Pregabalin for chronic pain: Does one medication fit all?

Abstract

Pregabalin is frequently prescribed for chronic non-cancer pain. No previous study has examined its off-label use.
Our primary aim was to assess the proportion of patients taking pregabalin for conditions approved by Health Canada ("on-label") and compare their perspectives on its use to those who use pregabalin for other conditions ("off-label").
Patients who have used pregabalin within the past year were recruited from two registries of chronic non-cancer pain patients treated in tertiary care clinics: the Quebec Pain Registry and the Fibromyalgia Patients Registry. Data on the use of pregabalin and its perceived benefits were collected from the registries and from completed questionnaires.
Out of 4339 screened chronic non-cancer pain patients, 355 (8.18%) met the study selection criteria. Three-quarters of them (268/355) used pregabalin for pain conditions not approved by Health Canada and were therefore regarded as off-label users. The most prevalent condition for pregabalin use was lumbar back pain (103/357; 28.85%). There were no significant differences between on- and off-label users in their perceived satisfaction from pregabalin therapy and its effect on function and quality of life. Among former users, the most prevalent reason for discontinuation was adverse effects, mainly dry mouth and weight gain.
We conclude that despite specific indications for pregabalin prescription, it is mainly used off-label, notably for low back pain. Nevertheless, off-label users were equally satisfied with its clinical effects. Although formal exploration of broader analgesic properties of pregabalin is warranted, treating heterogeneous chronic pain conditions with pregabalin may be legitimate.
The main limitations of the study are patients' low response rate, the recruitment of participants solely from a tertiary pain center and not from the general patients' population and a possible recall bias that may have arisen from the retrospective nature of the study.

Full text

Full Terms & Conditions of access and use can be found at
http://www.tandfonline.com/action/journalInformation?journalCode=icmo20
Download by: [McGill University Library] Date: 21 February 2016, At: 07:38
Current Medical Research and Opinion
ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20
Pregabalin for chronic pain: does one medication
fit all?
Hili Giladi, Manon Choinière, Mary-Ann Fitzcharles, Mark A. Ware, Xianming
Tan & Yoram Shir
To cite this article: Hili Giladi, Manon Choinière, Mary-Ann Fitzcharles, Mark A. Ware, Xianming
Tan & Yoram Shir (2015) Pregabalin for chronic pain: does one medication fit all?, Current
Medical Research and Opinion, 31:7, 1403-1411, DOI: 10.1185/03007995.2015.1040750
To link to this article: http://dx.doi.org/10.1185/03007995.2015.1040750
Accepted author version posted online: 13
Apr 2015.
Published online: 11 May 2015.
Submit your article to this journal
Article views: 135
View related articles
View Crossmark data

Current Medical Research & Opinion Vol. 31, No. 7, 2015, 1403–1411
0300-7995 Article ST-0411.R1/1040750
doi:10.1185/03007995.2015.1040750 All rights reserved: reproduction in whole or part not permitted
Original article
Pregabalin for chronic pain: does one medication
fit all?
Hili Giladi
The Alan Edwards Pain Management Unit (AEPMU),
McGill University Health Centre, Montreal, Quebec,
Canada
Manon Choinie
`re
Centre de recherche du Centre hospitalier de
l’Universite
´de Montre
´al (CRCHUM); Department of
Anesthesiology, Faculty of Medicine, University of
Montreal, Montre
´al, Quebec, Canada
Mary-Ann Fitzcharles
Mark A. Ware
The Alan Edwards Pain Management Unit (AEPMU),
McGill University Health Centre, Montreal, Quebec,
Canada
Xianming Tan
Biostatistics Core Facility, McGill University Health
Centre, Montreal, Quebec, Canada
Yoram Shir
The Alan Edwards Pain Management Unit (AEPMU),
McGill University Health Centre, Montreal, Quebec,
Canada
Address for correspondence:
Dr. Hili Giladi MD, PO Box 390, 8499000 Midreshet
Ben Gurion, Israel.
Tel: +972 50 212 9465; Fax: +972 8 9579642;
giladih@post.bgu.ac.il
Keywords:
Chronic pain – Health Canada – Off-label –
Pharmacotherapy – Pregabalin
Accepted: 9 April 2015; published online: 11 May 2015
Citation: Curr Med Res Opin 2015; 31:1403–11
Abstract
Background:
Pregabalin is frequently prescribed for chronic non-cancer pain. No previous study has examined its
off-label use.
Objectives:
Our primary aim was to assess the proportion of patients taking pregabalin for conditions approved by Health
Canada (‘on-label’) and compare their perspectives on its use to those who use pregabalin for other
conditions (‘off-label’).
Methods:
Patients who have used pregabalin within the past year were recruited from two registries of chronic
non-cancer pain patients treated in tertiary care clinics: the Quebec Pain Registry and the Fibromyalgia
Patients Registry. Data on the use of pregabalin and its perceived benefits were collected from the registries
and from completed questionnaires.
Results:
Out of 4339 screened chronic non-cancer pain patients, 355 (8.18%) met the study selection criteria.
Three-quarters of them (268/355) used pregabalin for pain conditions not approved by Health Canada and
were therefore regarded as off-label users. The most prevalent condition for pregabalin use was lumbar
back pain (103/357; 28.85%). There were no significant differences between on- and off-label users in their
perceived satisfaction from pregabalin therapy and its effect on function and quality of life. Among former
users, the most prevalent reason for discontinuation was adverse effects, mainly dry mouth and weight gain.
Conclusions:
We conclude that despite specific indications for pregabalin prescription, it is mainly used off-label, notably
for low back pain. Nevertheless, off-label users were equally satisfied with its clinical effects. Although
formal exploration of the broader analgesic properties of pregabalin is warranted, treating heterogeneous
chronic pain conditions with pregabalin may be legitimate.
Limitations:
The main limitations of the study are patients’ low response rate, the recruitment of participants solely from
a tertiary pain center and not from the general patient population and a possible recall bias that may have
arisen from the retrospective nature of the study.
Introduction
Pregabalin was initially compounded in the late 1980s as an anticonvulsant
1
.
It was introduced in the 1990s and was first approved by regulatory authorities
for use in 2004 in Europe
2
and in North America
2
. Since its introduction, it has
been approved for use in specific neuropathic pain conditions including diabetic
!2015 Informa UK Ltd www.cmrojournal.com Pregabalin for chronic pain Giladi et al. 1403
Downloaded by [McGill University Library] at 07:38 21 February 2016

peripheral neuropathy (DPN)
2
, post-herpetic neuralgia
(PHN)
2
, spinal cord injury (SCI)
3
and central neuropathic
pain
4
. It is also approved for the treatment of fibromyalgia
(FM)
5
. In Europe only, it is approved for general anxiety
disorders
6
. Pregabalin is not approved for nociceptive pain
conditions such as low back pain or for other, non-central
neuropathic pain conditions like cervical, thoracic or
lumbar radiculopathy. Pregabalin acts by binding to the
a2-dsubunit of voltage-gated calcium channels in central
nervous system tissues, thereby reducing release of excita-
tory neurotransmitters. However, the clinical relevance
of this mechanism in humans is unknown
5
. In the
United States and in Europe, pregabalin is still a patented
drug with relatively high costs both for patients and health
insurers. In the province of Quebec (Canada), pregabalin
was patented until May 2013 and was fully covered by the
provincial drug plan, and physicians of any specialty could
prescribe it to their patients without the need to provide
the rationale for its use or to specify the diagnosis for which
it is prescribed.
For individuals experiencing neuropathic pain or FM,
pregabalin offers a potentially effective treatment option.
Prior to its introduction, the mainstay of therapy for
these conditions was confined to tricyclic antidepressants
(TCAs)
7
and later to gabapentin
8
. The use of TCAs is
frequently associated with orthostatic hypotension
9
,
greater risk of adverse cardiovascular effects
10
and greater
relative risk of overall mortality
11
. Gabapentin therapy
improved therapeutic outcome in patients with
neuropathic pain, but was limited by its wide therapeutic
dosing range
12
, the need for high and frequent dosing,
its non-linear absorption properties
12
and its variable
bioavailability
13
. Currently, in Quebec, tricyclic anti-
depressants and gabapentin are covered by the provincial
drug plan. Duloxetine (Cymbalta*), indicated for
treatment of neuropathic pain and fibromyalgia
14
,
necessitates special approval for coverage by the provincial
drug plan.
In the past three years, we observed that a growing
number of patients treated in tertiary pain management
clinics reported using pregabalin for their chronic pain
condition. A preliminary data analysis, performed in
2011 on 3096 patients enrolled in the Quebec Pain
Registry (QPR, see below), indicated that 1034/3096
(33%) were either current or past-year users of pregabalin
(unpublished data). For comparison, 1228/3096 (39%) of
patients reported using acetaminophen during that time
period (unpublished data). This suggested that pregabalin
was being used off-label, i.e., outside its Health Canada
regulatory approved indications
15
, for multiple chronic
pain conditions. The primary aim of the current study
was to determine, for the first time, the prevalence of the
off-label use of pregabalin in a heterogeneous group of
patients with chronic non-cancer pain (CNCP). In
addition, we aimed to compare the perceived effectiveness
of pregabalin and the patterns of its use in on-label vs.
off-label users, including average doses, time to clinical
effect and adverse-effect profile. The results of this study
could indicate whether the use of pregabalin in chronic
pain diagnoses beyond those officially endorsed by health
regulators is warranted.
Patients and methods
This was a descriptive cross-sectional study, focusing on
CNCP patients who have been referred to large university-
affiliated tertiary care facilities offering multidisciplinary
pain treatment in the province of Quebec (Canada) and
who were current or past-year users of pregabalin. The
study was approved by the Institutional Ethics Boards
and conducted in accordance with Good Clinical
Practice (GCP) and applicable Canadian regulatory
requirements. Written informed consent was obtained
from all participants.
Eligibility and recruitment
Eligible participants were adult patients with CNCP with
pain duration of more than 3 months, who were either
current users of pregabalin or who had been treated with
pregabalin in the previous 12 months. To avoid recall bias,
former users of pregabalin, who discontinued its use more
than a year prior to enrollment in the study, were excluded.
Patients were recruited from two datasets of chronic pain
patients: the Quebec Pain Registry and the Fibromyalgia
Patients Registry (FMPR).
The Quebec Pain Registry is a province-wide database
containing clinical and demographic information on
patients with CNCP, who are referred for a first consult-
ation at one of the three Pain Centers of Expertise in the
province of Quebec (McGill University Health Centre,
Centre hospitalier de l’Universite
´de Montre
´al, Centre
hospitalier de l’Universite
´de Sherbrooke). The QPR
prospectively collects data at four time points: prior to
the first visit to the pain clinic, and 6, 12, and 24
months following their initial appointment. The Registry
documents patients’ demographic data, medical and pain
history, pain diagnosis, consumption habits, and past-year/
current pharmacological and non-pharmacological treat-
ments for pain. Patient diagnoses are established by the
pain clinicians of the participating clinics using a compre-
hensive list of 112 different pain diagnostic codes. In
accordance with the IMMPACT recommendations
(Initiative on Methods, Measurement and Pain assessment
in Clinical Trials
16,17
), validated questionnaires and stan-
dardized scales are also used to collect information on
*Cymbalta is a registered trade name of Eli Lilly and Company, Indianapolis, IN,
USA
Current Medical Research & Opinion Volume 31, Number 7 July 2015
1404 Pregabalin for chronic pain Giladi et al. www.cmrojournal.com !2015 Informa UK Ltd
Downloaded by [McGill University Library] at 07:38 21 February 2016

various outcome measures including pain intensity,
functional capacity and mood symptoms. The QPR started
enrolling patients in late 2008 and is ongoing, currently
containing data of more than 8000 patients. More than
90% of these patients have given their consent to use
their data for research purposes. More information about
the QPR is available at www.quebecpainregistry.org.
The Fibromyalgia Patients Registry includes all FM
patients seen at the Alan Edwards Pain Management
Unit at the McGill University Health Centre since
2007. At present the FMPR comprises more than 240
patients who were evaluated and diagnosed by a single
rheumatologist. Collected data include demographics,
medical and pain history, disease severity, coping, disabil-
ity and general health of the patient
18
. All patients
enrolled in this registry gave their consent to use their
data for research purposes. Patients enrolled in the
FMPR were not registered in the QPR, and therefore
complement QPR’s missing data on FM patients from
the Alan Edwards Pain Management Unit at the McGill
University Health Centre.
Procedures
Data were obtained from the QPR database by a query
requesting the pain diagnoses of all current and past-year
users of pregabalin with CNCP lasting more than
3 months. The pain diagnosis of all patients from the
FMPR was ‘fibromyalgia’.
In order to obtain relevant additional information
not already contained in QPR’s and FMPR’s data, a
supplemental self-administered questionnaire on the use
of pregabalin was distributed among consenting partici-
pants. For QPR patients, a letter signed by the Medical
Director of each participating clinic was sent to the
potential participants, requesting them to contact the
principal investigator of the present study if they were
interested in participating. Patients enrolled in the
FMPR have agreed to be contacted directly for research
purposes upon enrolment and were therefore approached
directly using a phone call or at their clinic visit. Patients
had the opportunity to fill in the study questionnaire
online, either in English or in French, using LimeSurvey
software
19
, or to receive by mail an identical paper
questionnaire along with a return stamped envelope.
Patients who did not respond within four weeks were
contacted once for a reminder by the research assistant.
Following the reminder, patients who did not respond
within four weeks were excluded from the study.
Measures
The study questionnaire included 30 items and took
approximately 25 minutes to complete. The first question
verified that the participant was indeed a present or past-
year user of pregabalin. The rest of the questionnaire was
divided into three parts: the first part was intended for both
present and past-year users, and included questions about
the reasons for pregabalin prescription, the first prescriber’s
specialty, time until clinical effect was achieved and
adverse effects. The second part was intended for present
users only, where patients were asked to specify concomi-
tant use of pain medications, duration of pregabalin treat-
ment, and total daily dose and frequency of its use. The
third part was intended for past-year users only, and
included questions about the reasons for discontinuation
of pregabalin. Present and past-year pregabalin users
were not presented with the same questions in order to
avoid recall bias by past users. The questions covered the
following topics and were all specific to pregabalin:
First prescriber (family physician, specialist, etc.) and
side effects. Patients were entitled to select multiple
adverse effects, and list others in free text.
Pain diagnosis that prompted the prescribing physician
to recommend pregabalin.
Time elapsing from beginning of therapy until clinical
effect was achieved. Patients could choose from one of
five optional time frames: from the minute pregabalin
was taken for the first time; one hour post initial use;
one day to one week post initial use; one week to one
month post initial use; more than one month post
initial use. Two additional optional answers were
‘I do not remember’ and ‘I experienced no pain relief’.
Dosage of pregabalin and the concomitant use of other
types of analgesic medications. To prevent recall bias,
this section was directed to current pregabalin users
only.
Patients’ satisfaction with pregabalin treatment,
measured by a 6 point Likert scale (very unsatisfied –
very satisfied
20
).
Patients’ global impression of change following prega-
balin treatment using a 7 point Likert scale
21
, focusing
on impression of change in terms of pain (greatly
increased – greatly decreased), level of function
(greatly deteriorated – greatly improved) and quality
of life (greatly deteriorated – greatly improved).
Reasons for discontinuation of pregabalin. Past-year
pregabalin users were entitled to select multiple
reasons for discontinuation.
Data analysis
The primary analysis was to compare different subgroups of
eligible patients (e.g., off-label users vs. on-label users)
with respect to specific preselected variables of interest.
Specifically, Fisher’s exact test was used for comparing
nominal responses, the proper Cochran–Mantel–
Haenszel test for ordinal responses, and the Wilcoxon
Current Medical Research & Opinion Volume 31, Number 7 July 2015
!2015 Informa UK Ltd www.cmrojournal.com Pregabalin for chronic pain Giladi et al. 1405
Downloaded by [McGill University Library] at 07:38 21 February 2016

Rank Sum test for numerical responses. All analyses were
carried out using a two-sided test at an alpha level of 5%
unless otherwise specified. No formal adjustments were
made for the multiplicity of testing due to multiple
outcomes.
Results
A total of 355 patients were eligible for the study, 325 from
the QPR and 30 from the FMPR. Eighty-two of the 325
eligible QPR patients (25.2%) and 27/30 (90%) eligible
FMPR patients completed and returned the study
questionnaire. Of the 109 participants, 91 were current
users of pregabalin, 17 were past-year users and one patient
did not respond to this question (Figure 1).
Clinical indications for pregabalin use are shown in
Table 1. These data were obtained from all 355 eligible
patients’ registry data, as well as the questionnaires. The
most prevalent reason for prescribing pregabalin was
lumbar pain with or without radiculopathy (103/355
patients; 29%), followed by FM (59/355 patients;
16.6%). Seventy-three percent (260/355, 95% confidence
interval: 68.6%–77.8%) of patients received pregabalin for
a pain problem not approved by Health Canada (off-label).
Of the 95 patients taking the medication on-label, 59 were
diagnosed as having FM, 25 with other peripheral
neuropathy and the rest with PHN (n¼9) or spinal cord
injury (n¼2).
Results obtained from the self-administered question-
naire used in the present study (N¼109) revealed that
therapy with pregabalin was initiated by a pain specialist
in 33% of the responders, by other specialists in 39% and
by a family practitioner in 28%. Eighty patients (73%)
reported a pain diagnosis that was consistent with the
diagnosis made by the pain management specialist at the
tertiary pain center. Seventeen patients (16%) reported a
pain diagnosis that was different from the one given by the
pain specialist. For nine patients (8%) the pain diagnosis
report was missing and three patients (3%) reported that
pregabalin was prescribed for reasons not related to pain.
The time to attain a positive response after initiating
pregabalin therapy varied between one day and more
than a month and was not significantly different among
the on-label users (1 week to 1 month) and off-label users
(1 day to 1 week) (p¼0.16). One fifth of the patients
(n¼18) indicated that pregabalin did not provide any
pain relief. Of them, one third (n¼6) were using
pregabalin on-label.
The average daily dose of pregabalin among current
users was 279 176 mg. Of these, 21% used less than
150 mg/day, 40% were taking 150–300 mg/day and 39%
were using 300–600 mg daily. The average daily dose
of prescribed pregabalin did not differ significantly
Patients from
QPR (n=325)
Total patients for on-
and off-label analysis
(n=355), questionnaires
mailed to all
Patients from
FMPR (n=30)
No response
(n=246)
Returned filled
questionnaires
(n=109) Pregabalin use
ststus unknown
(n=1)
Past-year
pregabalin
users (n=17)
Current
pregabalin
users (n=91)
Figure 1. Patient disposition. QPR: Quebec Pain Registry; FMPR: Fibromyalgia Patients Registry.
Current Medical Research & Opinion Volume 31, Number 7 July 2015
1406 Pregabalin for chronic pain Giladi et al. www.cmrojournal.com !2015 Informa UK Ltd
Downloaded by [McGill University Library] at 07:38 21 February 2016

among the on- and off-label users (300 183 mg vs.
237 155 mg, respectively; p¼0.11). Of the current preg-
abalin users, 77 (85%) reported its use with at least one
other type of analgesic medication. Users of pregabalin as a
single agent did not differ from the multiple analgesic users
in their global impression of change in their pain
(p¼0.14) and their overall satisfaction with the treat-
ment (p¼0.17). However, the group of patients using
pregabalin as a single agent reported a significantly greater
impression of change in terms of their level of function
(p¼0.02) and quality of life (p¼0.04). Notably, these
differences became insignificant when specifically
comparing users of pregabalin (n¼14) with patients
using pregabalin concomitantly with opioids (n¼58;
p40.05 for all parameters).
When questioned about adverse effects, 77/109
pregabalin users (70%) reported having adverse effects
associated with its use. From the group of former pregaba-
lin users, 12/17 patients (70%) reported that the reason for
discontinuation of the medication was adverse effects.
This was the most common reason for discontinuation,
followed by lack of clinical effect (n¼9; 53%). The
most common adverse effect reported among all patients
was dry mouth (n¼57; 52%), followed by weight gain
(n¼44; 40%), drowsiness (n¼42; 59%), confusion
(n¼41; 38%) and gastrointestinal symptoms (n¼40;
37%). One patient discontinued the medication because
of suicidal ideation.
Global satisfaction, as well as perceived overall
improvement in pain, level of function and quality of life
was not significantly different between the on- and
off-label pregabalin users (Figure 2). Two thirds of patients
(68%; n¼74) were at least somewhat satisfied with their
treatment with pregabalin; 74% (n¼80) had at least some
pain relief with it; 55% (n¼59) reported at least slightly
improved function; and 70% (n¼75) experienced at least
slight improvement in their quality of life. Additional
comparisons of the four outcome measures were done
between specific subpopulations treated with pregabalin.
When comparing FM patients (n¼33; i.e., on-label
indication) to patients with lumbar back pain (n¼24,
i.e., off-label indication), no significant differences were
found with respect to satisfaction, reported changes in
pain, function, and quality of life (p40.34 for all).
Similar results were found when comparing patients with
cervical, thoracic and lumbar pain without radiculopathy
(n¼17) to patients with radicular cervical, thoracic and
lumbar pain (n¼21; p40.28). No significant difference
was found when comparing patients with lumbar pain
(n¼11) to patients with radicular lumbar pain (n¼13;
p40.13). Finally, when comparing FM patients to patients
with complex regional pain syndrome (CRPS; n¼10, i.e.,
off-label indication) no significant differences were found
in terms of satisfaction, reported changes in pain, function,
and quality of life (p40.18 for all).
Discussion
Since the introduction of pregabalin to the Canadian
market in 2005, we observed that it has gained significant
popularity among health providers and patients alike.
In Quebec, pregabalin is being used almost as frequently
as acetaminophen for patients with chronic pain (unpub-
lished data). We have conducted for the first time an
analysis of the actual use of pregabalin in tertiary care
settings, exploring reasons for use, discontinuation, and
overall impact on clinical outcomes of this medication.
The main finding of the study was that pregabalin in our
population is mostly used off-label, mainly for lumbar back
pain. No significant differences were found in the
self-reported outcomes between patients receiving
pregabalin for its approved and non-approved indications
for various chronic pain conditions. These findings suggest
that pregabalin could be useful in treating chronic pain
syndromes other than those for which the medication is
Table 1. Pain diagnoses of pregabalin users (N¼355) and of patients who returned a full questionnaire (N¼109).
Diagnosis QPR and FMPR patients, n¼355 Patients who returned the questionnaire, n¼109
Number of
patients (n)
Percentage of
patients (%)
Number of
patients (n)
Percentage of
patients (%)
Lumbar pain with or without radiculopathy 103 29.0 24 22
Fibromyalgia 59 16.6 32 29
Cervical pain with or without radiculopathy 38 10.7 7 6.4
Complex regional pain syndrome 32 9.0 9 8.25
Peripheral neuropathies 25 7.0 3 2.75
Thoracic pain with or without radiculopathy 22 6.2 6 5.5
Postherpetic neuralgia 9 2.5 1 0.9
Spinal cord injury 2 0.6 0 0
Other 65 18.4 27 24.8
QPR: Quebec Pain Registry; FMPR: Fibromyalgia Patients Registry.
Current Medical Research & Opinion Volume 31, Number 7 July 2015
!2015 Informa UK Ltd www.cmrojournal.com Pregabalin for chronic pain Giladi et al. 1407
Downloaded by [McGill University Library] at 07:38 21 February 2016

indicated, similar to the indications of tramadol or
acetaminophen
22,23
.
Off-label use of medications is common. For example,
thalidomide was tragically marketed and prescribed in the
late 1950s as a sedative and antiemetic
24
. After causing
severe deformities in over 8000 newborns
25
, it was taken
off the market, but several decades later it was found to be
an effective treatment for leprosy and multiple myeloma
and is currently used for these indications
24
.
Acetylsalicylic acid (aspirin) was initially advertized as a
potent pain reliever and a remedy for rheumatism in
1899
26
, but is currently used as a primary and secondary
preventive agent of cardiovascular diseases
27
. Pregabalin
was initially developed as an anticonvulsant
1
, but is mainly
used as an analgesic medication, both in acute and in
chronic pain conditions. Most of the trials examining
the off-label analgesic use of pregabalin have been done
in acute pain conditions, examining the role of periopera-
tive pregabalin in decreasing postoperative pain and
opioid consumption. These studies yielded conflicting
results, some showing pregabalin to be beneficial
28–30
whereas others did not find it to be effective or superior
to placebo
31–33
. Randomized, controlled trials (RCTs)
testing the off-label role of pregabalin in CNCP yielded
conflicting results as well. For example, pregabalin was
found to be beneficial in patients with low back pain
34
,
chronic pancreatitis
35
and in the prevention of chronic
daily headache
36
. However, pregabalin was not found to
be advantageous for chronic prostatitis/chronic pelvic pain
syndrome
37
and its efficacy in neuropathic pain associated
with chronic lumbosacral radiculopathy was question-
able
38
. Mixed results were also seen when pregabalin
was prescribed for its approved indications. For example,
an observational study on patients with peripheral
neuropathy found pregabalin to be substantially
beneficial
39
, while other RCTs found that it brings only
modest pain relief
40
. Finally, while some studies found
pregabalin to be favorable in FM patients
41
other
40(a) (b)
(c) (d)
35
30
25
20
15
10
5
very unsatisfied
greatly deteriorated
greatly deteriorated
greatly increased
considerably deteriorated
slightly deteriorated
slightly improved
considerably improved
greatly improved
remained unchanged
considerably deteriorated
considerably increased
slightly deteriorated
slightly increased
slightly improved
slightly decreased
considerably improved
considerably decreased
greatly improved
greatly decreased
remained unchanged
remained unchanged
very satisfied
not satisfied
somewhat not satisfied
somewhat satisfied
satisfied
0
40
45
50
35
30
25
20
15
10
5
0
40
35
30
25
20
15
10
5
0
35
30
25
20
15
10
5
0
on-label percentage of users off-label percentage of users
Figure 2. Outcomes of on- or off-label use of pregabalin in chronic pain patients. (a) Overall satisfaction with pregabalin. (b) Degree of pain relief with
pregabalin. (c) Degree of change in functional level with pregabalin. (d) Degree of change of quality of life with pregabalin.
Current Medical Research & Opinion Volume 31, Number 7 July 2015
1408 Pregabalin for chronic pain Giladi et al. www.cmrojournal.com !2015 Informa UK Ltd
Downloaded by [McGill University Library] at 07:38 21 February 2016

studies demonstrated at most a moderate effect of this
medication
42
. One explanation for the different outcomes
could be attributed to the known anxiolytic properties
of pregabalin
43,44
, prompting its approval for this
indication in many European countries
6
. Since anxiety is
commonly associated with chronic pain
45
, it is possible
that the beneficial effect of pregabalin could be partially
attributed to its anxiolytic properties.
Some of the clinical findings of this study merit further
discussion. Firstly, two thirds of the participants have been
prescribed pregabalin by either a primary care physician or
a non-pain-management specialist. Since almost three
quarters of the patients’ pain diagnoses reports were
consistent with the diagnosis given by the pain manage-
ment physician at the tertiary pain center it is clear that
primary care physicians are competent and knowledgeable
enough to diagnose chronic pain problems. Secondly, what
could be the reason for the widespread off-label use of
pregabalin? Although speculative, it could be attributed
to the prescribing physician’s unawareness of the
approved pregabalin indications, to lack of knowledge in
differentiating between types of CNCP or perhaps the
pressure to provide means of pain relief regardless of the
type of pain. Thirdly, although the use of polypharmacy
has been advocated in various CNCP conditions, we found
that the use of pregabalin as a single agent, compared to its
concomitant use with other analgesics, was associated with
perceived improved function and quality of life. This
result is supported by previous studies showing that the
concomitant use of opioids with pregabalin did not result
in additional pain reduction when compared to the use of
pregabalin alone
46
. It is possible that patients treated with
multiple medications suffered from pain conditions that
were more resistant to treatment. Fourthly, according to
the manufacturer’s monograph, the expected length of
time from the first pregabalin intake to the achievement
of a clinical effect is one week in patients with DPN, SCI
and PHN (no specific data exist relating to patients with
FM
5
). These recommendations do not mirror actual
clinical practice, where dose escalation is frequently
done gradually
47
. Indeed, we found that a clinical effect
was apparent within one week in only one half of patients,
whereas the others started experiencing some effect after
one week or later. Consequently, pregabalin therapy
should probably be maintained for a longer, albeit
undefined time period before ruling it out as a therapeutic
option. Lastly, the most common adverse effects reported
in the present study were similar to earlier reports, mainly
dizziness, drowsiness, edema and dry mouth
5
. Weight gain
was reported to be more prevalent in the current study
(40%) but it should be noted that no quantitative
objective measurements of weight gain were performed.
Although more than two-thirds of the responders reported
that the use of pregabalin was associated with clinical side
effects, a high rate of global satisfaction (68%) and
improvement in quality of life (71%) with pregabalin
were found as well. It is reasonable to assume that,
although common, these side effects were not considered
to be severe.
The current study has number of limitations. The
response rate of eligible patients who returned the study
questionnaire was low (30.7%). The reason for the low
response rate from the QPR (25.2%) could be attributed
to the fact that QPR patients could not be invited directly
to participate in the study; they were informed about the
study and were requested to initiate the first contact with
the study coordinator if interested to join the study.
Indeed, the response rate of patients from the FMR was
much higher (90%), because they were approached
directly. Still, the primary outcome data on the use of
pregabalin in relation to pain diagnosis was independent
of patients’ response rate, because it was extracted directly
from the QPR and FMPR (N¼355), including the pain
diagnoses. A second limitation of the study is that all par-
ticipants were treated in tertiary pain centers and may not
represent the general chronic pain patient population;
patients in our study are likely to be more refractory to
treatment than patients with chronic pain in the general
population. It is also important to point out that part of the
data collected with our study questionnaire was based on
patients’ retrospective recall (e.g., time to clinical effect of
pregabalin, reasons for discontinuation). Although
responders to these questions were only past-year former
users and current users, these findings may be subject to
some recall bias. Finally, the QPR diagnoses of chronic
pain syndromes were determined by multiple physicians
of heterogeneous background and expertise. This
could potentially lead to certain bias, depending on the
individual physician.
Conclusion
The current study indicates that the majority of
patients with chronic pain, treated in tertiary pain
units in the province of Quebec and using pregabalin
for their pain, used it off-label. Seemingly, in
their attempt to help in diminishing patients’ suffering,
physicians of multiple disciplines, including pain man-
agement physicians, do not follow the official indica-
tions for pregabalin use, as approved by Health Canada.
Still, the reported clinical benefits from pregabalin were
similar in our study participants taking this medication
on- and off-label, including patients with non-
neuropathic or non-FM chronic pain conditions.
Future prospective studies should, therefore, explore
whether pregabalin is an acceptable non-specific
analgesic medication, similar to acetaminophen or
tramadol, in patients with CNCP.
Current Medical Research & Opinion Volume 31, Number 7 July 2015
!2015 Informa UK Ltd www.cmrojournal.com Pregabalin for chronic pain Giladi et al. 1409
Downloaded by [McGill University Library] at 07:38 21 February 2016

Transparency
Declaration of funding
This study was supported by unrestricted education and research
grants from the Louise and Alan Edwards Foundation, Montreal,
Canada.
Declaration of financial/other relationships
This study was envisioned and conducted as a researcher-
initiated project. H.G., M.-A.F., X.T. and Y.S. have disclosed
that they have no significant relationships with or financial inter-
ests in any commercial companies related to this study or article.
M.A.W. and M.C. have no relevant relationships to disclose
related to this study, but have disclosed that they have received
speaker fees and grants from Pfizer Canada Inc.
CMRO peer reviewer 1 has no relevant financial or other rela-
tionships to disclose. Peer reviewer 2 has no relevant financial or
other relationship pertaining to this study, but has disclosed that
he has received honoraria and/or has participated in advisory
boards on behalf of: Alkermes, AstraZeneca, Grunenthal,
Johnson & Johnson, Lundbeck, Merck, Merz, M’s Science
Corporation, Otsuka Pharmaceuticals, Pierre Fabre
Pharmaceuticals, Pfizer, PharmaNeuroBoost, Richter, Roche,
Servier, Synosis, Takeda, Theracos, Targacept, Transcept and
Xytis. Peer reviewer 3 also has no relevant financial or other
relationships related to this specific research, but maintains the
following relationships: Consultant for Inspirion, Baxter, Purdue
Pharma LLP, Grunenthal GmhB, Iroko, and Johnson and
Johnson.
Acknowledgments
The authors thank Anna Serapins, He
´le
`ne Lancto
ˆt and Sylvie
Toupin for their editorial assistance.
Previous presentation: This study was presented as a poster in
the Canadian Pain Society conference in May 2013 in Winnipeg,
Manitoba, Canada.
References
1. Silverman RB. From basic sciences to blockbuster drug: the discovery of
Lyrica. Angew Chem Int Ed Engl 2008;47:3500-4
2. Dworkin RH, Kirkpatrick P. Pregabalin. Nat Rev Drug Discov 2005;4:455-56
3. FDA highlights of prescribing information (online). Available at: http://
www.accessdata.fda.gov/drugsatfda_docs/label/2012/021446s028lbl.pdf
[Last accessed 16 April 2014]
4. Lyrica European Union Prescribing Information (online). Available at: http://
www.medicines.org.uk/EMC/medicine/14707/PIL/LyricaþCapsules [Last
accessed 16 April 2014]
5. Lyrica product monograph 2013. Available at http://www.pfizer.ca/en/our_
products/products/monograph/141 [Last accessed 16 April 2014]
6. Tassone DM, Boyce E, Guyer J, et al. Pregabalin: a novel gamma-aminobu-
tyric acid analogue in the treatment of neuropathic pain, partial-onset seizures
and anxiety disorders. Clin Ther 2007;29:26-48
7. Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuro-
pathic pain: an update and effect related to mechanism of drug action.
Pain 1999;83:389-400
8. Rosenberg JM, Harrell C, Ristic H, et al. The effect of gabapentin in neuro-
pathic pain. Clin J Pain 1997;13:251-5
9. Tanenberg RJ, Irving GA, Risser RC, et al. Duloxetine, pregabalin, and
duloxetine plus gabapentin for diabetic peripheral neuropathic pain
management in patients with inadequate pain response to gabapentin: an
open-label, randomized, noninferiority comparison. Mayo Clin Proc
2011;86:615-26
10. Ray WA, Meredith S, Thapa PB, et al. Cyclic antidepressants and the risk of
sudden cardiac death. Clin Pharmacol Ther 2004;75:234-41
11. Cohen HW, Gibson G, Alderman MH. Excess risk of myocardial infarction in
patients treated with antidepressant medications: association with use of
tricyclic agents. Am J Med 2000;108:2-8
12. Guay DRP. Pregabalin in neuropathic pain: a more ‘pharmaceutically elegant’
gabapentin? Am J Geriatr Pharmacother 2005;3:274-87
13. Bockbrader HN, Wesche D, Miller R, et al. A comparison of the pharmaco-
kinetics and pharmacodynamics of pregabalin and gabapentin. Clin
Pharmacokinet 2010;49:661-9
14. Cymbalta product monograph 2015. Available at: http://www.lilly.ca/en/pdf/
product-monograph/18_cymbalta-pm_11mar2015.pdf [Last accessed 7
April 2015]
15. Mesgarpour B, Mu¨ ller M, Herkner H. Search strategies to identify reports on
‘off-label’ drug use in EMBASE. BMC Med Res Methodol 2012;12:190
16. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic
pain clinical trials: IMMPACT recommendations. Pain 2005;113:9-19
17. Turk DC, Dworkin RH, Allen RR, et al. Core outcome domains for chronic pain
clinical trials: IMMPACT recommendations. Pain 2003;106:337-45
18. Fitzcharles MA, Ste-Marie PA, Gamsa A, et al. Opioid use, misuse and abuse
in patients labeled as fibromyalgia. Am J Med 2011;124:955-60
19. Limesurvey online survey software. Available at: http://www.limesurvey.org
[Last accessed 3 March 2013]
20. Haythornthwaite JA, Fauerbach JA. Assessment of acute pain, pain relief and
patient satisfaction. In: Turk DC, Melzack R, eds. Handbook of Pain
Assessment, 2nd edn. New York: Guilford Press, 2001:417-30
21. Dworkin RH, Nagasako EM, Hetzel RD, et al. Assessment of pain and pain-
related quality of life in clinical trials. In: Turk DC, Melzack R, eds. Handbook of
Pain Assessment, 2nd edn. New York: Guilford Press, 2001:659-92
22. Tylenol professional product information. Available at: http://www.tylenolpro-
fessional.com/assets/TYL_PPI.pdf page 5 [Last accessed 16 April 2014]
23. Ultram product monograph. Available at: http://www.accessdata.fda.gov/
drugsatfda_docs/label/2009/020281s032s033lbl.pdf [Last accessed 16
April 2014]
24. Goldman DA. Thalidomide use: past history and current implications for prac-
tice. Oncol Nurs Forum 2001;28:471-7
25. Vanchieri C. Preparing for thalidomide comeback. Ann Intern Med
1997;127:951-2
26. Rinsema TJ. One hundred years of aspirin. Med Hist 1999;43:502-7
27. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary
prevention of vascular disease: collaborative meta-analysis of individual par-
ticipant data from randomized trials. Lancet 2009;373:1849-60
28. Pakravan M, Roshani M, Yazdani S, et al. Pregabalin and gabapentin for
post-photorefractive keratectomy pain: a randomized controlled trial. Eur J
Ophthalmol 2012;22(Suppl 7):s106-13
29. Balaban F, Yag
˘ar S, O
¨zgo
¨k A, et al. A randomized, placebo-controlled study of
pregabalin for postoperative pain intensity after laparoscopic cholecystec-
tomy. J Clin Anesth 2012;24:175-8
30. Bornemann-Cimenti H, Lederer AJ, Wejbora M, et al. Preoperative pregabalin
administration significantly reduces postoperative opioid consumption and
mechanical hyperalgesia after transperitoneal nephrectomy. Br J Anaesth
2012;108:845-9
31. Nimmaanrat S, Tangtrakulwanish B, Klabklay P, et al. Perioperative admin-
istration of pregabalin in patients undergoing arthroscopic anterior cruciate
ligament reconstruction: does it help to relieve postoperative pain? J Med
Assoc Thai 2012;95:1297-301
32. Paech MJ, Goy R, Chua S, et al. A randomized, placebo-controlled trial of
preoperative oral pregabalin for postoperative pain relief after minor gyneco-
logical surgery. Anesth Analg 2007;105:1449-53
33. YaDeau JT, Paroli L, Kahn RL, et al. Addition of pregabalin to multimodal
analgesic therapy following ankle surgery: a randomized, double-blind, pla-
cebo-controlled trial. Reg Anesth Pain Med 2012;37:302-7
Current Medical Research & Opinion Volume 31, Number 7 July 2015
1410 Pregabalin for chronic pain Giladi et al. www.cmrojournal.com !2015 Informa UK Ltd
Downloaded by [McGill University Library] at 07:38 21 February 2016

34. Romano
`CL, Romano
`D, Bonora C, et al. Pregabalin, celecoxib and their
combination for treatment of low back pain. J Orthoped Traumatol
2009;10:185-91
35. Olesen SS, Bouwense SA, Wilder-Smith OH, et al. Pregabalin reduces pain in
patients with chronic pancreatitis in a randomized, controlled trial.
Gastroenterology 2011;141:536-43
36. Rizzato B, Leone G, Misaggi G, et al. Efficacy and tolerability of pregabalin
versus topiramate in the prophylaxis of chronic daily headache with analgesic
overuse: an open-label, prospective study. Clin Neuropharmacol
2011;34:74-8
37. Pontari MA, Krieger JN, Litwin MS, et al. Pregabalin for the treatment of men
with chronic prostatitis/chronic pelvic pain syndrome: a randomized controlled
trial. Arch Intern Med 2010;170:1586-93
38. Baron R, Freynhagen R, To
¨lle TR, et al. The efficacy and safety of pregabalin in
the treatments of pain associated with chronic lumbosacral radiculopathy.
Pain 2010;150:420-7
39. Navarro A, Saldan
˜a MT, Pe
´rez C, et al. Patient-reported outcomes in subjects
with neuropathic pain receiving pregabalin: evidence from medical practice in
primary care settings. Pain Med 2010;11:719-31
40. Moon DE, Lee DI, Lee SC, et al. Efficacy and tolerability of pregabalin using a
flexible, optimized dose schedule in Korean patients with peripheral
neuropathic pain: a 10-week, randomized, double-blind, placebo-controlled,
multicenter study. Clin Ther 2010;32:2370-85
41. Crofford LJ, Rowbotham MC, Mease PJ, et al. Pregabalin for the treatment
of fibromyalgia syndrome: results of a randomized, double-blind, placebo-
controlled trial. Arthritis Rheum 2005;52:1264-73
42. Smith MT, Moore BJ. Pregabalin for the treatment of fibromyalgia. Expert Opin
Pharmacother 2012;13:1527-33
43. Bandelow B, Sher L, Bunevicius R, et al. Guidelines for the pharmacological
treatment of anxiety disorders, obsessive-compulsive disorder and
posttraumatic stress disorder in primary care. Int J Psychiatry Clin Pract
2012;16:77-84
44. Wensel TM, Powe KW, Cates ME. Pregabalin for the treatment of generalized
anxiety disorder. Ann Pharmacoth 2012;46:424-9
45. Crombez G, Eccleston C, Van Damme S, et al. Fear-avoidance model of
chronic pain: the next generation. Clin J Pain 2012;28:475-83
46. Zin CS, Nissen LM, O’Callaghan JP, et al. A randomized, controlled trial of
oxycodone versus placebo in patients with postherpetic neuralgia and painful
diabetic neuropathy treated with pregabalin. J Pain 2010;11:462-71
47. Tzellos TG, Papazisis G, Toulis KA, et al. A2delta ligands gabapentin and
pregabalin: future implications in daily clinical practice. Hippokratia
2010;14:71-5
Current Medical Research & Opinion Volume 31, Number 7 July 2015
!2015 Informa UK Ltd www.cmrojournal.com Pregabalin for chronic pain Giladi et al. 1411
Downloaded by [McGill University Library] at 07:38 21 February 2016