pregabalina en dolor por neuropatia diabetica

1. CME Pregabalin relieves symptoms of
painful diabetic neuropathy
A randomized controlled trial
H. Lesser, MD, PhD; U. Sharma, PhD; L. LaMoreaux, MPH; and R.M. Poole, MD, FACP
Abstract—Objective: Pregabalin, an alpha2-delta ligand with analgesic, anxiolytic, and anticonvulsant activity, has been
evaluated for treatment of neuropathic pain. The authors assessed the efficacy and tolerability of pregabalin (75, 300, 600
mg/day) vs placebo in patients with diabetic peripheral neuropathy (DPN). Methods: Patients with a 1- to 5-year history of
DPN and average weekly pain score of Ն4 on an 11-point numeric pain-rating scale were enrolled in a 5-week, double-
blind, multicenter, placebo-controlled study. Patients (n ϭ 338) were randomized to receive one of three doses of pregaba-
lin or placebo TID. Pregabalin 600 mg/day was titrated over 6 days; lower doses were initiated on day 1. Results: Patients
in the 300- and 600-mg/day pregabalin groups showed improvements in endpoint mean pain score (primary efficacy
measure) vs placebo (p ϭ 0.0001). Improvements were also seen in weekly pain score, sleep interference score, patient
global impression of change, clinical global impression of change, SF-McGill Pain Questionnaire, and multiple domains of
the SF-36 Health Survey. Improvements in pain and sleep were seen as early as week 1 and were sustained throughout
the 5 weeks. Responders (patients with Ն50% reduction in pain compared to baseline) were 46% (300 mg/day), 48% (600
mg/day), and 18% (placebo). Pregabalin was well tolerated with a low discontinuation rate. The most common adverse
events were dizziness and somnolence. Conclusions: In patients with diabetic peripheral neuropathy, pregabalin demon-
strated early and sustained improvement in pain and a beneficial effect on sleep, which were confirmed by positive patient
global impression. Pregabalin was well tolerated at all doses.
NEUROLOGY 2004;63:2104–2110
Pregabalin1
has demonstrated efficacy in treating
neuropathic pain (NeP) and sleep interference asso-
ciated with diabetic peripheral neuropathy (DPN)
and postherpetic neuralgia (PHN).2,3
Studies with
laboratory animals show pregabalin selectively binds
to the ␣2-␦ subunit protein of voltage-gated calcium
channels in various regions of brain4
and in the su-
perficial dorsal horn of the spinal cord (F. Bian et al.,
R Williams et al., personal communications). In
vitro, pregabalin acts as a presynaptic inhibitor of
the release of excitatory neurotransmitters in stimu-
lated neurons.5-8
It reduces influx of calcium into iso-
lated synaptic endings,9
thereby reducing release of
synaptic vesicles by exocytosis. This has been mea-
sured in vitro with several excitatory neurotransmit-
ters, including glutamate,5
substance P, and
calcitonin gene-related peptide,10
which are particu-
larly relevant for potential analgesic action. Pre-
gabalin’s effect of inhibiting neurotransmitter
release is enhanced by prolonged depolarization or
prior inflammation.9,11
Pregabalin has no activity at
GABAA, GABAB, or benzodiazepine receptors,12
and
there are no known pharmacokinetic drug–drug in-
teractions with pregabalin.
Gabapentin is widely used to treat NeP, in part,
because it has fewer troublesome side effects than
tricyclics and almost no drug interactions.13-15
Yet, it
shows nonlinear bioavailability and requires titra-
tion to the higher doses (i.e., Ն1,800 mg/day) at
which response rates have been greatest.13,14,16
Though structurally related to gabapentin, pregaba-
lin exhibits linear pharmacokinetics across its thera-
peutic dose range, with low intersubject variability,
unlike the less-than-proportional pharmacokinetics
observed with increasing doses of gabapentin.17
This
study evaluated the effectiveness of pregabalin vs
placebo in relieving NeP associated with DPN. At-
tention was given to the impact of diabetic NeP on
sleep and health-related quality of life, as these are
documented, relevant comorbidities of DPN.18
Methods. This was a randomized, double-blind, placebo-
controlled, parallel-group, multicenter study conducted in accor-
dance with the Declaration of Helsinki and in compliance with
ICH Good Clinical Practice Guidelines. The protocol and a copy of
the informed consent document were reviewed and approved by
the institutional review board at each of the 45 study centers, all
located in the United States. Each patient or legal guardian read
and signed informed consent before initiating any study
procedures.
The study consisted of a 1-week baseline phase and a 5-week
double-blind treatment phase that included a 1-week titration and
4-week fixed-dose period. Following week 5 of the double-blind
From the University of Rochester School of Medicine & Dentistry (Dr. Lesser), Rochester, NY; Pfizer Global Research and Development (Drs. Sharma and
LaMoreaux), Ann Arbor, MI; and Pfizer Global Research and Development (Dr. Poole), New London, CT.
Sponsored by Pfizer Global Research and Development.
Drs. Sharma, LaMoreaux, and Poole own stock in Pfizer Global Research and Development. Dr. Poole owns stock in excess of $10,000.
Received December 24, 2003. Accepted in final form July 26, 2004.
Address correspondence and reprint requests to Dr. Harold Lesser, 1415 Portland Ave, Suite 480, Rochester, NY 14621; e-mail: Harold.Lesser@viahealth.org
2104 Copyright © 2004 by AAN Enterprises, Inc.

2. phase, patients had the option of entering an open-label follow-on
study. During the baseline and double-blind phases, patients re-
corded a daily pain score in a pain diary. At the end of the base-
line phase, eligible patients were randomized to receive placebo,
75, 300, or 600 mg/day of pregabalin during the double-blind pe-
riod. Pregabalin or matching placebo capsules were administered
orally, three times a day for a period of 5 weeks. Patients random-
ized to the 600 mg/day arm titrated to the full dose over the 6-day
titration period, while patients randomized to receive pregabalin
75 mg/day and 300 mg/day began at the full dose without
titration.
The randomization code was generated with a block size of
eight and was maintained by the Clinical Pharmacy Operations
department, with no access by other individuals or departments.
Medication was shipped to the sites in blocks in unit-dose trays;
each dose contained three capsules (active medication or placebo
in both the 25 mg and 100 mg capsule sizes). Each patient was
assigned the next sequential random number at the site and took
one small and two larger capsules, with the proper mix of active
medication and placebo, for each dose to achieve double-blinding.
The first dose of study medication was taken on August 21, 1998,
and the last observation was recorded on June 24, 1999. The blind
was maintained until all decisions regarding data evaluability
were made.
Eligible patients were men and women 18 years of age or older
with a diagnosis of type 1 or type 2 diabetes mellitus and distal
symmetric sensorimotor polyneuropathy for 1 to 5 years. Female
patients were required to be nonpregnant, nonlactating, post-
menopausal, or surgically sterilized; women at risk of pregnancy
were required to be using an appropriate method of contraception.
Each patient’s antidiabetic medication was to be stabilized prior
to initiation of the study and held constant throughout the study,
provided adequate glucose control was maintained to ensure pa-
tient safety. Patients must have completed at least four daily pain
diaries during the baseline phase, and had to have an average
baseline daily pain score of Ն4 (on a 0 to 10 scale). Patients were
also required to have a score of Ն40 mm on the visual analog scale
(VAS) of the Short-Form McGill Pain Questionnaire (SF-MPQ)19
at baseline and randomization visits.
Patients with hemoglobin A1c levels of Ͼ 11% were excluded,
as were patients with clinically significant or unstable hepatic,
respiratory, or hematologic illnesses, unstable cardiovascular dis-
ease, or symptomatic peripheral vascular disease. Since pregaba-
lin is renally excreted, patients with an estimated creatinine
clearance of Յ60 mL/minute based on serum creatinine levels
were excluded.20
Patients with any conditions that might confound
pain assessment (for example, other severe pain or a skin condi-
tion in the area affected by neuropathy) were excluded, as were
patients who had failed to respond to previous treatment with
gabapentin at doses Ն1,200 mg/day for treatment of pain associ-
ated with diabetic neuropathy. Patients were allowed to take up to
3 g of acetaminophen daily and to continue stable treatment with
selective serotonin reuptake inhibitors (SSRIs). All other NeP
medications were prohibited during the course of the study.
The primary efficacy measure was pain, as recorded by the
patient in a daily diary; rating was based on an 11-point numeri-
cal scale that ranged from 0 (no pain) to 10 (worst possible pain).
Each day on awakening, patients circled the number on the scale
that best described their average pain over the previous 24 hours.
Mean pain scores were computed at endpoint (the last seven
scores while on study drug) and for each week in the study. Sec-
ondary efficacy measures were the daily sleep interference diary,
SF-MPQ (including the pain descriptors total score, the VAS, and
present pain intensity [PPI]) completed by the patient at each
clinic visit, and the Clinical Global Impression of Change (CGIC)
and Patient Global Impression of Change (PGIC) administered at
the completion visit. Additionally, the SF-36 Health Survey (SF-
36)21
to assess quality of life and the Profile of Mood States
(POMS)22
questionnaire to determine mood stability were admin-
istered at study randomization and completion. For the SF-36,
scores for eight HRQoL domains—physical functioning, role limi-
tations due to physical problems, social functioning, bodily pain,
mental health, role limitations due to emotional problems, vital-
ity, and general health perception—were calculated, with higher
scores indicating a better HRQoL. The POMS measured and pro-
vided scores for total mood disturbance as well as six mood
scales—tension-anxiety, depression-dejection, anger-hostility,
vigor-activity, fatigue-inertia, and confusion-bewilderment—
based on patient assessments of 65 mood descriptors.
The safety of pregabalin was assessed by examining the occur-
rence, nature, severity, and relationship of adverse events (AEs)
to study drug. Adverse events were converted from the
investigator-reported terms to preferred terms23
for purposes of
data analysis. Other safety measures included clinical laboratory
data, physical examinations, peripheral sensory examinations,
electrocardiograms (ECGs) with a 2-minute rhythm strip, and
vision function testing (Snellen visual acuity testing, dilated fun-
duscopic examination, and Humphrey perimetry [120-point Visual
Screening using the quantified defects routine]).
Sample size. The anticipated treatment effect was estimated
based on the results from two studies of gabapentin vs placebo in
postherpetic neuralgia and painful diabetic neuropathy, for which
the differences in endpoint weekly mean pain scores were 1.8 and
1.3.13,14
It was estimated that 80 patients per group would provide
90% power to detect a difference of at least 1.3 at the 2.5% two-
sided significance level.
Statistical analysis. All statistical testing was two-sided and
performed using SAS procedures.24
All analyses were performed
on available data from the intent-to-treat (ITT) population, de-
fined as all randomized patients who received at least one dose of
study medication. For each analysis, the primary comparisons
were between 300 mg/day pregabalin vs placebo and 600 mg/day
pregabalin vs placebo. The 75-mg/day pregabalin vs placebo com-
parison was considered a secondary comparison. Mean pain
scores, SF-MPQ scores, mean sleep interference scores, SF-36 do-
mains, and POMS scales were analyzed using an analysis of co-
variance (ANCOVA) main effects model, with treatment and
center in the model and the respective baseline as a covariate. In
each case, adjusted least squares means were obtained from the
model and 95% CIs on the difference in least squares means
between each dose of pregabalin and placebo were constructed.
Because there were two principal comparisons (300 mg/day pre-
gabalin vs placebo and 600 mg/day pregabalin vs placebo), p val-
ues were adjusted using the Hochberg25
procedure in order to
protect the type I error rate at the 0.05 level.
Estimates of global impressions of change (PGIC, CGIC) were
analyzed using the Cochran-Mantel-Haenszel (CMH) test with
Figure 1. Summary of participant flow during the study.
*One patient randomized to the 300 mg/day group with-
drew before taking study medication because of concern
over baseline abnormal ECG. ITT ϭ intention to treat.
December (1 of 2) 2004 NEUROLOGY 63 2105

3. modified ridit scores, adjusting for center. As specified by the
protocol, patients who experienced a 50% or greater decrease in
pain from baseline to endpoint were considered responders. The
proportion of responders was analyzed using the CMH test with
table scores, adjusting for center.
Results. A total of 578 patients were screened and 338
were randomized to treatment. Of the 240 patients not
randomized, 238 did not meet the eligibility criteria or
withdrew because of administrative reasons and 2 had
severe adverse events prior to taking medication. One pa-
tient who was randomized withdrew before taking study
medication and was not included in the ITT population
(figure 1). The characteristics of the 337 ITT patients are
summarized in table 1. The treatment groups were well
balanced with respect to demographic and disease charac-
teristics. Most patients (306 patients, 91%) were diagnosed
with type 2 diabetes, and most (319 patients, 95%) were
receiving medications for their diabetes, either insulin
(various forms) or oral antidiabetic agents such as met-
formin hydrochloride, glibenclamide, glipizide, and troglita-
zone. Pain scores at baseline were similar across treatment
groups. A total of 69 patients received concurrent NeP medi-
cations; 46 (14%) used acetaminophen, the only pain medica-
tion allowed during the study. Twenty-five patients took
protocol-prohibited analgesics during the study or with inad-
equate washout periods prior to study start.
More than 85% of patients in each treatment group com-
pleted the study (see figure 1). During the 5-week double-
blind treatment phase, 35 patients withdrew prior to
completing the study; 18 of these were due to AEs. More
patients receiving pregabalin 600 mg/day withdrew due to
AEs (12.2% [10/82]) as compared with the other treatment
groups (75 mg/day, 2.6% [2/77]; 300 mg/day, 3.7% [3/81]; pla-
cebo, 3.1% [3/97]). A very high percentage of completers chose
to enter the open-label phase of the trial (93% of the 75 mg
group [62/67], 92% of the 300 mg group [70/76], 97% of the
600 mg group [68/70], and 97% of the placebo group [86/89]).
An additional 5 patients in the 75-mg/day group, 2 in the
600-mg/day group, and 2 in the placebo group entered open
label without completing the study.
The primary efficacy measure, endpoint mean pain
score, was significantly improved by pregabalin 300 and
600 mg/day when compared to placebo (table 2). The effi-
cacy of pregabalin 75 mg/day, as anticipated, was not dif-
ferent from placebo.
Both pregabalin 300 and 600 mg/day significantly re-
duced pain compared to placebo as early as week 1 follow-
ing treatment initiation, the first time point for which a
Table 1 Summary of patient characteristics: intent-to-treat population
Characteristic
Placebo,
n ϭ 97
Pregabalin
75 mg/d,
n ϭ 77
Pregabalin
300 mg/d,
n ϭ 81
Pregabalin
600 mg/d,
n ϭ 82
All
patients,
n ϭ 337
Sex, n (%)
Men 59 (60.8) 43 (55.8) 48 (59.3) 52 (63.4) 202 (59.9)
Women 38 (39.2) 34 (44.2) 33 (40.7) 30 (36.6) 135 (40.1)
Race, n (%)
White 91 (93.8) 74 (96.1) 76 (93.8) 77 (93.9) 318 (94.4)
Black 5 (5.2) 1 (1.3) 3 (3.7) 3 (3.7) 12 (3.6)
Other 1 (1.0) 2 (2.6) 2 (2.5) 2 (2.4) 7 (2.1)
Age, y
Mean (SD) 57.8 (11.6) 61.3 (10.5) 59.0 (9.2) 62.0 (9.7) 59.9 (10.5)
Median 60.0 61.0 60.0 62.0 61.0
Min, max 26, 77 34, 85 40, 77 29, 80 26, 85
Estimated creatinine clearance at
baseline (mL/min)
Mean (SD) 98.7 (29.1) 97.5 (32.8) 101.9 (30.4) 94.2 (30.0) 98.1 (30.5)
Median 97.7 89.0 93.8 87.4 90.9
Min, max 42.0, 199.1 56.3, 229.6 62.3, 227.4 53.7, 199.4 42.0, 229.6
Diabetes type, n (%)
Type 1 14 (14.4) 6 (7.8) 5 (6.2) 6 (7.3) 31 (9.2)
Type 2 83 (85.6) 71 (92.2) 76 (93.8) 76 (92.7) 306 (90.8)
Baseline pain score
Mean (SD) 6.6 (1.5) 6.7 (1.3) 6.2 (1.4) 6.2 (1.5) 6.4 (1.4)
Median 6.7 6.6 6 6.3 6.4
Min, max 2.9, 9.6 3.7, 10.0 3.9, 10.0 3.7, 10.0 2.9, 10.0
Antidiabetic medication, n (%)
Insulin 47 (48.5) 30 (39.0) 33 (40.7) 32 (39.0) 142 (42.1)
Oral 67 (69.1) 55 (71.4) 65 (80.2) 60 (73.2) 247 (73.3)
2106 NEUROLOGY 63 December (1 of 2) 2004

4. weekly mean could be computed (figure 2). These effects
were significant at each week of the study and persisted
through endpoint. There was a significantly higher propor-
tion of responders (patients with Ն50% reduction in pain)
in the 300-mg/day pregabalin group (37/81, 46%) and 600-
mg/day pregabalin group (39/81 patients, 48%) compared
with placebo (17/97, 18%). Further, a greater proportion of
patients in the 600-mg/day group achieved higher levels of
response, such as Ն60%, Ն70%, and Ն80% reduction in
pain. For example, the proportion of patients achieving a
Ն70% reduction in pain was significantly higher in the
600-mg/day group (22/81, 27%) than the 300 mg/day group
(13/81, 16%) or the placebo group (6/97, 6%) (figure 3).
Using the clinically important improvement rate of 30%,26
response rates were similar in the 300-mg/day (50/81, 62%)
and 600-mg/day (53/81, 65%) groups and lower with pla-
cebo (32/97, 33%).
Similarly, the mean sleep interference score was im-
proved by both pregabalin 300 and 600 mg/day compared
with placebo by week 1 (figure 4). The sleep interference
scores for the 300- and 600-mg/day pregabalin groups were
lower than the sleep interference scores of the placebo
group at each week during the double-blind phase and
differed by 1.3 and 1.6 (p ϭ 0.0001) for the two doses at
endpoint.
Other secondary efficacy measures demonstrated a sim-
ilar pattern of findings. For the SF-MPQ, treatment with
pregabalin 300 and 600 mg/day significantly reduced total
score (comprised of sensory and affective scores, both of
which improved with pregabalin 300 and 600 mg), PPI,
and VAS compared with placebo (table 3). The PGIC and
CGIC scores were likewise better for both of these pre-
gabalin doses compared with the placebo group (p ϭ 0.001
for each comparison) (figure 5). For the top two categories,
“much improved” and “very much improved,” on PGIC,
pregabalin rates were 55.7% (44/79) for 300 mg/day and
69.2% (54/78) for 600 mg/day, while the placebo rate was
24.2% (23/95). For these categories on CGIC, pregabalin
rates were 58.2% (46/79) for 300 mg/day and 64.1% (50/78)
for 600 mg/day, while the placebo rate was 26.3% (25/95).
Pregabalin treatment also led to improvements in spe-
cific patient-reported outcomes of health status as mea-
sured by the social function, bodily pain, and vitality
domains of the SF-36. Both the 300 and 600 mg/day pre-
gabalin groups were better than placebo in the social func-
tioning domain (p Ͻ 0.05 and p Ͻ 0.01) and in the bodily
pain domain (p Ͻ 0.005 and p Ͻ 0.0005). Additionally, the
75 and 300 mg/day pregabalin groups were better than
placebo in the vitality domain (p Ͻ 0.05 and p Ͻ 0.01).
Further, the 300 mg/day pregabalin group had better re-
Table 2 Endpoint* mean pain scores: results of analysis of covariance
Treatment N
Least squares
mean SE
Treatment comparison
Difference from
placebo 95% CI
Adjusted†
p value
Placebo 97 5.06 0.21
Pregabalin
75 mg/day
77 4.91 0.24 Ϫ0.15 (Ϫ0.76, 0.46) 0.6267
Pregabalin
300 mg/day
81 3.80 0.23 Ϫ1.26 (Ϫ1.86, Ϫ0.65) 0.0001
Pregabalin
600 mg/day
81 3.60 0.23 Ϫ1.45 (Ϫ2.06, Ϫ0.85) 0.0001
* Endpoint ϭ Last seven available scores while on study medication.
† Adjustment based on Hochberg’s procedure applies to pregabalin 300 mg/day and 600 mg/day only, per protocol.
Figure 2. Least-squares mean pain scores by week, ob-
served cases. PGB ϭ pregabalin.
Figure 3. Cumulative percent reduction in pain from
baseline to endpoint by treatment group. PGB ϭ
pregabalin.
December (1 of 2) 2004 NEUROLOGY 63 2107

5. sults than the placebo group on the tension-anxiety mood
scale of the POMS (p Ͻ 0.05).
Pregabalin was generally well tolerated. No age- or sex-
related differences were noted in the frequency of AEs.
Among patients receiving the 300 and 600 mg/day doses,
the most frequently occurring AEs were CNS-related and
usually mild or moderate in intensity (table 4). Dizziness,
somnolence, and peripheral edema were the most common
AEs reported. To determine, post hoc, whether CNS AEs
may have unblinded patients to their treatment assign-
ment, the primary efficacy analysis was repeated after ex-
clusion of patients reporting dizziness or somnolence. The
primary results remained significant following this analy-
sis, with the difference from placebo on endpoint mean
pain scores being Ϫ0.89 for pregabalin 300 mg/day (p Ͻ
0.05) and Ϫ1.38 for 600 mg/day (p Ͻ 0.005). Thus, it does
not appear that the presence of dizziness or somnolence
had an impact on the primary result. A total of eight pa-
tients experienced serious AEs during the study—one in
the 75-mg/day pregabalin group, four in the 600-mg/day
pregabalin group, and three in the placebo group. Of these
serious AEs, only one led to discontinuation from the study
(a patient receiving placebo who withdrew due to an aller-
gic reaction). No deaths were reported during the study.
The number of patients who experienced deterioration
based on the neurologic examinations of gait, muscle
strength, or reflexes was similar across treatment groups.
A total of seven patients, three in the placebo group, three
in the 75 mg/day group, and one in the 300 mg/day group,
experienced weight gain Ն7% between baseline and study
completion. However, none of these was reported as an
adverse event. No other clinically significant changes were
noted in physical examinations, including vital signs and
orthostatic hypotension. No unusual clinical laboratory
values were noted during the study.
Discussion. In this double-blind, placebo-
controlled trial, pregabalin at 300 and 600 mg/day
was safe and effective for the treatment of NeP asso-
ciated with DPN. The effect was measurable and
significant by the end of the first week and sustained
throughout the 5 weeks of the study.
The improvement demonstrated on the primary
efficacy measure (i.e., reduction in endpoint mean
Figure 4. Least-squares mean sleep interference scores by
week, observed cases. PGB ϭ pregabalin.
Table 3 Short-Form McGill Pain Questionnaire (SF-MPQ): total score, VAS, and PPI at endpoint*: results of analysis of covariance
Treatment (mg/day) N
Least squares
mean SE
Treatment comparisons
Difference from
placebo 95% CI
Adjusted†
p value
SF-MPQ total score
Placebo 97 15.06 0.84
Pregabalin 75 77 15.06 0.94 0.01 (Ϫ2.43, 2.44) 0.9966
Pregabalin 300 81 10.17 0.92 Ϫ4.89 (Ϫ7.29, Ϫ2.48) 0.0001
Pregabalin 600 81 9.88 0.91 Ϫ5.18 (Ϫ7.58, Ϫ2.79) 0.0001
VAS score
Placebo 97 53.49 2.46
Pregabalin 75 77 49.70 2.74 Ϫ3.79 (Ϫ10.90, 3.32) 0.2947
Pregabalin 300 81 37.40 2.69 Ϫ16.09 (Ϫ23.11, Ϫ9.08) 0.0001
Pregabalin 600 81 34.48 2.65 Ϫ19.01 (Ϫ26.00, Ϫ12.01) 0.0001
PPI score
Placebo 97 1.79 0.10
Pregabalin 75 77 1.67 0.11 Ϫ0.12 (Ϫ0.41, 0.18) 0.4286
Pregabalin 300 81 1.20 0.11 Ϫ0.59 (Ϫ0.88, Ϫ0.30) 0.0001
Pregabalin 600 81 1.18 0.11 Ϫ0.61 (Ϫ0.90, Ϫ0.32) 0.0001
* Endpoint ϭ Last observation after randomization while on study medication.
† Adjustment based on Hochberg’s procedure applies to pregabalin 300 and 600 mg/day only, per protocol.
VAS ϭ Visual Analogue Scale; PPI ϭ present pain intensity.
2108 NEUROLOGY 63 December (1 of 2) 2004

6. pain score) was also seen on secondary pain-related
measures. These included improvement in sleep in-
terference, specific measures of HRQoL such as so-
cial functioning and bodily pain, and overall status
since the beginning of the study as measured by the
PGIC.
Pregabalin was well-tolerated at all evaluated doses.
Even with no titration for the 300-mg/day dose and
only 1 week of titration for the 600-mg/day dose,
more than 85% of patients completed the study in
each of these groups and almost all elected to con-
tinue in the open-label phase of the study. The most
frequent AEs of dizziness, somnolence, and periph-
eral edema were generally graded as mild to moder-
ate, and in most cases they did not lead to
discontinuation from the study. Peripheral edema,
the third most common dose-related adverse event,
usually began within 2 to 3 weeks after initiation of
therapy. Peripheral edema was not associated with
changes in renal or liver function, serum sodium,
serum albumin, or hematocrit. None of the following
was reported in patients with peripheral edema:
worsening congestive heart failure, pulmonary dis-
ease, deep vein thrombosis, hypoalbuminemia,
azotemia, liver function abnormalities, excessive pro-
teinuria, orthostatic hypotension, or hypertension.
Peripheral edema also showed no correlation with
weight gain.
Treatment with pregabalin was not associated
with serious AEs such as orthostatic hypotension
and other risks common in elderly patients and pa-
tients with cardiac arrhythmias as associated with
some TCAs,27
or with gastrointestinal effects seen
with nonsteroidal anti-inflammatory drug (NSAID)
use.28
There are no known pharmacokinetic drug-
drug interactions. The low rate of discontinuation
secondary to AEs is particularly appealing and fa-
vors the potential use of pregabalin in the long-term
treatment of DPN.
There is evidence of a dose-response relationship
for pregabalin. The 75-mg/day dose was not effective,
while the 300- and 600-mg/day doses were both effec-
tive compared with placebo. The threshold for bene-
fit likely lies between 75 mg/day and 300 mg/day and
may be better defined by studies of other doses, such
as 150 mg.
While the proportion of responders was similar in
the 300-mg/day and 600-mg/day groups, the higher
dose was found to provide consistent advantages in
mean pain score reduction in comparison to the 300-
mg/day dose. For example, while 37/81 (46%) and
39/81 (48%) of patients in the 300- and 600-mg/day
groups achieved a Ն50% reduction in mean score
from study baseline to endpoint, 22/81 (27%) of pa-
tients in the 600-mg/day group achieved a Ն70% re-
duction in score compared with 13/81 (16%) in the
Figure 5. Distribution of Patient Global Impression of
Change (PGIC) (A) and Clinical Global Impression of Change
(CGIC) (B). PGB ϭ pregabalin. Unshaded bars ϭ worsening;
hatched bars ϭ no change; solid black bars ϭ improvement.
Table 4 Summary of frequently occurring adverse events*
Adverse event
preferred term
Placebo,
n ϭ 97
Pregabalin
75 mg/day,
n ϭ 77
300 mg/day,
n ϭ 81
600 mg/day,
n ϭ 82
Dizziness 5 (5.2) 6 (7.8) 22 (27.2) 32 (39.0)
Somnolence 4 (4.1) 3 (3.9) 19 (23.5) 22 (26.8)
Peripheral edema 2 (2.1) 3 (3.9) 6 (7.4) 11 (13.4)
Headache 10 (10.3) 5 (6.5) 7 (8.6) 8 (9.8)
Amblyopia† 1 (1.0) 2 (2.6) 4 (4.9) 7 (8.5)
Ataxia 2 (2.1) 5 (6.5) 3 (3.7) 7 (8.5)
Confusion 2 (2.1) 0 (0.0) 4 (4.9) 7 (8.5)
Constipation 1 (1.0) 0 (0.0) 3 (3.7) 7 (8.5)
Neuropathy 8 (8.2) 7 (9.1) 7 (8.6) 7 (8.5)
Asthenia 3 (3.1) 3 (3.9) 4 (4.9) 6 (7.3)
Pain 5 (5.2) 4 (5.2) 4 (4.9) 6 (7.3)
Amnesia 1 (1.0) 2 (2.6) 0 (0.0) 5 (6.1)
Accidental injury 0 (0.0) 4 (5.2) 2 (2.5) 4 (4.9)
Dry mouth 0 (0.0) 2 (2.6) 6 (7.4) 4 (4.9)
Euphoria 0 (0.0) 0 (0.0) 5 (6.2) 4 (4.9)
Diarrhea 7 (7.2) 4 (5.2) 1 (1.2) 3 (3.7)
Infection 7 (7.2) 3 (3.9) 8 (9.9) 1 (1.2)
Values are n (%).
* Adverse events that occurred in Ն5% of patients in any pregabalin
group.
† Reported by investigators as “blurred vision,” “blurring of vision,” or
“blurry vision.”
December (1 of 2) 2004 NEUROLOGY 63 2109

7. 300-mg/day group. This observation was supported
by the increased proportion of patients on the 600
mg/day dosage (54/78, 69%) who rated themselves on
the PGIC as much improved or very much improved
compared with patients receiving 300 mg/day (44/79,
56%). Although there was a higher incidence of AEs
at the higher dose, there clearly were some patients
in the 600-mg/day group whose pain relief was sub-
stantial enough to balance this, as shown by the high
rate of completion and continuation into open-label
treatment.
This trial of 338 patients represents the largest
double-blind, placebo-controlled trial in the diabetic
NeP literature. The number of patients enrolled in
this study exceeds the combined number of patients
who participated in pivotal trials for amitriptyline
(n ϭ 29),29
carbamazepine (n ϭ 30),30
phenytoin (n ϭ
40),31
and gabapentin (n ϭ 165)13
(total n ϭ 264). The
240 patients on active treatment nearly matches the
266 active patients in a review of 10 studies on tricy-
clic antidepressants for diabetic NeP.32
Direct comparisons of pregabalin with TCAs and
gabapentin have not been conducted. Although it is
structurally and mechanistically related to gabapen-
tin, pregabalin exhibits linear pharmacokinetics
with low intersubject variability as compared with
gabapentin, which exhibits less-than-proportional
pharmacokinetics with increasing dose. These proper-
ties may make pregabalin easier to prescribe, with a
better-defined effective dose range and no need for
lengthy titrations generally required with gabapentin.
The efficacy profile for pregabalin was both statis-
tically and clinically significant and is in the same
range as other drugs of first choice currently used to
treat the NeP associated with DPN. In this study,
65% (53/81) of patients receiving 600 mg/day of pre-
gabalin achieved a clinically important reduction in
pain score (Ն30%)26
and 48% (39/81) achieved a
Ն50% reduction in pain score. The results presented
here indicate that pregabalin is safe and effective as
treatment of neuropathic pain and other symptoms
associated with DPN.
Acknowledgment
The authors thank the following investigators of the Pregabalin
Diabetic Neuropathy 1008–29 Study Group for their contributions
toward the collection of the data reported in this article: David
J. Hewitt, MD, Robert Biesbroeck, MD, E. Richard Blonsky, MD,
Christopher M. Chappel, MD, Bruce W. Irwin, MD, James D.
Dexter, MD, George Dailey, MD, Joseph W. DeHaven, MD, Jerry
Drucker, MD, David L. Fried, MD, Robert Schwendimann, MD,
Gary Gerard, MD, Stasha Gominak, MD, Richard Holub, MD,
Charles Kilo, MD, Jack A. Klapper, MD, Ronica Kluge, MD, Mark
W. Layton, MD, Harold Lesser, MD, William McIntosh, MD, Marc
R. Rendell, MD, Gerald Riess, MD, Martin S. Rusinowitz, MD,
Soren Ryberg, MD, Michael K. Sauter, MD, Daniel Sax, MD,
James Otis, MD, John P. Sheehan, MD, Norman G. Soler,
MD, Stuart R. Stark, MD, David Strutin, MD, Richard Taylor,
MD, Y. Swamy Venkatesh, MD, Jeanette Wendt, MD, Donald B.
Sanders, MD, Leonard Zemel, MD, Victor Biton, MD, Michael J.
Giuliani, MD, William B. Dawson, MD, James L. Neifing, MD,
Charles E. Argoff, MD, Kenneth Gorson, MD, John E. Castaldo,
MD, Alfredo Jacome, MD, Joanna Cooper, MD, and George Grun-
berger, MD.
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2110 NEUROLOGY 63 December (1 of 2) 2004

8. DOI 10.1212/01.WNL.0000145767.36287.A1
2004;63;2104-2110Neurology
H. Lesser, U. Sharma, L. LaMoreaux, et al.
trial
Pregabalin relieves symptoms of painful diabetic neuropathy: A randomized controlled
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