevalence, recognition, and management. J Clin Psychiatry. 2002;63(Suppl 8):24–34.

8.

Lieb R, Becker E, Altamura C. The epidemiology of generalized anxiety disorder in Europe. Eur Neuropsychopharmacol. 2005;15(4):445–52.

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Kessler RC, Petukhova M, Sampson NA, et al. Twelve-month and lifetime prevalence and lifetime morbid risk of anxiety and mood disorders in the United States. Int J Methods Psychiatr Res. 2012;21(3):169–84.

ACKNOWLEDGMENTS An unrestricted grant was provided by Pfizer, S.L.U., Madrid, Spain, for the literature search,

Sponsorship and article processing charges for this study were funded by Pfizer, S.L.U. Dr. Darba` is the guarantor for this article and takes responsibility for the integrity of the work as a whole. Conflict of interest. J Darba`, L. Kaskens, C. ´ lvarez, R. Navarro-Artieda, and A. ´ Perez, E. A Sicras-Mainar declare that they have no conflict of interests as a consequence of this manuscript nor have they received any payment related

10. Chang BS, Lowenstein DH. Epilepsy. N Engl J Med. 2003;349(13):1257–66.

with their authorship.

11. Fisher RS, van Emde Boas W, Blume W, et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. 2005;46(4):470–2.

Compliance with ethics guidelines. This systematic review is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

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