Efficacy of gabapentin for prevention of postherpetic neuralgia: study protocol for a randomized controlled clinical trial
Rullán et al. Trials
Efficacy of gabapentin for prevention of postherpetic neuralgia: study protocol for a randomized controlled clinical trial
Manuel Rullán 3
Oana Bulilete 2
Alfonso Leiva 0 1 7
Aina Soler 0 1 7
Antonia Roca 6
María José González-Bals 5
Patricia Lorente 4
Joan Llobera 0 1 7
0 Primary Care Research Unit of Mallorca, Baleares Health Services (IB-Salut) , 07005 Palma , Spain
1 Instituto de Investigación Sanitaria de Palma (IdISPa) , 07010 Palma , Spain
2 Son Espases Hospital, Baleares Health Services (IB-Salut) , 07010 Palma , Spain
3 Pollença Health Care Centre, Baleares Health Services (IB-Salut) , 07460 Pollença , Spain
4 Calvià Health Care Centre, Baleares Health Services (IB-Salut) , 07184 Calvià , Spain
5 Manacor Health Care Centre, Baleares Health Services (IB-Salut) , 07500 Manacor , Spain
6 Son Serra-La Vileta Health Care Centre, Baleares Health Services (IB-Salut) , 07013 Palma , Spain
7 Instituto de Investigación Sanitaria de Palma (IdISPa) , 07010 Palma , Spain
Background: Postherpetic neuralgia (PHN) is a chronic neuropathic pain that results from alterations of the peripheral nervous system in areas affected by the herpes zoster virus. The symptoms include pain, paresthesia, dysesthesia, hyperalgesia, and allodynia. Despite the availability of pharmacological treatments to control these symptoms, no treatments are available to control the underlying pathophysiology responsible for this disabling condition. Methods/design: Patients with herpes zoster who are at least 50 years old and have a pain score of 4 or higher on a visual analogue scale (VAS) will be recruited. The aim is to recruit 134 patients from the practices of general physicians. Participants will be randomized to receive gabapentin to a maximum of 1800 mg/day for 5 weeks or placebo. Both arms will receive 1000-mg caplets of valacyclovir three times daily for 7 days (initiated within 72 h of the onset of symptoms) and analgesics as needed. The primary outcome measure is the percentage of patients with a VAS pain score of 0 at 12 weeks from rash onset. The secondary outcomes measures are changes in quality of life (measured by the SF-12 questionnaire), sleep disturbance (measured by the Medical Outcomes Study Sleep Scale), and percentage of patients with neuropathic pain (measured by the Douleur Neuropathique in 4 Questions). Discussion: Gabapentin is an anticonvulsant type of analgesic that could prevent the onset of PHN by its antihypersensitivity action in dorsal horn neurons. Trial registration: ISRCTN Registry identifier: ISRCTN79871784. Registered on 2 May 2013.
Postherpetic neuralgia; Gabapentin; Herpes zoster; Prevention; Primary health care
Herpes zoster (HZ), often called shingles, is a common
disease characterized by a painful, unilateral vesicular
eruption that is caused by reactivation of a dormant
varicella zoster virus within the dorsal root or cranial
nerve ganglia. The most frequent complication following
an acute episode of HZ infection is postherpetic neuralgia
(PHN), a chronic and debilitating neuropathic pain
syndrome that is refractory to most therapeutic strategies.
PHN is considered a clinically significant problem
because it may last for years and because it negatively
impacts a patient’s quality of life across all four health
domains: physical, psychological, functional, and social.
The symptoms associated with PHN are sleep
disturbances, mood changes, depression, and anxiety .
The authors of a recent systematic review reported
that the incidence of HZ infection was between 3 and 12
cases per 1000 patient-years for individuals older than
50 years of age, and that the overall risk of PHN ranges
from 5% to more than 30% . Differences in the
reported incidence of PHN are due to the lack of
consensus on the definition of PHN (i.e., use of different
durations of persisting pain from the onset of shingles
for a positive diagnosis) and differences in the age
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
distributions of study populations. When PHN is defined
as pain lasting for 3 months, the incidence is 18% in
individuals older than 50 years of age and 33% in
individuals older than 80 years of age .
The development of PHN is associated with increased
patient age and severity of acute pain . The diversity
of the PHN symptoms (pain, paresthesia, dysesthesia,
hyperalgesia, and allodynia) seems to be related to a
variety of underlying changes in the nervous system, but
this is still unclear. HZ infection is associated with
damage to the central and peripheral nervous systems.
Although the pathophysiology of PHN is incompletely
understood, two possible mechanisms could be
responsible: sensitization (peripheral and central neuron
generation of spontaneous discharges) and deafferentation
(neural damage and inflammation with subsequent
edema) . In addition, previous research indicated
severe depletion of epidermal free nerve endings in the
skin biopsies of patients with PHN, and authors of
postmortem studies reported atrophy of the spinal
dorsal root ganglia, demyelination with fibrosis, and cell
Gabapentin, a structural analogue of γ-aminobutyric
acid, has been used for the treatment of PHN for
decades, and the results of several randomized controlled
trials (RCTs) show that it is a well-tolerated and
efficacious treatment in patients with PHN . However,
gabapentin used for the prevention of PHN has shown
contradictory results. Researchers in an uncontrolled,
open-label study reported that administration of
gabapentin plus valacyclovir during the acute phase of HZ
infection reduced the incidence of PHN . A more
recent prospective, controlled, two-armed study using
low doses of gabapentin and valacyclovir showed no
statistical differences between the two groups regarding
PHN prevention .
The primary objective of the present study is to evaluate
the efficacy of an optimal dose of gabapentin added to the
usual treatment—valacyclovir and analgesics as
needed—in the prevention of PHN at 12 weeks in patients older
than 50 years old who have moderate to severe pain.
Design and setting
We designed a multicenter, parallel, randomized,
doubleblind, placebo-controlled trial with recruitment of 134
patients from 17 primary care centers in Mallorca, Spain.
Participants will be randomly allocated to receive
gabapentin or placebo for 8 weeks to evaluate the
efficacy of gabapentin in the prevention of PHN.
Figure 1 summarizes the study design and time line,
and Fig. 2 displays the schedule of enrollment,
interventions, and assessments.
Male or female patients who are at least 50 years old, have
a clinical diagnosis of uncomplicated HZ, present within
the first 72 h of vesicle formation, and have an average pain
score of at least 4 on a visual analogue scale (VAS) before
therapy will be recruited. Table 1 summarizes the eligibility
criteria. The study methods are in accordance with the
Standard Protocol Items: Recommendations for
Interventional Trials (SPIRIT) statement (Additional file 1).
Each participating primary care center will have at least
one physician from the research team invite potential
candidates to participate in the clinical trial and to
perform all procedures. All patients diagnosed with acute
HZ will be referred to this physician and will be invited
to participate in the trial. Willing participants who meet
the eligibility criteria will be enrolled after they read and
sign an informed consent agreement (Additional file 2).
The central pharmacy of Hospital Son Espases will
package the study treatments (placebo or gabapentin) using
an unblinded randomization code list. The link between
the randomization code and the corresponding
treatment will remain blinded for all other study team
members. During the process of randomization, each subject
will be assigned a randomization code and will be given
the treatment package with that code. This sequential
randomization will be generated in blocks of six. To assess
the effectiveness of masking, patients and investigators
will be asked to guess whether they think they received
the treatment or placebo at the final visit, and then will be
asked to indicate what led them to that belief.
The primary goals in management of HZ are to inhibit
ongoing viral replication, alleviate pain, and prevent
complications such as local shingles infections or PHN
. Local measures to prevent vesicle infection will be
recommended to all recruited patients. These measures
include frequent hand-washing, drying out of shingles
after a shower without scratching the blisters, and
covering blisters until they are crusted over.
Antiviral therapy is considered the firstline treatment
for HZ and should be initiated within 72 h of onset.
Thus, all participants will receive 1000-mg caplets of
valacyclovir hydrochloride three times daily for 7 days.
The World Health Organization three-step pain relief
ladder will be used for pain management. In
particular, if pain occurs, there will be prompt oral
administration of drugs in the following order, until the
patient is free of pain: nonopioids (paracetamol); then,
Fig. 1 Study time line and flowchart of participants. IC Informed consent
as necessary, mild opioids (codeine); then strong
opioids, such as morphine.
Bottles of 300-mg gabapentin capsules and of matching
placebos will be dispensed according to the randomization
schedule, which is retained by the clinical trial pharmacist.
The participants, research staff, and investigators who
assess outcomes will be masked to treatment allocations.
Gabapentin will be initiated at 300 mg/day and then
increased in a stepwise manner according to the
instructions for use. The dose will be increased, regardless of
whether efficacy is achieved at a lower dose, to a ceiling
daily dose of 1800 mg/day. In patients who develop
intolerable adverse effects, the dose will be reduced. The
optimal dose established during the titration period will
be maintained throughout the remainder of the study and
followed by 1 week of dose-tapering. Use of systemic
corticosteroids and tricyclic antidepressants will not be
Assessing medication adherence
The treatment will be monitored at every visit by the
responsible physician at every participating health care
center. We will ask the patients to comply with a
medical diary that has to be followed until the next
appointment or a daily medication box, if wanted. At the
last visit, the participants must return their bottles, and
a final count will be made by the physician. A biannual
study newsletter will be sent to all the researchers, and
an annual meeting will take place between the principal
investigator and all the study collaborators.
Data collection methods and record-keeping
Case report forms will be used to record data for all
participants. The researchers will receive training for
standardized data collection procedure. All data will be
stored in a locked cabinet of every researcher until the
inclusion period finishes. Patient information will be
coded using a unique numerical identification, and the
data will be entered into an electronic database and its
validity secured. Logical checks will be performed for
missing data and to find inconsistencies. The researchers
and data analysts will have full access to data.
Measurement of outcomes
Measures and variables are summarized, with a timeline,
in Table 2. The main outcome measure will be the
incidence of PHN at 12 weeks, defined as an average daily
VAS pain score of 0.
Secondary outcome variables
Response rate The response rate of the groups at 6 and
12 weeks is a secondary outcome measure. Responders
will be defined as those with a 50% reduction in VAS
pain compared with baseline. This outcome was chosen
Fig. 2 Schedule of enrollment, interventions, and assessments. MOS Medical Outcomes Study
Patients with evidence of cutaneous or visceral dissemination of herpes
zoster infection (cutaneous dissemination is defined as more than 20
discrete lesions outside adjacent dermatomes) or ocular involvement
of herpes zoster
Patients with histories of intolerance or hypersensitivity to any active
components of or excipient from the study drugs
Patients with severe hepatic impairment or impaired renal function
(creatinine clearance <79 ml/minute)
Patients who have received cytotoxic drugs or immunosuppressive therapy
within the previous 3 months (e.g., long-term systemic corticosteroids)
Patients with any diagnosed immune dysfunction
Patients who have received immunomodulatory medications (including
interferon) within the previous 4 weeks
Quality of life The 12-item Short Form Health Survey
(SF-12®), a short version of the SF-36®, will be used to
assess quality of life. This questionnaire has two questions
on physical functioning, two questions on role limitations
because of physical health problems, one question on
bodily pain, one question on general health perceptions,
one question on vitality (energy/fatigue), one question on
social functioning, two questions on role limitations
because of emotional problems, and two questions on
general mental health (psychological distress and
psychological well-being). The SF-12 is applicable in
different cultures, and a validated Spanish version is
available [15, 16].
Sleep interference The Medical Outcomes Study Sleep
Scale will be used to assess the quality and quantity of
Patients with diagnoses of uncomplicated herpes zoster
presenting within the first 72 h of vesicle formation and
an average pain score of at least 4 on a visual analogue
scale of pain before therapy
Patients who are willing and able to comply with the
requirements of the study
following a recommendation from the Committee for
Medicinal Products for Human Use in their clinical
guidelines on clinical medicinal products intended for
the treatment of neuropathic pain .
Percentage of patients with neuropathic pain (Douleur
Neuropathique in 4 Questions) The change from
baseline to the end of the study in the DN4 questionnaire
(Douleur Neuropathique in 4 Questions) score will be
used to assess changes in neuropathic pain. This scale
includes ten items, with each “yes” response scored as 1,
and is subdivided into descriptors (seven items) and
signs relating to the sensory examination (three items).
A score above 4 indicates neuropathic pain. This
questionnaire has been validated previously [12, 13], and a
validated Spanish version is available .
Table 2 Instruments, assessments, and timing of assessments
Sampling form Inclusion/exclusion criteria
Sociodemographic data form
Sociodemographic data (age, sex, BMI)
Baseline clinical data form
Visual analogue scale pain score
Severity of pain before/after therapy
Medical history, concomitant medications, and analgesic drugs to
control HZ-related pain
Health-related quality of life
Indirect method: patient questionnaires, patient self-reports, and pill counts
Adverse event evaluations related to study medication
Extent of sleep problems (sleep initiation, maintenance, respiratory problems,
quantity, perceived adequacy, and somnolence)
Neuropathic pain consisting of interview questions and physical tests
Number of patients on analgesics at the end of the study
Baseline, 1, 4, 6, and 12 weeks
Baseline, 4, 6, and 12 weeks
Baseline and 12 weeks
1, 4, 6, and 12 weeks
Baseline and 12 weeks
Baseline and 12 weeks
Analgesic consumption form
Total consumption of analgesic drugs during the study period
Abbreviations: BMI Body mass index, DN4 Douleur Neuropathique in 4 Questions, HZ Herpes zoster, MOS Medical Outcomes Study, SF-12 12-item Short Form
sleep. This questionnaire has 12 items that assess the
key constructs of sleep. It is self-administered, and
patients are asked to recall sleep-related activities over
the past 4 weeks. It comprises scoring in six domains:
sleep disturbance (four items), snoring (one item),
awakening with shortness of breath or a headache (one item),
quantity of sleep (one item), optimal sleep (one item),
sleep adequacy (two items), and daytime somnolence
(three items). This scale has been validated in Spanish
for patients with neuropathic pain .
Patient Global Impression of Change Scale The
Patient Global Impression of Change Scale comprises a
single question in which the patient is asked to rate his/
her present condition relative to how it was prior to
treatment on a scale from 1 (very much better) to 7
(very much worse). This scale has been used in previous
studies in which researchers assessed patients’
impressions of improvement following PHN treatment .
Analgesic consumption Medications taken for control
of pain will be recorded at baseline and at every
followup visit during the study period.
Patients will be interviewed at each study visit regarding
the occurrence of any adverse events (AEs), including
type of event, time of onset, duration, and severity.
Safety analyses will be performed on the safety
population, which will consist of all patients who received at
least one dose of the study drug. Safety data will include
the incidence of treatment-emergent AEs, serious
adverse events (SAEs), and the number and percentage of
patients reporting one or more AEs in each group.
Participants will be free to withdraw from participation
at their own request at any time without giving reasons
for their decision. Withdrawals will be documented in
the case report forms and in patients’ medical records,
with active follow-up for ongoing SAEs.
All information regarding AEs will be presented in
the case report form. The study investigators will
investigate the causal relationship of the study drug and
the intensity of AEs. Any SAE (e.g., death, a
lifethreatening event, inpatient hospitalization or
prolongation of existing hospitalization, persistent or significant
disability/incapacity) in any patient during the course of
the study will be reported to the ethics committee .
The sample size calculation is based on the primary
outcome measure and the primary analysis for the
intention-to-treat population. Researchers in a previous
nonrandomized, noncontrolled experimental study
reported the incidence of PHN was 20% . Thus, we
estimated a 45% incidence of PHN in the placebo group,
based on its incidence in patients older than 50 years old
with an average VAS pain score of 4 or more reported in a
longitudinal study . We adjusted the sample size for an
estimated follow-up loss rate of 20% and a 0.05 two-sided
level of significance (α = 5%). Thus, we will need 67 patients
in each group to detect a difference of at least 25% in the
incidence of PHN in the treatment and placebo arms.
We will test for significant baseline differences in the
placebo and gabapentin arms by use of descriptive analysis,
with continuous variables summarized by means and SDs
for normal distributions and by medians and 25th and
75th percentiles for nonnormal distributions. All analyses
of the effectiveness and cost-effectiveness will involve
intention-to-treat populations (i.e., all randomized
patients, regardless of participation in any treatment
session). This approach reduces the bias that may occur
when participants not receiving assigned treatments are
excluded from analysis. All tests will be two-sided, and an
α value of 0.05 will be considered statistically significant.
We will compare the proportions of patients in each
arm with PHN at 12 weeks against the null hypothesis
of no difference between the groups. We will use the
chi-square test in multivariate analysis and will adjust
for potential confounders, if any, using a logistic
regression model. We will estimate relative and absolute risk
reduction and the number needed to treat, defined as
the estimated number of patients who need to be treated
with gabapentin for prevention of PHN in one patient.
The health economic analysis will be performed by
calculating the incremental cost-effectiveness ratio (ICER) at
12 weeks. We will systematically collect data on use of all
resources, including inpatient care, consultations with
health care providers, use of drugs, and laboratory tests.
To measure effects, the SF-12 scores will be transformed
into EQ-5D utility scores and quality-adjusted life-years
(QALYs) will be determined. The ICER will be calculated
as the difference in the mean costs of the two groups
divided by difference in the mean effects of the two groups:
A nonparametric bootstrap procedure will be used to
perform the uncertainty analysis for the ICER. This
procedure considers the skewness of cost data and the
covariance of costs and QALYs. To control for possible
confounding variables and to account for clustering, an
alternative procedure (net-benefit regression) will also be
used. Cost-effectiveness acceptability curves will be
created to illustrate statistical uncertainty. We will
determine the safety of interventions in the safety population
and use per-protocol analysis with the chi-square test by
comparing the AEs among patients.
All estimates will include 95% confidence intervals.
The number needed to treat will be calculated as the
reciprocal of the difference between the proportion of
patients with PHN in the placebo and gabapentin arms.
This study will follow the principles outlined in the
Declaration of Helsinki. All patients will be asked to
provide written informed consent and will be told that
participation is voluntary and can be withdrawn at any
time without any negative consequences concerning
their current or future medical treatments. Our study
protocol has been approved by the Primary Care
Research Committee, the Mallorca Ethical Committee of
Clinical Research (IB 1857/12), and the Spanish Agency
on Drugs and Medical devices (for Agencia Española de
Medicamentos y Productos Sanitarios). Any protocol
modification will be approved by the executive
committee, submitted to the ethics committee for approval, and
noted to the ISRCTN registry. Trial participants will be
notified if relevant protocol changes will be made.
PHN is a persistent nerve pain that has an adverse effect
on quality of life in patients with HZ. It has a high
prevalence among patients with HZ who are older than 50 years
old and in those with moderate to severe pain, although
previous studies have used different definitions of PHN.
The definition of PHN in the proposed study is persistent
pain for more than 90 days since the onset of shingles,
considered the most accepted definition for PHN [21, 22].
Treatments for PHN attempt to alleviate the pain, and
several pharmacological strategies are available. This
includes tricyclic antidepressants, anticonvulsants,
analgesics, and topical agents. However, no disease-modifying
therapy is available , and preventive strategies are
urgently needed. Preventive strategies such as varicella
zoster virus live-attenuated vaccine (approved by the
U.S. Food and Drug and Administration for adults older
than 50 years old) showed reductions of the incidence of
HZ infection and PHN , but RCTs are needed to
confirm these results.
Gabapentin acts on supraspinal region to stimulate
noradrenaline-mediated descending inhibition [24–26].
We hypothesize that preventing central sensitization in
patients with HZ will reduce the incidence of PHN.
Thus, gabapentin may provide pain relief, but whether
pain relief could also prevent the onset of PHN is not
yet clear. In our study, participants in both arms will
receive analgesic treatments as needed to provide pain
relief. There is a significant increase in the risk of PHN
following acute zoster infection, including prodromal
pain and severe rush. Thus, participants in both of our
study arms will also receive valacyclovir within 72 h after
rash appearance. Valacyclovir is preferred over other
antivirals because it more easily produces consistently
high levels in the blood, patient compliance is better,
and less frequent dosing is required.
The effectiveness of gabapentin for the prevention of
NPH was previously evaluated in two studies.
Researchers in an uncontrolled open-label study concluded
that the combination of gabapentin and valacyclovir
reduces the incidence of PHN ; however, although the
gabapentin dose could be titrated up to 3600 mg/day,
only a few patients reached that dose, and the median
dose was 1085 mg/day for 34 days. This study was
criticized because there was no control group; instead,
the authors compared the incidence of PHN with
historic control subjects described in a meta-analysis of six
RCTs of antiviral agents used to treat acute zoster
infection . These authors also concluded that larger-scale
blinded studies are necessary to confirm their results.
A prospective controlled study showed that low doses
of gabapentin were not effective in the prevention of
PHN . However, the study was nonrandomized, and
patients were not blinded to treatment.
The two main strengths of our study are that, as far as
we know, it is the first RCT to examine the effect of
gabapentin on prevention of PHN, and it is an
independent clinical trial funded by a public research agency.
The ceiling dose of gabapentin is 1800 mg/day because
it has been established that a dose greater than
1800 mg/day does not generally provide greater benefit;
the bioavailability of gabapentin varies inversely with
dose, and high-dose regimens are associated with lower
patient compliance . Gabapentin is compared with
placebo treatment because there is no convincing
evidence that other treatments can reduce PHN after
HZ has been established. Currently, the management of
HZ and PHN is based largely on general practice. This
RCT is developed entirely in a primary care setting and
will have the participation of 17 primary care teams.
The external validity will be assured because the
effectiveness of gabapentin treatment in the prevention of
PHN will be assessed in the same settings in which
most HZ cases are treated.
Limitations of our study include the possibility of a
high discontinuation rate due to gabapentin’s potential
side effects, possible interactions of gabapentin with
other drugs, and the complex dosage regimen. The most
recognizable side effects of gabapentin are dizziness,
somnolence, and drowsiness, so their presence might
compromise the blinding of patients and investigators.
Although we considered the use of an active placebo (a
placebo that mimics the side effects of the drug under
evaluation), we finally decided to use a “pure” placebo because of
ethical considerations for the patients included in the study.
HZ and PHN have major impacts on patients’ lives
 and constitute a significant economic burden for
health care systems and societies at large . A
treatment that effectively prevents PHN in patients at high
risk could improve the quality of life of patients with HZ
and also reduce health care costs.
Additional file 1: SPIRIT checklist. (PDF 41 kb)
Additional file 2: Model consent form. (DOC 38 kb)
The authors thank the general practitioners for their participation and Olga
Delgado and the pharmacy department of Son Espases Hospital for their
help and advice.
Members of the PHN group: Martí Cladera (Centro de Salud Pollença),
Catalina Comas (Centro de Salud Camp Redó), Ma. Antonia Mir (Centro de
Salud Inca), Apolonia Cifre (Centro de Salud Platja Palma), Biel Lliteras (Centro
de Salud Llucmajor), Salvador Gestoso (Centro de Salud Son Pisà), Antoni
Jover (Centro de Salud Arquitecto Bennàssar), Francisca Bestard (Centro de
Salud Son Gotleu), Francisca Comas (Centro de Salud Rafal Nou), Luis López
(Centro de Salud Cala d’Or), Rosa Ortuño (Centro de Salud Pere Garau), Joan
Peiro (Centro de Salud Andratx), Maria Cerdó (Centro de Salud Coll Rabassa),
Violeta Ramírez (Centro de Salud Alcudia), Merce Gutierrez (Centro de Salud
San Agustí), Rosemary Argüelles (Centro de Salud Muntanya), and Ma.
Dolores Gutierrrez (Centro de Salud Martí Serra).
This study was funded by the Ministry of Health, Carlos III Institute (grant PI12/
01813). We also received support from the Health Promotion and Preventive
Activities-Primary Health Care Network, sustained by the Ministry of Health, Carlos
III Institute, Redes Temáticas de Investigación Cooperativa en Salud (RETIC) award
RD12/0005/0011, co-financed by the European Union European Regional
Development Fund. The funders had no role in the study design, data collection,
analysis, decision to publish, or preparation of the manuscript.
Availability of data and materials
The dataset to be generated during the present designed study will be
available from the corresponding author on reasonable request via email.
MR, JL, OB, AL, and AS collectively drafted the study protocol and sought
funding and ethical approval. AL and OB participated in the central monitoring
of data collection. MR and JL are responsible for the management of the trial,
analysis and interpretation of the data. MR, JL, OB, AL, AR, MG and PL are
responsible of the drafting and revision of the manuscript. AL and OB
conducted the analysis. MR is the principal investigator of the study, had full
access to all of the data in the study, and takes responsibility for the integrity of
the data and the accuracy of the data analysis. All authors read the manuscript
Ethics approval and consent to participate
This study will follow the principles outlined in the Declaration of Helsinki. The
trial has been approved by the by the Primary Care Research Committee, the
Mallorca Ethical Committee of Clinical Research (IB 1857/12), and the Spanish
Agency on Drugs and Medical devices (for Agencia Española de Medicamentos
y Productos Sanitarios [AEMPS]). A consent form for participation has been
obtained from all participants, and the patients are free to withdraw from
the study at any time upon their request. The funders had no role in the
study design, data collection, analysis, decision to publish, or preparation
of the manuscript.
1. Drolet M , Brisson M , Schmader KE , Levin MJ , Johnson R , Oxman MN , et al. The impact of herpes zoster and postherpetic neuralgia on health-related quality of life: a prospective study . CMAJ . 2010 ; 182 : 1731 - 6 .
2. Kawai K , Gebremeskel BG , Acosta CJ . Systematic review of incidence and complications of herpes zoster: towards a global perspective . BMJ Open . 2014 ; 4 : e004833 .
3. Yawn BP , Gilden D. The global epidemiology of herpes zoster . Neurology . 2013 ; 81 : 928 - 30 .
4. Forbes HJ , Thomas SL , Smeeth L , Clayton T , Farmer R , Bhaskaran K , et al. A systematic review and meta-analysis of risk factors for postherpetic neuralgia . Pain . 2016 ; 157 : 30 - 54 .
5. Jericho B. Postherpetic neuralgia: a review . Internet J Orthop Surg . 2009 ; 16 ( 2 ). http://print.ispub.com/api/0/ispub-article/12886.
6. Jeon YH . Herpes zoster and postherpetic neuralgia: practical consideration for prevention and treatment . Korean J Pain . 2015 ; 28 : 177 - 84 .
7. Meng FY , Zhang LC , Liu Y , Pan LH , Zhu M , Li CL , et al. Efficacy and safety of gabapentin for treatment of postherpetic neuralgia: a meta-analysis of randomized controlled trials . Minerva Anestesiol . 2014 ; 80 : 556 - 67 .
8. Lapolla W , Digiorgio C , Haitz K , Magel G , Mendoza N , Grady J , et al. Incidence of postherpetic neuralgia after combination treatment with gabapentin and valacyclovir in patients with acute herpes zoster: open-label study . Arch Dermatol . 2011 ; 147 : 901 - 7 .
9. Lee EG , Lee HJ , Hyun DJ , Min K , Kim DH , Yoon MS . Efficacy of low dose gabapentin in acute herpes zoster for preventing postherpetic neuralgia: a prospective controlled study . Dermatol Ther . 2016 ; 29 : 184 - 90 .
10. Whitley RJ , Volpi A , McKendrick M , van Wijck A , Oaklander AL . Management of herpes zoster and post-herpetic neuralgia now and in the future . J Clin Virol . 2010 ; 48 ( 1 ): S20 - 8 .
11. European Medicines Agency (EMA). Guideline on the clinical development of medicinal products intended for the treatment of pain . London: EMA, Committee for Medicinal Products for Human Use (CHMP); 17 Dec 2015 . http://www.ema. europa.eu/docs/en_GB/document_library/Scientific_ guideline/ 2015 /12/WC500199242.pdf. Accessed 3 Feb 2016 .
12. Bouhassira D , Attal N , Alchaar H , Boureau F , Brochet B , Bruxelle J , et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4) . Pain . 2005 ; 114 : 29 - 36 .
13. Treede RD , Jensen TS , Campbell JN , Cruccu G , Dostrovsky JO , Griffin JW , et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes . Neurology . 2008 ; 70 : 1630 - 5 .
14. Perez C , Galvez R , Huelbes S , Insausti J , Bouhassira D , Diaz S , et al. Validity and reliability of the Spanish version of the DN4 (Douleur Neuropathique 4 questions) questionnaire for differential diagnosis of pain syndromes associated to a neuropathic or somatic component . Health Qual Life Outcomes . 2007 ; 5 : 66 .
15. Vilagut G , Valderas JM , Ferrer M , Garin O , López-García E , Alonso J. Interpretation of SF-36 and SF-12 questionnaires in Spain: physical and mental components [in Spanish] . Med Clin (Barc) . 2008 ; 130 : 726 - 35 .
16. Schmidt S , Vilagut G , Garin O , Cunillera O , Tresserras R , Brugulat P , et al. Reference guidelines for the 12-Item Short-Form Health Survey version 2 based on the Catalan general population [in Spanish] . Med Clin (Barc) . 2012 ; 139 : 613 - 25 .
17. Rejas J , Ribera MV , Ruiz M , Masrramón X. Psychometric properties of the MOS (Medical Outcomes Study) Sleep Scale in patients with neuropathic pain . Eur J Pain . 2007 ; 11 : 329 - 40 .
18. Sabatowski R , Gálvez R , Cherry DA , Jacquot F , Vincent E , Maisonobe P , et al. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebocontrolled clinical trial . Pain . 2004 ; 109 : 26 - 35 .
19. Meyboom RHB , Royer RJ . Causality classification at pharmacovigilance centres in the European Community . Pharmacoepidemiol Drug Saf . 1992 ; 1 : 87 - 97 .
20. Jung BF , Johnson RW , Griffin DRJ , Dworkin RH . Risk factors for postherpetic neuralgia in patients with herpes zoster . Neurology . 2004 ; 62 : 1545 - 51 .
21. Dworkin RH , Schmader KE . The epidemiology and natural history of herpes zoster and postherpetic neuralgia . In: Watson CPN, Gershon AA, editors. Herpes zoster and postherpetic neuralgia . 2nd ed . New York : Elsevier ; 2001 . p. 39 - 64 .
22. Oxman MN , Levin MJ , Johnson GR , Schmader KE , Straus SE , Gelb LD , et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults . N Engl J Med . 2005 ; 352 : 2271 - 84 .
23. van Wijck AJM , Opstelten W , Moons KGM , van Essen GA , Stolker RJ , Kalkman CJ , et al. The PINE study of epidural steroids and local anaesthetics to prevent postherpetic neuralgia: a randomised controlled trial . Lancet . 2006 ; 367 : 219 - 24 .
24. Bauer CS , Tran-Van-Minh A , Kadurin I , Dolphin AC . A new look at calcium channel α2δ subunits . Curr Opin Neurobiol . 2010 ; 20 : 563 - 71 .
25. Cantí C , Nieto-Rostro M , Foucault I , Heblich F , Wratten J , Richards MW , et al. The metal-ion-dependent adhesion site in the von Willebrand factor-A domain of α2δ subunits is key to trafficking voltage-gated Ca2+ channels . Proc Natl Acad Sci U S A . 2005 ; 102 : 11230 - 5 .
26. Kukkar A , Bali A , Singh N , Jaggi AS . Implications and mechanism of action of gabapentin in neuropathic pain . Arch Pharm Res . 2013 ; 36 : 237 - 51 .
27. Fett N. Gabapentin not shown to prevent postherpetic neuralgia . Arch Dermatol . 2012 ; 148 : 400 - 1 .
28. Gan EY , Tian EAL , Tey HL . Management of herpes zoster and post-herpetic neuralgia . Am J Clin Dermatol . 2013 ; 14 : 77 - 85 .
29. Johnson RW , Bouhassira D , Kassianos G , Leplège A , Schmader KE , Weinke T. The impact of herpes zoster and post-herpetic neuralgia on quality-of-life . BMC Med . 2010 ; 8 : 37 .
30. Gater A , Uhart M , McCool R , Préaud E. The humanistic, economic and societal burden of herpes zoster in Europe: a critical review . BMC Public Health . 2015 ; 15 : 193 .