REVI EW ARTI CLE

Systematic Review and Meta-Analysis of

Pharmacological Therapies for Painful Diabetic
Peripheral Neuropathy
Sonya J. Snedecor, PhD*; Lavanya Sudharshan, MS*; Joseph C. Cappelleri, PhD

;
Alesia Sadosky, PhD

; Sonam Mehta, MS*; Marc Botteman, MSc*

*Pharmerit International, Bethesda, MD;

Pzer Inc, Groton, CT;

Pzer Inc, New York, NY, U.S.A.

& Abstract
Background: Painful diabetic peripheral neuropathy
(pDPN) is prevalent among persons with diabetes and
increases over time. Published guidelines recommend a
number of medications to treat this condition providing
clinicians with a variety of treatment options. This study
provides a comprehensive systematic review and meta-
analysis of published pharmacologic therapies for pDPN.
Methods: The published literature was systematically
searched to identify randomized, controlled trials of all
available pharmacologic treatments for pDPN (recom-
mended or nonrecommended) reporting predened efcacy
and safety outcomes. Bayesian xed-effect mixed treatment
comparison methods were used to assess relative therapeutic
efcacy and harms.
Results: Data from 58 studies including 29 interventions
and 11,883 patients were analyzed. Pain reduction over that
of placebo on the 11-point numeric rating scale ranged from
3.29 for sodium valproate (95% credible interval
[CrI] = [4.21, 2.36]) to 1.67 for Sativex (0.47, 0.60).
Estimates for most treatments were clustered between 0
and 1.5 and were associated with more study data and
smaller CrIs. Pregabalin ( 300 mg/day) was the most
effective on the 100-point visual analog scale (21.88;
[27.06, 16.68]); topiramate was the least (3.09; [3.99,
2.18]). Relative risks (RRs) of 30% pain reduction ranged
from 0.78 (Sativex) to 1.84 (lidocaine 5% plaster). Analysis of
the RR ratio of these 2 treatments reveals marginal signif-
icance for Sativex (3.27; [1.07, 9.81]), indicating the best
treatment is only slightly better than the worst. Relative risks
of 50% pain reduction ranged from 0.98 (0.56, 1.52)
(amitriptyline) to 2.25 (1.51, 3.00) (alpha-lipoic acid). RR
ratio for these treatments was not statistically different
(3.39; [0.88, 3.34]). Fluoxetine had the lowest risk of adverse
events (0.94; [0.62, 1.23]); oxycodone had the highest
(1.55; [1.45, 1.64]). Discontinuation RRs were clustered
around 0.8 to 1.5, with those on the extreme having greater
uncertainty.
Conclusions: Selecting an appropriate pDPN therapy is key
given the large number of available treatments. Comparative
results revealed relative equivalence among many of the
studied interventions having the largest overall sample sizes
and highlight the importance of standardization of methods
to effectively assess pain. &
Key Words: peripheral neuropathy, diabetes, diabetic
peripheral neuropathy, meta-analysis, systematic review,
neuropathic pain
BACKGROUND
Neuropathic pain (NeP), dened as pain caused by
a lesion or disease of the somatosensory nervous
system,
1
is characterized by delayed onset of pain after
Address correspondence and reprint requests to: Sonya J. Snedecor,
PhD, Pharmerit International, 4350 East-West Highway, Suite 430,
Bethesda, MD 20814, U.S.A. E-mail: ssnedecor@pharmerit.com.
Submitted: December 17, 2012; Revision accepted: February 08, 2013
DOI. 10.1111/papr.12054
2013 The Authors
Pain Practice 2013 World Institute of Pain, 1530-7085/13/$15.00
Pain Practice, Volume 14, Issue 2, 2014 167184
nervous system lesion, pain in area of sensory loss,
spontaneous pain (ongoing, paroxysms), and evoked
types of pain (hyperalgesia, allodynia).
2,3
NeP is most
commonly associated with diabetic neuropathy, pos-
therpetic neuralgia (PHN), or polyneuropathy and
occurs in about 6 to 7% of the general population and
in 15 to 20% of people with diabetes.
4
Diabetic neuropathies are a family of nerve disorders
affecting different parts of the nervous system and
presenting as various clinical manifestations. They can
be classied as peripheral, autonomic, proximal, and
focal.
5,6
The most common forms of these are diabetic
peripheral neuropathy (diabetic peripheral neuropathy
[DPN] or chronic sensorimotor distal symmetric poly-
neuropathy) and autonomic neuropathies.
5
Symptoms
depend on the type of neuropathy and affected nerves
where numbness, tingling, or pain in the feet is typical at
onset.
6
Those with painful diabetic peripheral neurop-
athy (pDPN) suffer from substantial patient level
burden, impaired quality of life, and decreased work
productivity.
7,8
Painful diabetic peripheral neuropathy management
consists of excluding other causes of painful peripheral
neuropathy, maximizing diabetic control and using
medications to alleviate pain.
9
Pharmacological treat-
ment for diabetic NeP includes treatment with tricyclic
antidepressants (TCAs), other types of antidepressants,
anticonvulsants, and opioids and opioid-like drugs.
Treatment guidelines for pDPN have been developed
by the American Academy of Neurology, the American
Association of Neuromuscular and Electrodiagnostic
Medicine, and the American Academy of Physical
Medicine and Rehabilitation:
10

Pregabalin is established as effective and should be

offered for relief of pDPN (Level A).

Venlafaxine, duloxetine, amitriptyline, gabapen-

tin, valproate, opioids (morphine sulfate, tram-
adol, and oxycodone controlled release), and
capsaicin are probably effective and should be
considered for treatment of pDPN (Level B).
The European Federation of Neurological Societies
recommends TCAs (including amitriptyline, desipramine,
and imipramine), gabapentin, pregabalin, and serotonin
norepinephrine reuptake inhibitors (including duloxetine
and venlafaxine) as rst-line treatment in peripheral
polyneuropathy related to diabetes. Tramadol or opioids
are recommended as second- or third-line treatment.
11
Selecting an appropriate pDPN therapy remains
challenging due to important differences in effectiveness
and harms associated with a large number of available
therapeutic options. This study aimed to assess the
totality of available treatments for pDPN by conducting
a comprehensive systematic review and meta-analytic
comparison of all available randomized, controlled
clinical trials evaluating available pharmacologic ther-
apies for the treatment of pDPN with the goal of
comparing efcacy (pain reduction) and harms (dis-
continuations and adverse events [AEs]).
METHODS
Databases Searched and Search Terms
This study presents the relative efcacies of the various
treatment options for pDPN conducted as part of a
larger comprehensive systematic review of randomized
clinical trials (RCTs) of over 35 treatments in 8 drug
classes for 7 NeP conditions (DPN, PHN, HIV-associ-
ated neuropathy, post-traumatic NeP, small ber NeP,
SCI, central poststroke pain, and multiple sclerosis
related pain). DPN was reported separately as it was
associated with the majority of available data.
A systematic search was performed using PubMed/
MEDLINE, Cochrane Database of Systematic Reviews,
Cochrane Central Register of Controlled Trials,
EMBASE, and Database of Abstracts of Reviews of
Effects (up to June 2011). The search strategy consisted
of 4 categories: (1) neuralgia or NeP; (2) NeP conditions;
(3) pharmacological treatments or classes of interest
(generic or brand names); and (4) terms for randomized
and blinded study designs. See Box 1 for full search
terms.
Box 1: Search Terms
Category 1: Neuropathic pain

neuralgia[MESH] OR neuropathic pain

[MESH]
Category 2: Neuropathic pain conditions

postherpetic OR HIV[MESH] OR HIV

OR central post stroke OR spinal cord
injury[MESH] OR spinal cord injury OR
diabetes[MESH] OR diabetes OR multi-
ple sclerosis[MeSH Terms] OR multi-
ple[All Fields] AND sclerosis[All
Fields] OR multiple sclerosis[All Fields]
168 SNEDECOR ET AL.
OR small ber[All Fields] OR central
neuropathic pain [All elds]
Category 3: Pharmacologic treatments and classes
of interest

citalopram OR cipramil OR celexa

OR uoxetine OR Prozac OR sara-
fem OR paxil OR aropax OR sertr-
aline OR zoloft OR lustral OR
escitalopram OR lexapro OR cipral-
ex OR (lidocain AND (transderm* OR
patch* OR skin OR cutaneous*)) OR ami-
triptyline OR elavil OR desipramine
OR norpramin OR nortriptyline OR
pamelor OR imipramine OR tofra-
nil OR doxepin OR sinequan OR
silenor OR gabapentin OR neurotin
OR pregabalin OR lyrica OR carba-
mazepine OR tegretol OR carbatrol
OR epitol OR topiramate OR topa-
max OR oxcarbazepine OR trileptal
OR lamotrigine OR lamictal OR
valproic acid OR depakote OR dep-
acon OR divalproex OR epival OR
bupropion OR trazodone OR capsa-
icin OR methodone OR morphine
ORoxycodone ORtramadol ORdro-
nabinol OR lacosamide OR vimpat
OR phenytoin OR Dilantin OR lev-
etiracetam OR keppra OR desvenla-
faxine OR pristiq OR milnacipran
OR savella OR protriptyline OR vi-
vactil OR duloxetine OR Cymbalta
OR venlafaxine OR Effexor

anticonvulsant[MESH] OR tricyclic antide-

pressant[MESH] OR lidoderm OR lyrica
OR cannabinoids[MESH] OR opioids
[MESH] OR serotonin reuptake inhibitor
[MESH] OR analgesic[MESH] OR topical
agent
Category 4: Trial specications

(randomized, controlled trial[MESH]) OR

(random allocation[MESH]) OR (singl* OR
doubl* OR trebl* OR tripl*) AND (blind*
OR mask*)
Study Selection and Quality Assessment
Two reviewers independently assessed titles and
abstracts of citations identied from literature searches
for potential inclusion in the meta-analyses. Inconsis-
tencies were resolved by consensus. Manual searching of
references included in published systematic reviews and
meta-analyses was also conducted to identify additional
studies. Further, full-text publications of citations iden-
tied upon initial review were retrieved and assessed for
inclusion. Results published only in abstract form were
not considered because results of studies could change
substantially between initial presentation at a confer-
ence and nal journal publication. Articles were not
restricted by publication year, but were restricted to
English. The Preferred Reporting Items for Systematic
Reviews and Meta-Analyses guidelines were followed
through all phases of this study.
12
Inclusion criteria consisted of randomized, controlled
trials in pDPN in adults aged 18 years. Studies
< 4 weeks in duration were excluded, as well as broad
pain studies, where pDPN patients were not distin-
guished in subgroup analyses. Studies of therapies,
combined with nondrug modalities like physical ther-
apy, administered intramuscularly or intravenously, no
longer used to treat NeP, over-the-counter agents, and
food supplements were also excluded.
Data Extraction
Study design, eligibility and exclusion criteria, treatment
comparators, dosage and duration, patient demograph-
ics (gender, age, and ethnicity), efcacy, and harms data
were extracted from each trial into a structured Micro-
soft Access database by 3 independent reviewers. For
crossover trials, nearly all studies reported results from
both crossover periods as if they were collected from
parallel trials. Discontinuations from 2 studies were
calculated manually, using withdrawal data reported for
each crossover period. The JADAD scale for reporting
randomized, controlled trials was used to assess the
quality of each study, based on a range of 0 (worst) to 5
(best). Studies were scored according to the presence of
3 key methodological features of randomization, blind-
ing, and accountability of all patients, including with-
drawals, which have been empirically shown to
correlate with bias.
13
The JADAD scale has been used
previously for assessment of quality of controlled trials
in pain.
14,15
Therapies for painful diabetic peripheral neuropathy 169
Outcomes of interest
Common outcomes measured and reported across
eligible studies were identied during initial review of
full-text publications. The primary assessments of
treatment efcacy, available from most studies, were
11-point numeric rating scale (NRS) and visual ana-
logue scale (VAS) measurements of average daily pain
or 24-hour pain severity. The proportions of patients
achieving pain reductions of 30 or 50% in either
the NRS or the VAS, considered of clinical relevance
and recommended by Initiative on Methods, Measure-
ment, and Pain Assessment in Clinical Trials for
assessment in chronic pain clinical trials,
16
were also
included as an assessment of efcacy. Total discontin-
uations and AEs were analyzed as harms outcomes, and
EQ-5D data were analyzed to assess differences in
health status.
Quantitative Data Analysis
Mean differences from study baseline to end point for
each treatment arm were computed for the continuous
pain reduction outcomes measures and EQ-5D utility.
Studies reporting pain outcomes on a 10-cm VAS were
considered as an 11-point NRS to allowfor comparisons
across studies. Studies reporting pain outcomes on a
smaller or larger numeric scale were adjusted to 11
points for inclusion into the analysis.
This study involved multiple treatments and different
combinations of comparisons within RCTs, and net-
work meta-analysis or mixed treatment comparison
(MTC) allowed us to combine these trials, incorporating
direct and indirect comparative evidence within a single
analysis. Mixed treatment comparison methodology
was used to determine overall relative efcacy and
harms for all therapies relative to placebo
17
and
conducted using WinBUGS
18
software.
Outcomes were the mean reduction (or gain) in pain
on NRS or VAS and EQ-5D utility from baseline to end
point over that of placebo, relative risks (RRs) of
achieving 30 and 50% pain reduction, and RRs of
discontinuation or AE compared with placebo. Model
uncertainty was expressed by credible intervals (CrI),
where the 2.5th to 97.5th percentiles were directly
interpreted as the 95% probability that the estimated
outcome falls within this range. Fixed-effect meta-
analyses were performed for all outcomes because many
treatments were associated with only one study, and
random-effect analyses require 2 data points per treat-
ment. Statistical homogeneity was assessed using the Q
statistic
19
when at least 3 data points comparing an
active intervention to placebo were available from at
least 2 different studies.
For treatments with multiple doses, a qualitative
assessment of the impact of dose on treatment outcome
was performed. Twenty-two studies compared multiple
dosages or dosing schedules of lanepitant, lamotrigine,
2,641 records identified
through electronic searches
64 additional articles
identified through systematic
reviews
1636 articles excluded at
abstract level
262 full text articles
assessed for eligibility
131 full-text articles excluded with reason
25 unpublished articles
50 treatment period less than 4 weeks
36 incompatible study design (not
randomized, not placebo-controlled)
9 excluded drugs or route of
administration
8 condition not of interest
8 outcomes of interest not reported
11 excluded for other reasons (subset of
article extracted, results not reported by
condition, non-drug comparator or
combination treatment )
131 articles across all neuropathic
pain conditions met eligibility criteria
1898 records were screened
after duplicates were
removed
71 articles in PDN population
I
d
e
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i
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58 articles included
in analysis
13 articles excluded
1 non-randomization subpopulation; 7 relevant
outcomes could not be extracted; 1 mixed pain
conditions; 1 no reference to painful DPN; 1 no
number of patients in each treatment arm; 1
reporting only median data
Figure 1. Literature search results.
170 SNEDECOR ET AL.
duloxetine, oxcarbazepine, pregabalin, sodium valpro-
ate, venlafaxine, lacosamide, ABT-594, alpha-lipoic
acid, and topiramate. Of all medications examined,
only interventions duloxetine, pregabalin, and venla-
faxine had dose-dependent effects. Differential treat-
ment effects were observed for 20 vs. 40 mg/days
(duloxetine) and 150 vs. 300 mg/d (pregabalin).
Estimates from studies not reporting specic doses were
included into the duloxetine 20 mg/day and pregab-
alin 300 mg/day groups. Thus, the MTC analyses
considered observations for all doses of duloxetine and
pregabalin and all other therapies to be independent
observations of the same treatment. Venlafaxine, which
was associated with fewer available studies, was also
found to have differential efcacy for low- and high-
dose administrations, which we examine in sensitivity
analysis.
Model Validation
To compare consistency of the modeled outcomes with
the observed data, the estimated placebo-adjusted
treatment effects were compared with the available
direct evidence. Model results were said to be consis-
tent if the difference between the indirect, placebo-
adjusted estimates for 2 treatments was equivalent to the
observed direct head-to-head data. That is, the treat-
ment effect of treatment A relative to treatment B
directly compared in an RCT should be equal to the
difference between the A vs. placebo and the B vs.
placebo estimates generated from the MTC analysis.
Consistency validation was performed for each efcacy
outcome when direct head-to-head clinical trial data
were available.
The xed-effect model methodology selected due to
limited data for some treatments cannot adjust for
within-trial correlations among treatments of multiarm
trials. Therefore, we compared the results of a random-
effect model adjusting for multiple-arm trials including
only the interventions duloxetine, lacosamide, lamotri-
gine, and pregabalin for which there were more avail-
able data to the base-case xed-effect model results.
RESULTS
Literature Search
Figure 1 presents the results of the literature search,
screening and review for studies eligible for inclusion in
the meta-analysis. The search yielded 1,898 articles. Of
these, 262 full-text publications were reviewed for
eligibility: 131 articles were included in the broad
systematic review, and 131 full-text articles were
excluded based on the study exclusion criteria.
Seventy-one RCTs published between 1969 and 2011
in pDPN were identied. The average JADAD score for
the 71 trials was 3.74. Fifty-seven of the 71 studies
included patients who had peripheral/distal neuropathy,
among which 25 reported on patients having polyneur-
opathy. Duration of therapy ranged from 4 weeks to
1 year. Most of the trials were conducted in the United
States (48%) or Europe (17%).
duloxene 20mg
Placebo
topiramate
capsaicin
oxcarbazepine
pregabalin 300mg
gabapenn
clonidine
venlafaxine
lacosamide
sodium valproate
lamotrigine
oxycodone
imipramine
lidocaine 5% plaster
amitriptyline
gabapenn
+ placebo
gabapenn +
oxycodone
pregabalin 150mg
zonisamide
duloxene 40mg
alpha-lipoic acid
lanepitant
desipramine
ABT-594
savex
tramadol
tapentadol
pentoxifylline
mexilene
lamotrigine
uoxene
Figure 2. Network diagram of all studies included in a meta-analysis of at least one efcacy or harms outcome.
Therapies for painful diabetic peripheral neuropathy 171
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g

2
9
3
4
/
8
7
O
x
c
a
r
b
a
z
e
p
i
n
e
1
,
8
0
0
m
g

2
6
.
5
4
8
/
8
8
B
i
e
s
b
r
o
e
c
k
e
t
a
l
.
5
8
A
m
i
t
r
i
p
t
y
l
i
n
e
2
3
5
P
a
r
a
l
l
e
l
,
8
w
e
e
k
s

2
9
.
1
(
3
1
.
1
7
)
6
0
.
0
5
6
.
2
%
C
a
p
s
a
i
c
i
n
(
t
o
p
i
c
a
l
0
.
0
7
5
%
)

2
6
.
1
(
2
9
.
5
7
)
C
a
p
s
a
i
c
i
n
s
t
u
d
y
g
r
o
u
p
5
9
P
l
a
c
e
b
o
2
7
7
P
a
r
a
l
l
e
l
,
8
w
e
e
k
s

2
1
.
1
2
0
/
1
3
9
6
0
.
0
5
0
.
2
%
C
a
p
s
a
i
c
i
n
(
t
o
p
i
c
a
l
0
.
0
7
5
%
)

3
0
.
5
3
8
/
1
3
8
C
h
a
d
e
t
a
l
.
6
0
P
l
a
c
e
b
o
4
6
P
a
r
a
l
l
e
l
,
4
w
e
e
k
s
7
/
2
2
C
a
p
s
a
i
c
i
n
(
t
o
p
i
c
a
l
0
.
0
7
5
%
)
5
/
2
4
C
o
h
e
n
e
t
a
l
.
6
1
P
l
a
c
e
b
o
4
0
P
a
r
a
l
l
e
l
,
6
m
o
n
t
h
s

2
.
6
5
9
.
5
P
e
n
t
o
x
i
f
y
l
l
i
n
e
4
0
0
m
g
T
I
D

2
.
5
5
D
a
l
l
o
c
c
h
i
o
e
t
a
l
.
6
2
A
m
i
t
r
i
p
t
y
l
i
n
e
2
5
P
a
r
a
l
l
e
l
,
1
2
w
e
e
k
s

3
.
2
5
(
1
.
5
)
0
/
1
2
1
1
/
1
2
7
1
.
0
4
0
.
0
%
G
a
b
a
p
e
n
t
i
n

4
.
7
5
(
2
.
0
)
0
/
1
3
4
/
1
3
D
e
j
g
a
r
d
e
t
a
l
.
6
3
P
l
a
c
e
b
o
1
9
C
r
o
s
s
o
v
e
r
,
1
0
w
e
e
k
s
3
2
/
1
9
5
0
.
0
6
2
.
5
%
M
e
x
i
l
e
t
i
n
e

1
6
1
/
1
9
D
o
g
r
a
e
t
a
l
.
6
4
P
l
a
c
e
b
o
1
4
6
P
a
r
a
l
l
e
l
,
1
6
w
e
e
k
s

1
4
.
7
(
2
6
.
4
)
2
2
/
7
7
1
4
/
7
7
1
5
/
7
7
6
0
.
1
5
8
.
2
%
O
x
c
a
r
b
a
z
e
p
i
n
e

2
4
.
3
(
2
7
.
2
)
3
1
/
6
9
2
4
/
6
9
2
5
/
6
9
E
i
s
e
n
b
e
r
g
e
t
a
l
.
6
5
P
l
a
c
e
b
o
5
9
P
a
r
a
l
l
e
l
,
8
w
e
e
k
s

1
.
2
5
/
2
2
8
/
3
0
5
5
.
2
6
2
.
3
%
L
a
m
o
t
r
i
g
i
n
e

2
.
2
1
2
/
2
4
5
/
2
9
F
r
e
e
m
a
n
e
t
a
l
.
6
6
P
l
a
c
e
b
o
3
1
3
P
a
r
a
l
l
e
l
,
6
6
d
a
y
s

1
.
8
3

1
7
.
2
5
7
/
1
5
2
3
3
/
1
5
2
4
4
/
1
5
3
9
0
/
1
5
3
5
5
.
7
5
9
.
0
%
T
r
a
m
a
d
o
l
/
A
P
A
P

2
.
7
1

3
0
.
6
9
0
/
1
6
0
6
0
/
1
6
0
3
1
/
1
6
0
9
6
/
1
6
0
G
a
o
e
t
a
l
.
6
7
P
l
a
c
e
b
o
2
1
5
P
a
r
a
l
l
e
l
,
1
2
w
e
e
k
s

2
.
3
1
(
1
.
8
8
)
6
7
/
1
0
9
5
5
/
1
0
9
1
7
/
1
0
9
7
8
/
1
0
9
5
9
.
3
4
7
.
0
%
D
u
l
o
x
e
t
i
n
e

2
.
6
9
(
1
.
9
6
)
7
4
/
1
0
6
5
7
/
1
0
6
1
9
/
1
0
6
8
6
/
1
0
6
G
o
l
d
s
t
e
i
n
e
t
a
l
.
b
6
8
P
l
a
c
e
b
o
9
3
P
a
r
a
l
l
e
l
,
8
w
e
e
k
s

2
.
0
8
2
/
2
6
6
1
.
0
6
3
.
4
%
L
a
n
e
p
i
t
a
n
t
5
0
m
g

1
.
9
3
8
/
2
7
L
a
n
e
p
i
t
a
n
t
1
0
0
m
g

2
.
1
1
6
/
2
7
L
a
n
e
p
i
t
a
n
t
2
0
0
m
g

0
.
5
8
4
/
1
3
172 SNEDECOR ET AL.
T
a
b
l
e
1
.
(
C
o
n
t
i
n
u
e
d
)
S
t
u
d
y
D
r
u
g
,
D
o
s
e
T
o
t
a
l
N
S
t
u
d
y
T
y
p
e
a
n
d
T
r
e
a
t
m
e
n
t
D
u
r
a
t
i
o
n
N
R
S
M
e
a
n
d
i
f
f
(
S
D
)
V
A
S
M
e
a
n
d
i
f
f
(
S
D
)
3
0
%
R
e
d
u
c
t
i
o
n
5
0
%
R
e
d
u
c
t
i
o
n
D
i
s
c
o
n
t
i
n
u
a
t
i
o
n
s
A
d
v
e
r
s
e
E
v
e
n
t
s
M
e
a
n
A
g
e
(
i
n
y
e
a
r
s
)
%
M
a
l
e
G
o
l
d
s
t
e
i
n
e
t
a
l
.
6
9
P
l
a
c
e
b
o
4
5
7
P
a
r
a
l
l
e
l
,
1
2
w
e
e
k
s

1
.
9
1
(
2
.
0
6
)
2
9
/
1
1
2
2
8
/
1
1
5
6
0
.
1
6
1
.
5
%
D
u
l
o
x
e
t
i
n
e
2
0
m
g
Q
D

2
.
3
6
(
2
.
0
0
)
4
6
/
1
1
2
2
4
/
1
1
5
D
u
l
o
x
e
t
i
n
e
6
0
m
g
Q
D

2
.
8
9
(
2
.
0
6
)
5
5
/
1
1
2
2
8
/
1
1
4
D
u
l
o
x
e
t
i
n
e
6
0
m
g
B
I
D

3
.
2
4
(
2
.
0
6
)
5
7
/
1
1
0
3
3
/
1
1
3
G
o
m
e
z
-
P
e
r
e
z
e
t
a
l
.
c
7
0
G
a
b
a
p
e
n
t
i
n
9
0
0
m
g
3
3
9
P
a
r
a
l
l
e
l
,
7
w
e
e
k
s
1
.
8
3
8
.
7
8
1
/
1
7
0
8
2
/
1
7
0
5
6
.
0
4
1
.
9
%
G
a
b
a
p
e
n
t
i
n
9
0
0
t
o
3
,
6
0
0
m
g
2
.
7
5
0
.
8
1
0
9
/
1
6
9
8
5
/
1
6
9
G
o
r
s
o
n
e
t
a
l
.
d
3
1
P
l
a
c
e
b
o
2
1
P
a
r
a
l
l
e
l
,
6
w
e
e
k
s

1
.
4
(
0
.
3
)
6
2
.
0
7
7
.
5
%
G
a
b
a
p
e
n
t
i
n

1
.
8
(
0
.
5
)
G
r
o
s
s
k
o
p
f
e
t
a
l
.
7
1
P
l
a
c
e
b
o
1
4
1
P
a
r
a
l
l
e
l
,
1
6
w
e
e
k
s

2
1
.
9
8
1
7
/
7
0
6
1
.
1
5
5
.
3
%
O
x
c
a
r
b
a
z
e
p
i
n
e
1
,
2
0
0
m
g

2
0
.
0
8
2
9
/
7
1
H
a
n
n
a
e
t
a
l
.
e
3
2
P
l
a
c
e
b
o
+
g
a
b
a
p
e
n
t
i
n
3
3
8
P
a
r
a
l
l
e
l
,
1
2
w
e
e
k
s
5
3
7
/
1
6
9
1
1
9
/
1
6
7
6
0
.
2
6
4
.
0
%
O
x
y
c
o
d
o
n
e
P
R
+
g
a
b
a
p
e
n
t
i
n
4
.
3
4
2
/
1
6
9
1
4
7
/
1
6
8
H
a
r
a
t
i
e
t
a
l
.
7
2
P
l
a
c
e
b
o
1
3
1
P
a
r
a
l
l
e
l
,
6
w
e
e
k
s

1
2
7
/
6
6
5
9
.
0
5
9
.
5
%
T
r
a
m
a
d
o
l

2
.
7
5
2
2
/
6
5
J
e
n
s
e
n
e
t
a
l
.
3
4

G
i
m
b
e
l
e
t
a
l
.
3
5
P
l
a
c
e
b
o
1
5
9
P
a
r
a
l
l
e
l
,
6
w
e
e
k
s

2
2
0
/
7
7
2
5
/
7
7
5
2
/
7
7
5
8
.
9
5
2
.
2
%
O
x
y
c
o
d
o
n
e
C
R

3
.
2
3
7
/
8
2
1
9
/
8
2
8
0
/
8
2
J
i
a
n
g
e
t
a
l
.
7
3
P
l
a
c
e
b
o
4
0
P
a
r
a
l
l
e
l
,
4
w
e
e
k
s

0
.
6
4
(
2
.
7
9
)

2
1
.
2
9
(
3
5
.
6
2
)
6
/
2
0
5
7
.
4
6
2
.
5
%
P
r
e
g
a
b
a
l
i
n

2
.
8
7
(
3
.
0
4
)

4
3
.
2
7
(
3
2
.
0
3
)
5
/
2
0
J
o
s
e
e
t
a
l
.
a
7
4
A
m
i
t
r
i
p
t
y
l
i
n
e
5
3
C
r
o
s
s
o
v
e
r
,
6
w
e
e
k
s

2
.
5
(
M
e
d
i
a
n
)

1
7
.
5
(
M
e
d
i
a
n
)
1
3
/
4
6
4
9
/
5
3
5
6
.
0
3
4
.
8
%
L
a
m
o
t
r
i
g
i
n
e

2
.
5
(
M
e
d
i
a
n
)

2
2
.
5
(
M
e
d
i
a
n
)
1
9
/
4
6
4
1
/
4
6
K
a
d
i
r
o
g
l
u
e
t
a
l
.
7
5
P
l
a
c
e
b
o
6
0
P
a
r
a
l
l
e
l
,
8
w
e
e
k
s

1
.
9
5
/
3
0
5
3
.
2
2
1
.
7
%
V
e
n
l
a
f
a
x
i
n
e

4
.
1
1
1
/
3
0
K
o
c
h
a
r
e
t
a
l
.
7
6
P
l
a
c
e
b
o
5
7
P
a
r
a
l
l
e
l
,
1
m
o
n
t
h
4
/
2
8
5
6
.
3
S
o
d
i
u
m
v
a
l
p
r
o
a
t
e
4
0
0
m
g
T
I
D
1
/
2
9
K
o
c
h
a
r
e
t
a
l
.
7
7
P
l
a
c
e
b
o
4
3
P
a
r
a
l
l
e
l
,
3
m
o
n
t
h
s
0
.
2
9
3
/
2
1
5
5
.
2
5
3
.
8
%
S
o
d
i
u
m
v
a
l
p
r
o
a
t
e
5
0
0
m
g
Q
D

3
1
/
2
2
K
v
i
n
e
s
d
a
l
e
t
a
l
.
7
8
P
l
a
c
e
b
o
1
5
C
r
o
s
s
o
v
e
r
,
5
w
e
e
k
s
0
/
1
5
5
4
.
2
I
m
i
p
r
a
m
i
n
e
3
/
1
5
L
e
s
s
e
r
e
t
a
l
.
4
4
P
l
a
c
e
b
o
3
3
7
P
a
r
a
l
l
e
l
,
5
w
e
e
k
s

1
.
5
4
3
2
/
9
7
1
7
/
9
7
8
/
9
7
5
9
.
9
5
9
.
9
%
P
r
e
g
a
b
a
l
i
n
7
5
m
g

1
.
7
9
1
0
/
7
7
P
r
e
g
a
b
a
l
i
n
3
0
0
m
g

2
.
4
5
0
/
8
1
3
7
/
8
1
5
/
8
1
P
r
e
g
a
b
a
l
i
n
6
0
0
m
g

2
.
6
5
3
/
8
1
3
9
/
8
1
1
2
/
8
2
M
a
x
e
t
a
l
.
7
9
P
l
a
c
e
b
o
3
7
C
r
o
s
s
o
v
e
r
,
6
w
e
e
k
s
2
5
/
2
9
5
7
.
0
A
m
i
t
r
i
p
t
y
l
i
n
e
2
8
/
2
9
M
a
x
e
t
a
l
.
8
0
P
l
a
c
e
b
o
2
4
C
r
o
s
s
o
v
e
r
,
6
w
e
e
k
s
1
7
/
2
0
6
2
.
0
D
e
s
i
p
r
a
m
i
n
e
1
8
/
2
0
M
a
x
e
t
a
l
.
8
1
P
l
a
c
e
b
o
5
4
C
r
o
s
s
o
v
e
r
,
6
w
e
e
k
s
3
1
/
4
6
5
8
.
0
A
m
i
t
r
i
p
t
y
l
i
n
e
3
1
/
3
8
D
e
s
i
p
r
a
m
i
n
e
2
9
/
3
8
F
l
u
o
x
e
t
i
n
e
2
9
/
4
6
M
o
r
e
l
l
o
e
t
a
l
.
8
2
A
m
i
t
r
i
p
t
y
l
i
n
e
2
5
C
r
o
s
s
o
v
e
r
,
6
w
e
e
k
s
4
/
2
4
1
7
/
2
4
6
0
.
4
G
a
b
a
p
e
n
t
i
n
3
/
2
3
1
8
/
2
3
Therapies for painful diabetic peripheral neuropathy 173
T
a
b
l
e
1
.
(
C
o
n
t
i
n
u
e
d
)
S
t
u
d
y
D
r
u
g
,
D
o
s
e
T
o
t
a
l
N
S
t
u
d
y
T
y
p
e
a
n
d
T
r
e
a
t
m
e
n
t
D
u
r
a
t
i
o
n
N
R
S
M
e
a
n
d
i
f
f
(
S
D
)
V
A
S
M
e
a
n
d
i
f
f
(
S
D
)
3
0
%
R
e
d
u
c
t
i
o
n
5
0
%
R
e
d
u
c
t
i
o
n
D
i
s
c
o
n
t
i
n
u
a
t
i
o
n
s
A
d
v
e
r
s
e
E
v
e
n
t
s
M
e
a
n
A
g
e
(
i
n
y
e
a
r
s
)
%
M
a
l
e
R
a
s
k
i
n
e
t
a
l
.
3
7
P
l
a
c
e
b
o
3
2
3
P
a
r
a
l
l
e
l
,
1
2
w
e
e
k
s

1
5
.
1
3
7
/
1
0
9
2
3
/
1
0
9
2
9
/
1
0
9
7
7
/
1
0
9
5
9
.
2
4
9
.
5
%
T
o
p
i
r
a
m
a
t
e

2
1
.
8
1
0
3
/
2
0
8
7
4
/
2
0
8
1
0
2
/
2
1
4
1
7
0
/
2
1
1
R
a
s
k
i
n
e
t
a
l
.
4
3
P
l
a
c
e
b
o
3
4
8
P
a
r
a
l
l
e
l
,
1
2
w
e
e
k
s

1
.
6
(
1
.
9
1
)
4
9
/
1
1
3
3
4
/
1
1
3
1
6
/
1
1
6
5
7
/
1
1
6
5
8
.
8
4
6
.
5
%
D
u
l
o
x
e
t
i
n
e
6
0
m
g
Q
D

2
.
5
(
1
.
9
1
)
7
7
/
1
1
4
5
7
/
1
1
3
1
5
/
1
1
6
7
1
/
1
1
6
D
u
l
o
x
e
t
i
n
e
6
0
m
g
B
I
D

2
.
4
7
(
1
.
9
2
)
7
3
/
1
1
3
4
4
/
1
1
4
2
1
/
1
1
6
7
3
/
1
1
6
R
a
s
k
i
n
e
t
a
l
.
c
8
3
D
u
l
o
x
e
t
i
n
e
6
0
m
g
B
I
D
4
4
9
P
a
r
a
l
l
e
l
,
2
7
w
e
e
k
s

2
.
7
1
2
1
/
3
3
4
3
2
1
/
3
3
4
5
9
.
9
5
2
.
1
%
D
u
l
o
x
e
t
i
n
e
1
2
0
m
g
Q
D

2
.
7
4
3
/
1
1
5
1
0
6
/
1
1
5
R
a
u
c
k
e
t
a
l
.
8
4
P
l
a
c
e
b
o
1
1
9
P
a
r
a
l
l
e
l
,
1
0
w
e
e
k
s

2
.
2
1

2
6
1
1
/
5
9
4
4
/
5
9
5
5
.
0
4
7
.
0
%
L
a
c
o
s
a
m
i
d
e
4
0
0
m
g

3
.
1
1

3
6
.
1
1
4
/
6
0
5
2
/
6
0
R
i
c
h
t
e
r
e
t
a
l
.
4
6
P
l
a
c
e
b
o
2
4
6
P
a
r
a
l
l
e
l
,
6
w
e
e
k
s

1
.
1
1
3
/
8
5
1
3
/
8
5
5
7
.
1
6
0
.
6
%
P
r
e
g
a
b
a
l
i
n
1
5
0
m
g

1
.
6
1
5
/
7
9
4
/
7
9
P
r
e
g
a
b
a
l
i
n
6
0
0
m
g

2
.
4
3
2
/
8
2
1
0
/
8
2
R
o
s
e
n
s
t
o
c
k
e
t
a
l
.
4
5
P
l
a
c
e
b
o
1
4
6
P
a
r
a
l
l
e
l
,
8
w
e
e
k
s

0
.
8
1
0
/
7
0
8
/
7
0
2
0
/
7
0
5
9
.
7
5
6
.
1
%
P
r
e
g
a
b
a
l
i
n
3
0
0
m
g
/
d
a
y

2
.
5
3
0
/
7
6
1
1
/
7
6
4
7
/
7
6
R
o
w
b
o
t
h
a
m
e
t
a
l
.
8
5
P
l
a
c
e
b
o
2
4
5
P
a
r
a
l
l
e
l
,
6
w
e
e
k
s

1
8
.
7
2
7
/
8
1
1
2
/
8
1
5
9
.
0
5
9
.
4
%
V
e
n
l
a
f
a
x
i
n
e
X
R
7
5
m
g

2
2
.
4
3
2
/
8
1
1
8
/
8
1
V
e
n
l
a
f
a
x
i
n
e
X
R
1
5
0
t
o
2
2
5
m
g

3
3
.
8
4
6
/
8
2
R
o
w
b
o
t
h
a
m
e
t
a
l
.
8
6
P
l
a
c
e
b
o
2
6
6
P
a
r
a
l
l
e
l
,
7
w
e
e
k
s

1
.
1
(
2
.
2
8
)
8
/
6
5
1
4
/
6
5
4
3
/
6
5
6
1
.
9
5
4
.
5
%
A
B
T
-
5
9
4
1
5
0
l
g
B
I
D

1
.
9
(
2
.
2
4
)
1
8
/
6
5
2
5
/
6
5
5
4
/
6
5
A
B
T
-
5
9
4
2
2
5
l
g
B
I
D

1
.
9
(
2
.
2
8
)
1
7
/
6
7
3
9
/
6
9
6
2
/
6
9
A
B
T
-
5
9
4
3
0
0
l
g
B
I
D

2
(
2
.
1
8
)
5
0
/
6
7
6
1
/
6
7
S
a
t
o
h
e
t
a
l
.
8
7
P
l
a
c
e
b
o
3
1
4
P
a
r
a
l
l
e
l
,
1
3
w
e
e
k
s
3
0
/
1
3
5
4
9
/
1
3
5
6
1
.
4
7
5
.
5
%
P
r
e
g
a
b
a
l
i
n
3
0
0
m
g
3
9
/
1
3
4
7
6
/
1
3
4
P
r
e
g
a
b
a
l
i
n
6
0
0
m
g
1
6
/
4
5
3
6
/
4
5
S
c
h
e
f

e
r
e
t
a
l
.
8
8
P
l
a
c
e
b
o
5
4
P
a
r
a
l
l
e
l
,
8
w
e
e
k
s

1
2
(
3
5
.
2
)
2
/
2
6
6
0
.
6
3
5
.
2
%
C
a
p
s
a
i
c
i
n
(
t
o
p
i
c
a
l
0
.
0
7
5
%
)

3
7
.
7
(
3
4
.
2
)
9
/
2
8
S
c
h
w
a
r
t
z
e
t
a
l
.
8
9
P
l
a
c
e
b
o
3
8
9
P
a
r
a
l
l
e
l
,
1
2
w
e
e
k
s
1
.
4
8
1
/
1
9
2
5
3
/
1
9
2
6
2
/
1
9
3
1
0
0
/
1
9
3
6
0
.
2
6
0
.
4
%
T
a
p
e
n
t
a
d
o
l
E
R
0
1
0
5
/
1
9
6
7
4
/
1
9
6
6
3
/
1
9
6
1
3
9
/
1
9
6
S
e
l
v
a
r
a
j
a
h
e
t
a
l
.
9
0
P
l
a
c
e
b
o
3
0
P
a
r
a
l
l
e
l
,
1
2
w
e
e
k
s

3
.
1
9
/
1
4
5
6
.
4
6
2
.
1
%
S
a
t
i
v
e
x

2
.
5
8
/
1
5
S
h
a
i
b
a
n
i
e
t
a
l
.
9
1
P
l
a
c
e
b
o
4
6
8
P
a
r
a
l
l
e
l
,
1
8
w
e
e
k
s

1
.
6
7
3
0
/
6
6
1
8
/
6
6
2
1
/
6
5
5
5
/
6
5
5
9
.
8
5
6
.
5
%
L
a
c
o
s
a
m
i
d
e
2
0
0
m
g

2
.
0
1
7
6
/
1
4
1
3
8
/
1
4
1
4
6
/
1
4
1
1
1
3
/
1
4
1
L
a
c
o
s
a
m
i
d
e
4
0
0
m
g

2
.
2
9
7
3
/
1
2
5
5
5
/
1
2
5
5
4
/
1
2
5
9
9
/
1
2
5
L
a
c
o
s
a
m
i
d
e
6
0
0
m
g

2
.
2
3
7
9
/
1
3
7
4
1
/
1
3
7
9
1
/
1
3
7
1
1
9
/
1
3
7
S
i
m
p
s
o
n

p
a
r
t
1
o
f
s
t
u
d
y
4
1
P
l
a
c
e
b
o
6
0
P
a
r
a
l
l
e
l
,
8
w
e
e
k
s

0
.
5
3
/
3
0
5
0
.
0
6
0
.
0
%
G
a
b
a
p
e
n
t
i
n

2
.
4
3
/
3
0
T
h
i
e
n
e
l
e
t
a
l
.
3
6
P
l
a
c
e
b
o
1
,
2
5
9
P
a
r
a
l
l
e
l
,
1
8
t
o
2
2
w
e
e
k
s

1
5
.
9
1
5
6
/
3
8
1
5
8
.
3
5
7
.
8
%
T
o
p
i
r
a
m
a
t
e
1
0
0
m
g
1
1
6
/
2
5
0
T
o
p
i
r
a
m
a
t
e
2
0
0
m
g

2
0
.
2
1
9
7
/
3
6
9
T
o
p
i
r
a
m
a
t
e
4
0
0
m
g

1
8
.
5
1
5
1
/
2
5
9
T
o
l
l
e
e
t
a
l
.
4
7
P
l
a
c
e
b
o
3
9
5
P
a
r
a
l
l
e
l
,
1
2
w
e
e
k
s

1
.
9
2
8
/
9
3
1
7
/
9
6
5
8
.
6
5
5
.
4
%
P
r
e
g
a
b
a
l
i
n
1
5
0
m
g

2
.
1
3
3
/
9
6
1
7
/
9
9
P
r
e
g
a
b
a
l
i
n
3
0
0
m
g

2
.
1
3
2
/
9
6
2
0
/
9
9
P
r
e
g
a
b
a
l
i
n
6
0
0
m
g

3
4
5
/
9
8
2
3
/
1
0
1
174 SNEDECOR ET AL.
T
a
b
l
e
1
.
(
C
o
n
t
i
n
u
e
d
)
S
t
u
d
y
D
r
u
g
,
D
o
s
e
T
o
t
a
l
N
S
t
u
d
y
T
y
p
e
a
n
d
T
r
e
a
t
m
e
n
t
D
u
r
a
t
i
o
n
N
R
S
M
e
a
n
d
i
f
f
(
S
D
)
V
A
S
M
e
a
n
d
i
f
f
(
S
D
)
3
0
%
R
e
d
u
c
t
i
o
n
5
0
%
R
e
d
u
c
t
i
o
n
D
i
s
c
o
n
t
i
n
u
a
t
i
o
n
s
A
d
v
e
r
s
e
E
v
e
n
t
s
M
e
a
n
A
g
e
(
i
n
y
e
a
r
s
)
%
M
a
l
e
V
i
n
i
k
e
t
a
l
.

S
t
u
d
y
1
3
3
P
l
a
c
e
b
o
3
6
0
P
a
r
a
l
l
e
l
,
1
9
w
e
e
k
s

2
.
3
3
2
/
8
5
2
3
/
8
5
2
8
/
9
0
6
2
/
8
8
5
9
.
9
5
4
.
1
%
L
a
m
o
t
r
i
g
i
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.
Therapies for painful diabetic peripheral neuropathy 175
Of the 71 studies, 17 were crossover in design. Ten
head-to-head trials were identied, and one study
examined gabapentin + placebo vs. gabapentin + oxy-
codone. Studies included patients similar in age, ranging
from a mean of 50 to 71 years. Most studies required a
minimum pain duration from 3 to 6 months, stable
glycemic control, and minimum pain severity at entry
equivalent to 4 on an 11-point scale.
A B
C D
NRS pain reducon
-3.29
-2.20
-1.45
-1.40
-1.30
-1.13
-1.08
-1.08
-1.06
-0.96
-0.83
-0.53
-0.52
-0.41
-0.39
0.05
0.20
0.34
0.60
-4.5 -3.0 -1.5 0.0 1.5
Mean NRS reducon over placebo (95%CrI)
Sodium valporate (1)
Venlafaxine (1)
Oxycodone (2)
Tapentadol (1)
Gabapenn (3)
Tramadol (2)
Lidocaine 5% plaster (1)
Pregabalin 300mg (10)
Duloxene 40mg (8)
Zonisamide (1)
ABT-594 (3)
Lamotrigine (7)
Lacosamide (9)
Pregabalin 150mg (3)
Duloxene 20mg (2)
Pentoxifylline (1)
Amitriptyline (1)
Lanepitant (3)
Savex (1)
Favors Placebo Favors Treatment
VAS pain reducon
-21.88
-18.84
-15.53
-13.39
-13.38
-12.56
-10.72
-9.43
-6.92
-5.93
-3.09
-30.0 -20.0 -10.0 0.0
Mean VAS reducon over placebo (95% CrI)
Pregabalin 300mg (1)
Mexilene (1)
Amitriptyline (1)
Tramadol (1)
Gabapenn (1)
Capsaicin (topical 0.075%) (3)
Zonisamide (1)
Venlafaxine (2)
Lacosamide (3)
Oxcarbazepine (5)
Topiramate (8)
Favors Placebo Favors Treatment
50% pain reducon (solid)
30% pain reducon (open)
Zonisamide (1)
Alpha-Lipoic Acid (3)
Lidocaine 5% plaster (1/1)
Venlafaxine (1)
ABT-594 (2)
Oxcarbazepine (1/1)
Pregabalin 300mg (11/3)
Duloxene 40mg (8/6)
Tramadol (1/1)
Topiramate (1/1)
Venlafaxine XR (2)
Tapentadol ER (1/1)
Oxycodone (1)
Pregabalin 150mg (2)
Lacosamide (5/7)
Lamotrigine (8/6)
Savex (1)
Amitriptyline (2)
0.98
1.14
1.23
1.29
1.31
1.40
1.54
1.65
1.69
1.76
1.79
1.80
1.90
1.93
2.25
3.11
0.78
1.02
1.30
1.24
1.29
1.41
1.49
1.54
1.59
1.78
1.45
1.67
1.84
0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 4.50
RR (95%CrI)
Favors Placebo Favors Treatment
Oxycodone (1)
% disconnuaon (solid)
% AEs (open)
Imipramine (1)
Zonisamide (1/1)
Alpha-Lipoic Acid (3)
Lanepitant (3)
ABT-594 (3/3)
Oxcarbazepine (5)
Capsaicin (topical 0.075%) (3)
Lacosamide (9/7)
Topiramate (4/1)
Venlafaxine XR (1)
Amitriptyline (4/4)
Duloxene 40mg (10/6)
Lamotrigine (8/6)
Pregabalin 300mg (9/4)
Duloxene 20mg (2/1)
Tapentadol (1/1)
Desipramine (2)
Gabapenn (4/4)
Pregabalin 150mg (3)
Oxycodone (2/1)
Tramadol (2/1)
Fluoxene (1)
Clonidine transdermal patch(1)
Mexilene (1)
Sodium valproate (2)
3.96
3.44
2.70
2.52
2.48
1.79
1.64
1.50
1.49
1.45
1.37
1.26
1.17
1.12
1.01
1.01
0.94
0.90
0.77
0.71
0.70
0.69
0.33
1.21
1.38
1.06
1.18
1.28
1.23
1.14
1.32
1.18
1.26
1.17
1.02
1.55
1.02
0.94
0.0 1.0 2.0 3.0 4.0 5.0
RR (95%CrI)
Favors Placebo Favors Treatment
Figure 3. Meta-analysis results for (A) numeric rating scale outcomesmean reduction in pain; (B) visual analogue scale outcome
mean reduction; (C) proportion of responders achieving 30% reduction in pain; (D) proportion of responders achieving 50% reduction
in pain. Numbers in parentheses indicate the number of available data points for the specied drug and outcome. All outcomes are
shown compared with placebo with 95% credible intervals.
176 SNEDECOR ET AL.
Thirteen studies were excluded from the meta-anal-
ysis: 7 had no relevant outcomes for extraction,
2026
one
was a nonrandomized subgroup of an RCT,
27
one DPN
and one PHN patients were combined,
28
one had no
specic reference to painful DPN,
29
one reported only
median efcacy data,
30
one was missing number of
patients in each treatment arm,
31
and one had out-of-
network comparisons of combination treatments.
32
One
study
33
reported 2 distinct patient populations compar-
ing lamotrigine to placebo and was considered as 2
separate studies in the meta-analysis. Two studies
reporting the same trial population were combined.
34,35
Data from the 58 remaining studies comprised 29
interventions: 11,883 patients were included in the
meta-analysis (Figure 2). Table 1 displays all included
studies and study characteristics. Because not all studies
reported all outcomes, some treatments could not be
included in every outcome analysis. Heterogeneity in
efcacy was identied only for pregabalin 300 mg,
resulting in part from variation in study durations,
where longer durations were associated with lower
treatment efcacy. Heterogeneity in discontinuations
was observed among lacosamide, pregabalin
150 mg, topiramate, capsaicin, and oxcarbazepine.
Discontinuation data were identied from no more than
3 studies per intervention, precluding identication of
any study-specic trends suggesting the source of hetero-
geneity.
Modeled Efcacy Outcomes
Mixed treatment comparisons estimating the mean
reduction in pain over that of placebo on the 11-point
NRS showed sodium valproate as most effective (3.29;
95% CrI: [4.22, 2.36]) and Sativex as least (+0.61;
[0.47, 1.68]) (Figure 3A). The treatments with
the most available comparisons were pregabalin
( 300 mg/day) (n = 10 comparisons from 8 studies),
lacosamide (n = 9 from 4 studies), duloxetine
( 40 mg/day) (n = 8 from 4 studies), and lamotrigine
(n = 7 from 3 studies), which had net reductions of
1.12 (1.30, 0.94), 0.52 (0.31, 0.72), 1.06
(1.22, 0.89), and 0.53 (0.28, 0.77), respec-
tively.
Most estimates clustered within the middle of the
efcacy range between 0 and 1.5 reduction in mean
NRS score. These treatments also tended to be associ-
ated with a larger number of data points and had smaller
CrIs. Data for the treatments estimated to be least
(Sativex, lanepitant, amitriptyline, and pentoxifylline),
and most (venlafaxine and sodium valproate) effective
were extracted from studies enrolling fewer patients
(and thus had larger CrIs). For example, estimates of the
4 least effective treatments were derived from studies
ranging from 25 to 93 total patients, and the 2
treatments estimated to be most effective were derived
from studies of 43 and 60 patients. In contrast,
interventions such as duloxetine, pregabalin, lamotri-
gine, and lacosamide were highly studied, with com-
parisons derived from 16 studies with sample sizes
ranging from 119 to 468 patients across 2 to 4 treatment
arms per study.
Although treatments on the extreme ends of the
efcacy scale were associated with larger CrIs, an
examination of the difference between the best predicted
treatment (sodium valproate) and the worst predicted
treatment (Sativex) showed an expected difference in
reduction of NRS score of 4.9 (95% CrI: [5.3,
2.5]), indicating a signicant difference in efcacy
among the 2 extreme treatments in the modeled
outcome. Figure 4A displays additional evidence of
treatment differentiation including probabilities of each
treatment being the best, second best, and so on
compared with placebo.
Pregabalin ( 300 mg/day) was the most effective in
reducing pain reported on VAS (21.88, [27.06,
16.68]); topiramate (25 to 400 mg), which had the
most available data points (8 from 2 studies
36,37
), was
the least effective (3.09, [3.99, 2.18]) (Figure 3B).
Amitriptyline, gabapentin, zonisamide, and tramadol all
demonstrated similar efcacy in the NRS and VAS
analyses. Pregabalin 300 mg showed greater efcacy
in the VAS analysis than in the NRS. As the number of
available data points increased and uncertainty
decreased, the VAS efcacy estimates trended toward
0, where treatments demonstrated no additional efcacy
over that of placebo (Figure 3B). The probabilities of
each treatments rank on the VAS from best to worst are
presented Figure 4B.
The mean probabilities of 30% reduction in pain
were not statistically different than placebo for Sativex
(RR of pain reduction = 0.78, [0.19, 1.66]), lamotrigine
(1.02, [0.80, 1.25]), and duloxetine 20 mg/day
(1.24, [0.89, 1.60]) (Figure 3C). Compared with pla-
cebo, lidocaine had the highest probability of 30%
reduction (1.84, [1.39, 2.21]). Relative risks of 50%
pain reduction ranged from 0.98 (0.56, 1.52) (amitrip-
tyline) to 2.25 (1.51, 3.00) (alpha-lipoic acid 600 to
1,800 mg) (Figure 3C). Analysis of the relative efcacies
of the least and most effective treatments showed that
Therapies for painful diabetic peripheral neuropathy 177
the probability of achieving 30% reduction in pain with
lidocaine 5% plaster relative to Sativex was higher with
marginal signicance (RR 3.27, 95% CrI [1.07, 9.81]).
However, the probabilities of achieving 50% reduction
in pain were not statistically different for the best
(zonisamide) and worst treatments (amitriptyline) (3.39
[0.88, 3.34]), indicating that although differentiation
among treatments was demonstrated with the NRS and
VAS, these differences did not translate the dichotomous
responder outcomes.
Comparisons of the mean increase in EQ-5D utility
were available for 3 interventions from 2 active agents.
Duloxetine 40 mg (60 mg QD or 60 mg BID) had
the highest mean increase in health state utility (0.05,
A
B
0
.
0
0
.
4
0
.
8
Rank of sodium valproate
P
r
o
b
a
b
i
l
i
t
y
0
.
0
0
.
4
0
.
8
0
.
0
0
.
4
0
.
8
Rank of venlafaxine
0
.
0
0
.
4
0
.
8
Rank of oxycodone
0
.
0
0
.
4
0
.
8
Rank of tapentadol
0
.
0
0
.
4
0
.
8
Rank of gabapentin
P
r
o
b
a
b
i
l
i
t
y
0
.
0
0
.
4
0
.
8
0
.
0
0
.
4
0
.
8
Rank of tramadol
0
.
0
0
.
4
0
.
8
Rank of pregabalin >=300mg
0
.
0
0
.
4
0
.
8
Rank of lidocaine 5% plaster
0
.
0
0
.
4
0
.
8
Rank of duloxetine >=40mg
P
r
o
b
a
b
i
l
i
t
y
0
.
0
0
.
8
0
.
0
0
.
4
0
.
8
Rank of zonisamide
0
.
0
0
.
4
0
.
8
Rank of ABT-594
0
.
0
0
.
4
0
.
8
Rank of lamotrigine
0
.
0
0
.
4
0
.
8
Rank of lacosamide
P
r
o
b
a
b
i
l
i
t
y
0
.
0
0
.
4
0
.
8
0
.
0
0
.
4
0
.
8
Rank of pregabalin <=150mg
0
.
0
0
.
4
0
.
8
Rank of duloxetine <=20mg
0
.
0
0
.
4
0
.
8
Rank of pentoxifylline
0
.
0
0
.
4
0
.
8
Rank of amitriptyline
P
r
o
b
a
b
i
l
i
t
y
0
.
0
0
.
4
0
.
8
0
.
0
0
.
4
0
.
8
Rank of lanepitant
0
.
0
0
.
4
0
.
8
Rank of sativex
0
.
0
0
.
4
0
.
8
Rank of placebo
NRS
VAS
0
.
0
0
.
2
0
.
4
0
.
6
0
.
8
1
.
0
Rank of pregabalin >=300mg
P
r
o
b
a
b
i
l
i
t
y
0
.
0
0
.
4
0
.
8
0
.
0
0
.
2
0
.
4
0
.
6
0
.
8
1
.
0
Rank of mexiletine
0
.
0
0
.
2
0
.
4
0
.
6
0
.
8
1
.
0
Rank of amitriptyline
0
.
0
0
.
2
0
.
4
0
.
6
0
.
8
1
.
0
Rank of tramadol
0
.
0
0
.
2
0
.
4
0
.
6
0
.
8
1
.
0
Rank of gabapentin
P
r
o
b
a
b
i
l
i
t
y
0
.
0
0
.
2
0
.
4
0
.
6
0
.
8
1
.
0
0
.
0
0
.
2
0
.
4
0
.
6
0
.
8
1
.
0
Rank of capsaicin
0
.
0
0
.
2
0
.
4
0
.
6
0
.
8
1
.
0
Rank of zonisamide
0
.
0
0
.
2
0
.
4
0
.
6
0
.
8
1
.
0
Rank of venlafaxine
0
.
0
0
.
2
0
.
4
0
.
6
0
.
8
1
.
0
Rank of lacosamide
P
r
o
b
a
b
i
l
i
t
y
0
.
0
0
.
2
0
.
4
0
.
6
0
.
8
1
.
0
0
.
0
0
.
2
0
.
4
0
.
6
0
.
8
1
.
0
Rank of oxcarbazepine
0
.
0
0
.
2
0
.
4
0
.
6
0
.
8
1
.
0
Rank of topiramate
Figure 4. Rankings for (A) NRS and (B) VAS treatment efcacy. Each plot represents the probability of being best, 2nd best, 3rd best,
and so on among all of the interventions included in the respective outcomes.
178 SNEDECOR ET AL.
[0.011, 0.13]) over 12 weeks compared with placebo
but was not statistically signicant. Duloxetine
20 mg showed a modest increase in mean health
state utility (0.02, [0.05, 0.10]), and Sativex showed
the least improvement (0.03, [0.36, 0.29]).
Harms Outcomes
Most studies reported total numbers of AEs and
discontinuations. Among the 24 interventions for which
discontinuation data were available, 14 were not esti-
mated to be statistically higher than placebo. Imipra-
mine had the highest RR of discontinuation (3.96, [3.06,
4.28]) (Figure 3D), and tramadol had a RR of discon-
tinuation statistically lower than placebo (0.71, [0.49,
0.98]). Most of discontinuation RRs clustered around
0.8 to 1.5, with estimates on the extreme having greater
uncertainty.
Oxycodone, ABT-594, pregabalin 300 mg, ami-
triptyline, duloxetine 40 mg had RRs of AEs statis-
tically higher than placebo with a lower bound of the
95% CrI greater than 1.12. Amitriptyline, lamotrigine,
and topiramate were marginally statistically higher than
placebo with 95% CrI lower bounds of 1.02, 1.01, and
1.00, respectively (Figure 3D). No study had AE risks
statistically lower than placebo.
Model Validation
To validate the models consistency with head-to-head
comparisons, we compared the treatment efcacies from
the reported studies with those from the MTC analysis
(Table 2). Two direct comparisons were available for
the NRS outcome, one each for the VAS and 30% pain
reduction, and 3 for the 50% pain reduction. The
consistency measures represent the difference between
the relative efcacies calculated from the study data and
from the MTC model. The continuous and dichotomous
consistency measures were centered around 0 (NRS and
VAS difference) and 1 (RR ratio), indicating the models
integration of the indirect evidence (ie, placebo-con-
trolled data) within the MTC analysis was consistent
with the directly observed head-to-head data.
Two doses of venlafaxine were consolidated in the
base-case analysis, although one study reported differ-
ential efcacy between high-dose and low-dose admin-
istrations of this treatment. However, this is the only
study to include this treatment. Thus, creating 2 separate
arms for each of the doses resulted in estimates
mimicking the reported data, rather than the average
of the 2 data points generated in the base-case analyses
(data available on request).
To test the impact of the lack of inclusion of
intercorrelations among multiarm trials, we created a
model estimating the NRS outcomes including only
those interventions with the most data points available.
We analyzed the random-effects model with and with-
out adjusting for multiarm trials and compared both
outcomes with those observed with the xed-effect
model. The mean reduction in VAS score was virtually
unchanged in all 3 modeling scenarios (data available
upon request). Furthermore, adjusting for multiarm
trials resulted in very little change in model estimates
relative to the nonadjusted model.
DISCUSSION
This study presents a comprehensive systematic review
and Bayesian meta-analysis of efcacy and/or harms
outcomes for 29 treatments for the management of
pDPN with data collected from 58 studies enrolling
11,883 subjects. To our knowledge, this is the most
comprehensive comparative effectiveness analysis con-
ducted to date for this pain indication.
The results obtained in this study are comparable
to those of previous meta-analyses assessing fewer
Table 2. Consistency Analysis Results for Efcacy Outcomes. Mean Consistency Measure is the Difference (for
Continuous NRS and VAS Outcomes) or the Relative Risk Ratio (for 30 and 50% Response Outcomes) between the
Treatment Effects Estimated Directly from the Data or Indirectly from the Mixed Treatment Comparison Results
Outcome Comparison Mean Consistency Measure 95% CrI
NRS Amitriptyline vs. gabapentin Difference = 0.007 (5.06, 5.04)
NRS Pregabalin 300 mg vs. lidocaine 5% plaster Difference = 0.007 (5.238, 5.235)
VAS Amitriptyline vs. capsaicin Difference = 2.763 (86.94, 81.44)
30% response Pregabalin 300 mg vs. lidocaine 5% plaster RR ratio = 1.03 (0.88, 1.24)
50% response Pregabalin 300 mg vs. lidocaine 5% plaster RR ratio = 1.03 (0.77, 1.42)
50% response Amitriptyline vs. lamotrigine RR ratio = 0.84 (0.52, 1.36)
50% response Amitriptyline vs. pregabalin 300 mg RR ratio = 1.15 (0.70, 1.86)
NRS, numeric rating scale; VAS, visual analogue scale; CrI, credible interval; RR, relative risk.
Therapies for painful diabetic peripheral neuropathy 179
studies.
38,39
Quilici et al.
39
analyzed data from9 clinical
trials and 2 published studies of duloxetine 60 mg,
pregabalin, and gabapentin for the treatment of pDPN.
The 2 published studies are included in our analysis.
40,41
The clinical trial data are presented by trial name, but
most were able to be reconciled with our analysis by
treatment arms and study duration.
28,4247
Direct and
indirect comparisons yielded identical results in their
study. For indirect comparisons vs. placebo, mean
reduction in 24-hour pain intensity was 1.44, 1.13,
and 0.90 for gabapentin, duloxetine, and pregabalin
(all dosages combined), respectively. Our respective
results are 1.06, 1.30, and 1.12 and 0.43 (for
pregabalin 300 mg and 150 mg). The authors
also presented the log odds ratio of achieving 50%
reduction in pain for duloxetine and pregabalin: 0.856
and 0.840, respectively, compared with 0.854 and
0.884/0.347 for pregabalin 300/ 150 mg in this
study.
The other indirect meta-analysis conducted by Chou
et al.
38
evaluated gabapentin to TCAs including desi-
pramine, imipramine, and amitriptyline for the treat-
ment of pDPN and PHN. The study outcome was 50%
reduction in pain score or at least moderate or good
improvement in pain or global efcacy on a categorical
scale. Ten studies of the pDPNpopulation were included
into the Chou meta-analysis. Of these, 8 studies were
included due to the use of moderate or good improve-
ment in pain as an inclusion criterion, but were excluded
from the 50% response outcome in our analysis. The
remaining 2 studies were excluded for consideration
from our analysis due to trial duration of < 4 weeks.
From their analysis, the authors concluded the outcomes
with gabapentin were not statically different than TCAs
including amitriptyline in their adjusted indirect analy-
ses. These results are comparable to the NRS and VAS
outcomes generated in our analysis, which demon-
strated statistical equivalence to amitriptyline and
gabapentin.
The present results are consistent with a study
showing comparability of lidocaine to amitriptyline,
capsaicin, gabapentin, and pregabalin in pain reduc-
tion
48
and a study conducting a standard meta-analysis
of the 50% response rate of anticonvulsants, TCAs,
duloxetine, mexiletine, and opioids compared with
placebo.
49
Similar results were also seen in two
12-week RCTs published after our literature review
was conducted. One study compared duloxetine, gaba-
pentin, and pregabalin and found no signicant differ-
ence among treatment groups,
50
and the other found that
duloxetine (60 mg/day) was noninferior to pregabalin
(300 mg/day).
51
Dose-dependent effects for duloxetine
and pregabalin were also observed in our study, consis-
tent with a Cochrane review suggesting that duloxetine
may be effective at 60 and 120 mg daily dose but not at
20 mg daily dose.
52
The results of this study should be interpreted in light
of its limitations. Treatments associated with higher
numbers of studies or studies including more patients
were estimated to fall within the median range of
efcacy for the NRS and harms outcomes. These
treatments were also associated with smaller CrIs,
indicating greater reliability of the outcomes supported
by more data. It follows that the comparative efcacy
among treatments whose individual estimates are less
certain and those that are more certain should also be
viewed with caution.
Heterogeneity was demonstrated in the efcacy
estimates for the pregabalin 300 mg intervention,
suggesting differential treatment effects as a function of
study duration. Given the low power of statistical
homogeneity tests, other treatments may have unex-
plored variation due to differential study durations.
Additionally, studies differed in year of publication,
which has been attributed to one of the drivers of
discordant results observed between direct meta-
analyses and adjusted indirect comparisons.
38
More-
over, a drugs effectiveness against placebo was used to
calculate its effectiveness against other active drugs
within the MTC, so differences in placebo responses as a
function of study year, duration, age, baseline pain
scores, etc. could affect the meta-analysis outcomes.
53
In
the present analysis, included studies were published
from1984 through 2011, and no formal adjustment was
made for differences in placebo effect or outcome
measurements as a function of publication year. These
factors could be explored across all observed studies, but
could not be explored on the drug level within the MTC
due to too few observations for many treatments.
In this analysis, all dosages of each treatment were
considered to be independent observations of the same
intervention, with the exception of 2 levels of stratica-
tion for pregabalin and duloxetine. The conclusions of
the studies themselves support this assumption, but we
cannot rule out the possibility that different dosages
introduced more heterogeneity into the data than
otherwise would have been observed if the studies had
all included identical interventions.
Another data limitation is the quality and complete-
ness of reporting. Although there is substantial evidence
180 SNEDECOR ET AL.
analyzing pharmacological treatments for pDPN with
therapies, the outcomes used to measure treatment
efcacy varied widely. Pain outcomes analyzed here
included the 11-pt NRS and 100 mm VAS, which was
dened to be 24-hr average pain or daily pain. However,
several studies presented outcomes using a variety of
other pain measures, limiting comparisons across the
different studies and therapies. Consistent reporting of
variability for continuous outcomes would assist in
generating more accurate estimates of relative efcacy.
Differentiation among the effects of some of the
interventions was identied for the NRS and VAS
outcomes, but these differences were not maintained in
the dichotomous 30% and 50% pain reduction out-
comes. Furthermore, it was observed that several treat-
ments had similar efcacy (or harm), and those with
highest and lowest efcacy were associated with the
least number of studies and data points. This under-
scores the need for studies with comparable sample sizes
and reported outcomes to ensure more accurate indirect
analysis estimates.
This study compiled all available data for pharma-
cologic treatments for pDPN into one comprehensive
framework to generate more compatible efcacy esti-
mates than could be made by simply examining
individual studies side-by-side. This analysis, which
used Bayesian MTC methodology, provided consistent
results for the subset of treatments that had been
previously analyzed using standard meta-analytical
and adjusted indirect comparison techniques, thereby
supporting the results produced herein for all treat-
ments.
Consolidated comparison of several treatments and
several studies demonstrated that many interventions
were similar, with few treatments showing lower and
higher efcacy and harm along with larger variation.
Heterogeneity analyses also revealed the need for
examination of the effects of study duration and other
factors on treatment effects to more accurately compare
study results. Overall, the results of this meta-analysis
can provide guidance to clinicians for treatment selec-
tion in the management of pDPN.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge Pooja Desai, Yash
Jalundhwala, Ewan Cobran, and Yi-Ting Tsai of
Pharmerit International for identication and extraction
of study data and Bruce Parsons of Pzer Inc for his
clinical perspective on the article. This study was funded
by Pzer Inc. Lavanya Sudharshan, Sonya J. Snedecor,
Sonam Mehta, and Marc Botteman are employees of
Pharmerit International and were paid consultants to
Pzer in the development and execution of this study
and article. Joseph C. Cappelleri and Alesia Sadosky are
employees and shareholders of Pzer Inc, the sponsor of
this study. L.S. and M.B. contributed to study identi-
cation. S.S., L.S, and S.M, contributed to extraction of
study data. S.S. and L.S. analyzed the data and wrote
the article. A.S., J.C., and M.B. contributed to the
data analyses. All authors reviewed and edited the
article.
REFERENCES
1. IASP Task Force on Taxonomy. Part III: Pain Terms, A
Current List with Denitions and Notes on Usage. Merskey H,
Bogduk N, eds. Classication of Chronic Pain Second Edition,
Seattle: IASP Press; 1994: 209214.
2. Baron R. Neuropathic pain: a clinical perspective.
Handb Exp Pharmacol. 2009;194:330.
3. Jensen TS, Gottrup H, Sindrup SH, et al. The clinical
picture of neuropathic pain. Eur J Pharmacol. 2001;429:
111.
4. Vinik A. The approach to the management of the
patient with neuropathic pain. J Clin Endocrinol Metab.
2010;95:48024811.
5. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic
neuropathies: a statement by the American Diabetes Associ-
ation. Diabetes Care. 2005;28:956962.
6. Beydoun A, Shaibani A, Hopwood M, et al. Ox-
carbazepine in painful diabetic neuropathy: results of a dose-
ranging study. Acta Neurol Scand. 2006;113:395404.
7. Gore M, Brandenburg NA, Hoffman DL, et al. Burden
of illness in painful diabetic peripheral neuropathy: the
patients perspectives. J Pain. 2006;7:892900.
8. Galer BS, Gianas A, Jensen MP. Painful diabetic
polyneuropathy: epidemiology, pain description, and quality
of life. Diabetes Res Clin Pract. 2000;47:123128.
9. Chong MS, Hester J. Diabetic painful neuropathy:
current and future treatment options. Drugs. 2007;67:569
585.
10. Bril V, England J, Franklin GM, et al. Evidence-based
guideline: treatment of painful diabetic neuropathy: report of
the American Academy of Neurology, the American Associ-
ation of Neuromuscular and Electrodiagnostic Medicine, and
the American Academy of Physical Medicine and Rehabilita-
tion. PM R. 2011;3:345352, 352 e121
11. Attal N, Cruccu G, Baron R, et al. EFNS guidelines on
the pharmacological treatment of neuropathic pain: 2010
revision. Eur J Neurol. 2010;17:1113e88.
12. Moher D, Liberati A, Tetzlaff J, et al. Preferred
reporting items for systematic reviews and meta-analyses: the
PRISMA statement. BMJ. 2009;339:b2535.
Therapies for painful diabetic peripheral neuropathy 181
13. Halpern S, Douglas , M. (eds). Appendix: JADAD
Scale for Reporting Randomized Controlled Trials, in
Evidence-based Obstetric Anesthesia. Oxford, UK: Blackwell
Publishing Ltd; 2007. doi: 10.1002/9780470988343.app1.
14. Watson CP, Gilron I, Sawynok J. A qualitative
systematic review of head-to-head randomized controlled
trials of oral analgesics in neuropathic pain. Pain Res Manag.
2010;15:147157.
15. Vargas-Espinosa ML, Sanmarti-Garcia G, Vazquez-
Delgado E. , et al. Antiepileptic drugs for the treatment of
neuropathic pain. A systematic review. Med Oral Patol Oral
Cir Bucal. 2012;17:e78693.
16. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome
measures for chronic pain clinical trials: IMMPACT recom-
mendations. Pain. 2005;113:919.
17. Lu G, Ades AE. Combination of direct and indirect
evidence in mixed treatment comparisons. Stat Med.
2004;23:31053124.
18. Lunn DJ, Thomas A, Best N, Spiegelhalter D. Win-
BUGS a Bayesian modelling framework: concepts, structure,
and extensibility. Stat Comput. 2000;10:325337.
19. Petitti D. Meta-analysis, decision analysis, and cost-
effectiveness analysis. New York, NY: Oxford University
Press; 2000.
20. Cohen KL, Lucibello FE, Chomiak M. Lack of effect
of clonidine and pentoxifylline in short-term therapy of
diabetic peripheral neuropathy. Diabetes Care.
1990;13:10741077.
21. Gomez-Perez FJ, Rull JA, Dies H, et al. Nortriptyline
and uphenazine in the symptomatic treatment of diabetic
neuropathy. A double-blind cross-over study. Pain.
1985;23:395400.
22. Gomez-Perez FJ, Choza R, Rios JM, et al. Nortriptyline-
uphenazine vs. carbamazepine in the symptomatic treatment of
diabetic neuropathy. Arch Med Res. 1996;27:525529.
23. Rull JA, Quibrera R, Gonzalez-Millan H, et al. Symp-
tomatic treatment of peripheral diabetic neuropathy with
carbamazepine (Tegretol): double blind crossover trial. Dia-
betologia. 1969;5:215218.
24. Young RJ, Ewing DJ, Clarke BF. A controlled trial of
sorbinil, an aldose reductase inhibitor, in chronic painful
diabetic neuropathy. Diabetes. 1983;32:938942.
25. Stracke H, Gaus W, Achenbach U, et al. Benfotiamine
in diabetic polyneuropathy (BENDIP): results of a randomised,
double blind, placebo-controlled clinical study. Exp Clin
Endocrinol Diabetes. 2008;116:600605.
26. Stracke H, Meyer UE, Schumacher HE, et al. Mexile-
tine in the treatment of diabetic neuropathy. Diabetes Care.
1992;15:15501555.
27. Baron R, Mayoral V, Leijon G, et al. Efcacy and
safety of combination therapy with 5% lidocaine medicated
plaster and pregabalin in post-herpetic neuralgia and diabetic
polyneuropathy. Curr Med Res Opin. 2009;25:16771687.
28. Freynhagen R, Strojek K, Griesing T, et al. Efcacy of
pregabalin in neuropathic pain evaluated in a 12-week,
randomised, double-blind, multicentre, placebo-controlled
trial of exible- and xed-dose regimens. Pain. 2005;115:
254263.
29. Malik RA, Williamson S, Abbott C, et al. Effect of
angiotensin-converting-enzyme (ACE) inhibitor trandolapril
on human diabetic neuropathy: randomised double-blind
controlled trial. Lancet. 1998;352:19781981.
30. Yuen KC, Baker NR, Rayman G. Treatment of chronic
painful diabetic neuropathy with isosorbide dinitrate spray: a
double-blind placebo-controlled cross-over study. Diabetes
Care. 2002;25:16991703.
31. Gorson KC, Schott C, Herman R, et al. Gabapentin in
the treatment of painful diabetic neuropathy: a placebo
controlled, double blind, crossover trial. J Neurol Neurosurg
Psychiatry. 1999;66:251252.
32. Hanna M, OBrien C, Wilson MC. Prolonged-release
oxycodone enhances the effects of existing gabapentin therapy
in painful diabetic neuropathy patients. Eur J Pain.
2008;12:804813.
33. Vinik AI, Tuchman M, Sarstein B, et al. Lamotrigine
for treatment of pain associated with diabetic neuropathy:
results of two randomized, double-blind, placebo-controlled
studies. Pain. 2007;128:169179.
34. Jensen MP, Friedman M, Bonzo D, et al. The validity
of the neuropathic pain scale for assessing diabetic neuropathic
pain in a clinical trial. Clin J Pain. 2006;22:97103.
35. Gimbel JS, Richards P, Portenoy RK. Controlled-
release oxycodone for pain in diabetic neuropathy: a random-
ized controlled trial. Neurology. 2003;60:927934.
36. Thienel U, Neto W, Schwabe SK, et al. Topiramate in
painful diabetic polyneuropathy: ndings from three double-
blind placebo-controlled trials. Acta Neurol Scand.
2004;110:221231.
37. Raskin P, Donofrio PD, Rosenthal NR, et al. Topira-
mate vs placebo in painful diabetic neuropathy: analgesic and
metabolic effects. Neurology. 2004;63:865873.
38. Chou R, Carson S, Chan BK. Gabapentin versus
tricyclic antidepressants for diabetic neuropathy and post-
herpetic neuralgia: discrepancies between direct and indirect
meta-analyses of randomized controlled trials. J Gen Intern
Med. 2009;24:178188.
39. Quilici S, Chancellor J, Lothgren M, et al. Meta-
analysis of duloxetine vs. pregabalin and gabapentin in the
treatment of diabetic peripheral neuropathic pain. BMC
Neurol. 2009;9:6.
40. Backonja M, Beydoun A, Edwards KR, et al. Gaba-
pentin for the symptomatic treatment of painful neuropathy in
patients with diabetes mellitus. A randomized controlled trial.
J Am Med Assoc. 1998;280:18311836.
41. Simpson DA. Gabapentin and venlafaxine for the
treatment of painful diabetic neuropathy. J Clin Neuromuscul
Dis. 2001;3:5362.
42. Wernicke JF, Pritchett YL, DSouza DN, et al.
A randomized controlled trial of duloxetine in diabetic
peripheral neuropathic pain. Neurology. 2006;67:14111420.
43. Raskin J, Pritchett YL, Wang F, et al. A double-blind,
randomized multicenter trial comparing duloxetine with
182 SNEDECOR ET AL.
placebo in the management of diabetic peripheral neuropathic
pain. Pain Med. 2005;6:346356.
44. Lesser H, Sharma U, LaMoreaux L, et al. Pregabalin
relieves symptoms of painful diabetic neuropathy: a random-
ized controlled trial. Neurology. 2004;63:21042110.
45. Rosenstock J, Tuchman M, Lamoreaux L, et al.
Pregabalin for the treatment of painful diabetic peripheral
neuropathy: a double-blind, placebo-controlled trial. Pain.
2004;110:628638.
46. Richter RW, Portenoy R, Sharma U, et al. Relief of
painful diabetic peripheral neuropathy with pregabalin: a
randomized, placebo-controlled trial. J Pain. 2005;6:253260.
47. Tolle T, Freynhagen R, Versavel M, et al. Pregabalin
for relief of neuropathic pain associated with diabetic neuro-
pathy: a randomized, double-blind study. Eur J Pain.
2008;12:203213.
48. Wolff RF, Bala MM, Westwood M, et al. 5%lidocaine
medicated plaster in painful diabetic peripheral neuropathy
(DPN): a systematic review. Swiss Med Wkly. 2010;140:297
306.
49. Wong MC, Chung JW, Wong TK. Effects of treatments
for symptoms of painful diabetic neuropathy: systematic
review. BMJ. 2007;335:87.
50. Devi P, Madhu K, Ganapathy B, et al. Evaluation of
efcacy and safety of gabapentin, duloxetine, and pregabalin
in patients with painful diabetic peripheral neuropathy. Indian
J Pharmacol. 2012;44:5156.
51. 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, ran-
domized, noninferiority comparison. Mayo Clin Proc.
2011;86:615626.
52. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for
treating painful neuropathy or chronic pain. Cochrane Data-
base Syst Rev. 2009;4:CD007115.
53. Selph S, Carson S, Fu R, et al. Drug Class Review:
Neuropathic Pain: Final Update 1 Report [Internet]. 2011.
54. Arezzo JC, Rosenstock J, LaMoreaux L, et al. Efcacy
and safety of pregabalin 600 mg/d for treating painful diabetic
peripheral neuropathy: Adouble-blindplacebo-controlledtrial.
BMC Neurol. 2008;8:33. doi: 10.1186/1471-2377-8-33.
55. Atli A, Dogra S. Zonisamide in the treatment of painful
diabetic neuropathy: a randomized, double-blind, placebo-
controlled pilot study. Pain Med. 2005;6:225234.
56. Bansal D, Bhansali A, Hota D, et al. Amitriptyline vs.
pregabalin in painful diabetic neuropathy: a randomized
double blind clinical trial. Diabet Med. 2009;26:10191026.
57. Baron R, Mayoral V, Leijon G, et al. 5% Lidocaine
medicated plaster versus pregabalin in post-herpetic neuralgia
and diabetic polyneuropathy: an open-label, non-inferiority
two-stage RCT study. Curr Med Res Opin. 2009;25:1663
1676.
58. Biesbroeck R, Bril V, Hollander P, et al. A double-
blind comparison of topical capsaicin and oral amitriptyline in
painful diabetic neuropathy. Adv Ther. 1995;12:111120.
59. Treatment of painful diabetic neuropathy with topical
capsaicin. A multicenter, double-blind, vehicle-controlled
study. The Capsaicin Study Group. Arch Intern Med.
1991;151:22252229.
60. Chad DA, Aronin N, Lundstrom R, et al. Does
capsaicin relieve the pain of diabetic neuropathy? Pain.
1990;42:387388.
61. Cohen SM, Mathews T. Pentoxifylline in the treatment
of distal diabetic neuropathy. Angiology. 1991;42:
741746.
62. Dallocchio C, Buffa C, Mazzarello P, et al. Gabapentin
vs. amitriptyline in painful diabetic neuropathy: an open-label
pilot study. J Pain Symptom Manage. 2000;20:280285.
63. Dejgard A, Petersen P, Kastrup J. Mexiletine for
treatment of chronic painful diabetic neuropathy. Lancet.
1988;1:911.
64. Dogra S, Beydoun S, Mazzola J, et al. Oxcarbazepine
in painful diabetic neuropathy: a randomized, placebo-con-
trolled study. Eur J Pain. 2005;9:543554.
65. Eisenberg E, Lurie Y, Braker C, et al. Lamotrigine
reduces painful diabetic neuropathy: a randomized, controlled
study. Neurology. 2001;57:505509.
66. Freeman R, Raskin P, Hewitt DJ, et al. Randomized
study of tramadol/acetaminophen versus placebo in painful
diabetic peripheral neuropathy. Curr Med Res Opin.
2007;23:147161.
67. Gao Y, Ning G, Jia WP, et al. Duloxetine versus
placebo in the treatment of patients with diabetic neuropathic
pain in China. Chin Med J. 2010;123:31843192.
68. Goldstein DJ, Wang O, Gitter BD, et al. Dose-response
study of the analgesic effect of lanepitant in patients with
painful diabetic neuropathy. Clin Neuropharmacol.
2001;24:1622.
69. Goldstein DJ, Lu Y, Detke MJ, et al. Duloxetine vs.
placebo in patients with painful diabetic neuropathy. Pain.
2005;116:109118.
70. Gomez-Perez FJ, Perez-Monteverde A, Nascimento O,
et al. Gabapentin for the treatment of painful diabetic
neuropathy: dosing to achieve optimal clinical response. Br J
Diabetes Vasc Dis. 2004;4:173178.
71. Grosskopf J, Mazzola J, Wan Y, et al. A randomized,
placebo-controlled study of oxcarbazepine in painful diabetic
neuropathy. Acta Neurol Scand. 2006;114:177180.
72. Harati Y, Gooch C, Swenson M, et al. Double-blind
randomized trial of tramadol for the treatment of the pain of
diabetic neuropathy. Neurology. 1998;50:18421846.
73. Jiang W, Ladd S, Martsberger C, et al. Effects of
pregabalin on heart rate variability in patients with painful
diabetic neuropathy. J Clin Psychopharmacol. 2011;31:207
213.
74. Jose VM, Bhansali A, Hota D, et al. Randomized
double-blind study comparing the efcacy and safety of
lamotrigine and amitriptyline in painful diabetic neuropathy.
Diabet Med. 2007;24:377383.
75. Kadiroglu AK, Sit D, Kayabasi H, et al. The effect of
venlafaxine HCl on painful peripheral diabetic neuropathy in
Therapies for painful diabetic peripheral neuropathy 183
patients with type 2 diabetes mellitus. J Diabetes Complica-
tions. 2008;22:241245.
76. Kochar DK, Jain N, Agarwal RP, et al. Sodium
valproate in the management of painful neuropathy in type 2
diabetes a randomized placebo controlled study. Acta
Neurol Scand. 2002;106:248252.
77. Kochar DK, Rawat N, Agrawal RP, et al. Sodium
valproate for painful diabetic neuropathy: a randomized
double-blind placebo-controlled study. QJM. 2004;97:3338.
78. Kvinesdal B, Molin J, Froland A, et al. Imipramine
treatment of painful diabetic neuropathy. JAMA.
1984;251:17271730.
79. Max MB, Culnane M, Schafer SC, et al. Amitriptyline
relieves diabetic neuropathy pain in patients with normal or
depressed mood. Neurology. 1987;37:589596.
80. Max MB, Kishore-Kumar R, Schafer SC, et al. Efcacy
of desipramine in painful diabetic neuropathy: a placebo-
controlled trial. Pain. 1991;45:39; discussion 12.
81. Max MB, Lynch SA, Muir J, et al. Effects of
desipramine, amitriptyline, and uoxetine on pain in diabetic
neuropathy. N Engl J Med. 1992;326:12501256.
82. Morello CM, Leckband SG, Stoner CP, et al. Ran-
domized double-blind study comparing the efcacy of gaba-
pentin with amitriptyline on diabetic peripheral neuropathy
pain. Arch Intern Med. 1999;159:19311937.
83. Raskin J, Wang F, Pritchett YL, et al. Duloxetine for
patients with diabetic peripheral neuropathic pain: a 6-month
open-label safety study. Pain Med. 2006;7:373385.
84. Rauck RL, Shaibani A, Biton V, et al. Lacosamide in
painful diabetic peripheral neuropathy: a phase 2 double-blind
placebo-controlled study. Clin J Pain. 2007;23:150158.
85. Rowbotham MC, Goli V, Kunz NR, et al. Venlafaxine
extended release in the treatment of painful diabetic neurop-
athy: a double-blind, placebo-controlled study. Pain.
2004;110:697706.
86. Rowbotham MC, Duan WR, Thomas J, et al. A
randomized, double-blind, placebo-controlled trial evaluating
the efcacy and safety of ABT-594 in patients with diabetic
peripheral neuropathic pain. Pain. 2009;146:245252.
87. Satoh J, Yagihashi S, Baba M, et al. Efcacy and safety
of pregabalin for treating neuropathic pain associated with
diabetic peripheral neuropathy: a 14 week, randomized,
double-blind, placebo-controlled trial. Diabet Med.
2011;28:109116.
88. Schefer NM, Sheitel PL, Lipton MN. Treatment of
painful diabetic neuropathy with capsaicin 0.075%. J Am
Podiatr Med Assoc. 1991;81:288293.
89. Schwartz S, Etropolski M, Shapiro DY, et al. Safety
and efcacy of tapentadol ER in patients with painful diabetic
peripheral neuropathy: results of a randomized-withdrawal,
placebo-controlled trial. Curr Med Res Opin. 2011;27:151
162.
90. Selvarajah D, Gandhi R, Emery CJ, et al. Randomized
placebo-controlled double-blind clinical trial of cannabis-
based medicinal product (Sativex) in painful diabetic neurop-
athy: depression is a major confounding factor. Diabetes Care.
2010;33:128130.
91. Shaibani A, Fares S, Selam JL, et al. Lacosamide in
painful diabetic neuropathy: an 18-week double-blind pla-
cebo-controlled trial. J Pain. 2009;10:818828.
92. Watson CP, Moulin D, Watt-Watson J, et al. Con-
trolled-release oxycodone relieves neuropathic pain: a ran-
domized controlled trial in painful diabetic neuropathy. Pain.
2003;105:7178.
93. Wymer JP, Simpson J, Sen D, et al. Efcacy and safety
of lacosamide in diabetic neuropathic pain: an 18-week
double-blind placebo-controlled trial of xed-dose regimens.
Clin J Pain. 2009;25:376385.
94. Yasuda HHN, Nakao K, Kasuga M, Kashiwagi A,
Kawamori R. Superiority of duloxetine to placebo in improv-
ing diabetic neuropathic pain: results of a randomized
controlled trial in Japan. J Diabetes Investig. 2011;2:132139.
95. Zeigler D, Lynch SA, Muir J, et al. Transdermal
clonidine versus placebo in painful diabetic neuropathy. Pain.
1992;48:403408.
96. Ziegler D, Ametov A, Barinov A, et al. Oral treatment
with alpha-lipoic acid improves symptomatic diabetic poly-
neuropathy: the SYDNEY 2 trial. Diabetes Care.
2006;29:23652370.
97. Ziegler D, Hidvegi T, Gurieva I, et al. Efcacy and
safety of lacosamide in painful diabetic neuropathy. Diabetes
Care. 2010;33:839841.
184 SNEDECOR ET AL.