Journal of Diabetes and Its Complications 29 (2015) 146156

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Journal of Diabetes and Its Complications

journal homepage: WWW.JDCJOURNAL.COM

From guideline to patient: a review of recent recommendations for

pharmacotherapy of painful diabetic neuropathy
Dan Ziegler a, b,, Vivian Fonseca c,
a
b
c

Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Dsseldorf, Germany
Department of Endocrinology and Diabetology, University Hospital, Dsseldorf, Germany
Section of Endocrinology, Tulane University Medical Center, New Orleans LA, USA

a r t i c l e

i n f o

Article history:
Received 2 December 2013
Received in revised form 9 July 2014
Accepted 19 August 2014
Available online 28 August 2014
Keywords:
Painful diabetic neuropathy
Treatment guidelines
Pharmacologic therapy
Antidepressants
Anticonvulsants
Opioids

a b s t r a c t
Painful diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus, affecting, by some
estimates, up to one quarter of diabetic patients. Since 2010, no fewer than 5 major international treatment
guidelines for painful DPN have been issued, and there are meaningful differences among them. Duloxetine,
pregabalin, gabapentin, and tricyclic antidepressants are the mainstays of treatment, but the choice of which class
or agent to use in any given patient should be informed by patient characteristics. This review seeks to describe
the differences among the recently issued guidelines, to assess the evidence on which they are based, and to offer
insight into the most appropriate treatment choices based on patient characteristics.
2015 Elsevier Inc. All rights reserved.

1. Introduction
An estimated 246 million people worldwide have diabetes mellitus
(DM), and this number is likely to increase in tandem with the global
epidemic of obesity (Pluijms et al., 2010). Diabetic polyneuropathy is
among the most common long-term complications of DM, affecting up
to 50% of diabetic patients (Tesfaye et al., 2010). The prevalence of
painful diabetic peripheral neuropathy (DPN) is estimated to be 10 to
15% of patients with diabetes (Guastella & Mick, 2009) and up to 26% in
some surveys (Davies et al., 2006). These painful symptoms can have a
profound negative impact on quality of life, sleep, and mood (Jensen
et al., 2007; O'Connor, 2009).

Competing interests: The authors did not receive funding for this article. DZ has
received honoraria for speaking and consulting activities from Takeda, Daiichi Sankyo
Europe, Eisai, Eli Lilly, Meda, Wrwag, and Pzer. VF declares that his institution has
received grants from Abbott, Eli Lilly, and Reata. He has received honoraria for
consulting activities from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Inc., Eli
Lilly, GlaxoSmithKline, Intarcia, Merck, Novo Nordisk, Pan American Laboratories, and
Sano, and he owns stock/options in NuMe Health.
Correspondence to: D. Ziegler, MD, FRCPE, Professor of Internal Medicine, Institute
for Clinical Diabetology, German Diabetes Center at the Heinrich Heine University,
Leibniz Center for Diabetes Research, Auf'm Hennekamp 65, 40225 Dsseldorf
Germany. Tel.: +49 211 33820.
Correspondence to: V.A. Fonseca, MD, FRCP, Professor of Medicine, TullisTulane
Alumni Chair in diabetes, Chief of the Section of Endocrinology, Tulane University
Medical Center, New Orleans, LA.
E-mail address: dan.ziegler@ddz.uni-duesseldorf.de (D. Ziegler).
http://dx.doi.org/10.1016/j.jdiacomp.2014.08.008
1056-8727/ 2015 Elsevier Inc. All rights reserved.

Approximately 80% of patients with diabetic neuropathy have

distal symmetric polyneuropathy; symptoms initially occur in the feet
and gradually work their way up (Pluijms et al., 2010). In a survey
conducted at 468 pain centers in Germany that assessed pain-symptom
proles in 2100 patients with painful DPN or postherpetic neuralgia
(PHN), Baron et al. (2009) identied 5 distinct symptom clusters. The
most common symptom cluster in painful DPN, seen in 26% of patients,
was burning pain, paresthesias, and numbness, with fewer than 20% of
patients complaining of either dynamic mechanical allodynia, thermal
hyperalgesia, or pain attacks.
Neuropathic pain (NeP) occurs more often in patients whose diabetes
is chronically poorly controlled (Pluijms et al., 2010), and increased blood
glucose uxie, increased range of variance in blood glucose levelsmay
contribute to the occurrence and severity of painful symptoms (Oyibo
et al., 2002). Age, obesity, and peripheral arterial disease (PAD) are also
associated with an increased risk of painful DPN (Ziegler, Rathmann,
Dickhaus, et al., 2009; Ziegler, Rathmann, Meisinger, et al., 2009).
Maximizing glucose control is a primary goal in patients at risk of
or who already have painful DPN (American Diabetes Association,
2012). A recent meta-analysis (Callaghan et al., 2012) suggests that
enhanced glucose control signicantly prevents the development of
clinical neuropathy in patients with type 1 diabetes; among patients
with type 2 diabetes, however, the reported reduction in incidence
did not reach statistical signicance. Early open-label studies
reported that intensive glucose control with continuous IV insulin
infusion may reduce painful symptoms in patients with established

D. Ziegler, V. Fonseca / Journal of Diabetes and Its Complications 29 (2015) 146156

147

Table 1
International guidelines: treatment of painful diabetic peripheral neuropathy.
Recommendation: 1 = rst choice, 2 = second choice, 3 = third choice
NR = not recommended; = not mentioned

Tricyclic antidepressants
Duloxetine
Venlafaxine
Valproate
Gabapentin
Pregabalin
Carbamazepine
Tramadol
Opioids
Capsaicin 0.1%
Lidocaine 5%

AACE (Handelsman
et al., 2011) 2011

AAN (Bril et al.,

2011) 2011

EFNS (Attal et al.,

2010) 2010

NICE (National Institute for

Health & Clinical Excellence) 2013

Toronto Consensus 2010

(Tesfaye et al., 2011)

1
1

1
1

2
2
2
2

2
2
2
2
2
1

2
2
2
3

1
1
1
NR
1
1
NR
23
23
NR

12
12

12
12

1
1

1
1

2
2

AACE, American Association of Clinical Endocrinologists; AAN, American Academy of Neurology; EFNS, European Federation of Neurological Societies; NICE, National Institute for
Health and Clinical Excellence (UK).

painful DPN (Bertelsmann et al., 1987; Boulton et al., 1982). To our

knowledge, controlled clinical trials to demonstrate whether
intensive diabetes therapy improves extant painful DPN have not
yet been published.
Typically, individualized treatment for pain should begin when
pain interferes with a patient's lifestyle. In cases of severe pain, pain that
signicantly limits daily activity, or pain accompanied by deterioration
of an underlying health condition, referral to a pain specialist should
be considered.
2. Objective and methods
Despite a wealth of literature on the subject and despite multiple
treatment guidelines, achieving optimal treatment of painful DPN is
elusive. The purpose of this article is to critically review recently
issued guidelines for the treatment of painful DPN and the evidence
on which they are built and to consider patient characteristics as
potential determinants of recommended treatments most likely to be
successful in individual cases.
In January 2013, 1 we searched PubMed for treatment guidelines of
US or European origin, published in English, using key words painful
diabetic peripheral neuropathy and analogs (neuropathic pain AND
diabetes; polyneuropathy AND pain) for the previous 5 years.
We reviewed bibliographies from 5 treatment guidelines returned to
identify clinical trial and meta-analyses cited as evidence in support of
those guidelines' recommendations. Adverse events was combined
with the above searches, and product inserts were reviewed.
3. Guideline recommendations for rst-line treatment
Five recent guidelines (Attal et al., 2010; Bril et al., 2011;
Handelsman et al., 2011; National Institute for Health & Clinical
Excellence; Tesfaye et al., 2011)created or endorsed by several
professional societiesoffer treatment recommendations specic to
painful DPN (Table 1). Drugs with demonstrated efcacy in improving
pain in DPN generally fall into 4 categories: anticonvulsants
(particularly 2- ligands), antidepressants (predominantly tricyclic
antidepressants [TCAs] and serotoninnorepinephrine reuptake inhibitors [SNRIs]), opiate-receptor agonists, and topical agents.
However, only two drugs, pregabalin and duloxetine, have been
approved for the treatment of NeP in diabetes by both the US Food and
Drug Administration and the European Medicines Agency. Agents of
1
Subsequent to the search as here described, NICE issued, in November 2013, an
update (CG173) to its 2010 neuropathic pain guideline (CG96). It is that updated 2013
NICE guideline that is described here.

the anticonvulsant, SNRI, and TCA classes are recommended as rstline treatment for painful DPN in at least one recent guideline.
3.1. Alpha2-delta ligands
Pregabalin and gabapentin were initially developed as anticonvulsants; both are approved for NeP indications in Europe and the US.
Pregabalin has pharmacokinetic advantages compared to gabapentin,
including BID dosing and dose-dependent efcacy (Attal et al., 2010).
Pregabalin has a more predictable and linear PK prole than gabapentin
and can be more rapidly titrated than gabapentin; thus, one can learn
faster whether it works for a given patient (Dworkin et al., 2007).
3.2. SNRIs
Duloxetine and venlafaxine ER have the advantage of once-daily
dosing. A longer titration may be required with venlafaxine (up to
3 weeks) than with duloxetine (Dworkin et al., 2007). Venlafaxine
has been associated with rapidly occurring, potentially serious,
withdrawal symptoms and should be slowly tapered (Fava et al.,
1997). SNRIs may have modest effects on fasting glucose, which may
require dosage adjustment of diabetes medications.
3.3. TCAs
TCAs increase norepinephrine and serotonin levels (via reuptake
inhibition) and have a variety of effects on sodium channels, N-methylD-aspartate (NMDA) receptors, and other pharmacologic pathways; as
such, they may be associated with multiple side effects. Although there
are no direct comparative trials, amitriptyline may have greater efcacy
in painful DPN than other TCAs (Bril et al., 2011). As a class, they require
long, slow titration, and a trial of 6 to 8 weeks is needed to assess effect
(Dworkin et al., 2007). TCAs are all available generically and have the
lowest drug costs of the commonly used treatments for painful DPN.
3.4. Overview of DPN guideline methodologies
Examining how the various guidelines were derived can aid in
understanding the differences among them. AAN and EFNS guidelines
were fundamentally quantitative in nature, with recommendations
based on the number of studies that demonstrated meaningful and
consistent improvements in pain, quality of life, and other outcomes
important in painful DPN (eg, sleep, mood). These studies were
classied according to methodologic quality and rigor: to achieve
level A evidence for efcacy, the AAN guidelines required at least two
class 1 studies (Bril et al., 2011), whereas the EFNS guidelines required

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D. Ziegler, V. Fonseca / Journal of Diabetes and Its Complications 29 (2015) 146156

at least one class 1 or two class 2 studies (Attal et al., 2010; Brainin et
al., 2004). The characteristics of a class 1 study were similar between
the two guidelines, although there were important differences. For
example, class 1 studies were restricted to high-quality randomized
controlled trials (RCTs) in the AAN guidelines, while the EFNS also
allowed class 1 designation to be given to high-quality systematic
reviews. In addition, the AAN specied that class 1 studies were
required to have a completion rate of 80% (Bril et al., 2011), while
the EFNS guidelines required a minimal potential for bias due to
dropouts and crossovers (Brainin et al., 2004).
In guidelines published by NICE, the AACE, and the Toronto group,
subjective factors played a greater role in recommendations than in
the AAN and EFNS guidelines. In the AACE guidelines, recommendation grades for painful DPN treatment (A = strong to D = not
evidence-based) began with a grading process including a formal
assessment of the quality and outcomes of clinical trials, similar to the
AAN and EFNS guidelines (Handelsman et al., 2011). Drugs that had
supporting data from RCTs or meta-analyses of RCTs were assigned
evidence level 1 (EL1) (Mechanick et al., 2010). Outcomes from other
trial designs (eg, nonrandomized trials, retrospective analyses, case
reports) were assigned lower evidence levels (EL2 or EL3). The AACE
Task Force then considered subjective input on the quality of the data
and additional qualiers, such as costbenet analyses and availability
of treatment. These factors could have a positive or negative impact on
the eventual recommendation grade, potentially moving a drug with
EL2 to a grade A recommendation or a drug with an EL1 to a grade B
recommendation. Less rigid than the AAN and EFNS guidelines, this
approach was thought to better reect the processes involved in realworld decision making. The Toronto guidelines were more subjective
still, based, as they were, solely on the consensus opinion of an
international panel of experts in DPN (Tesfaye et al., 2011).
National Institute for Health and Excellence (NICE) guidelines
suggest treatment algorithms for nonspecialist providers who treat
painful DPN. Funded by the NHS, these guidelines are designed to
evaluate whether a treatment is a good use of NHS resources. They
thus incorporate both clinical outcomes and cost effectiveness. Only
randomized, placebo- or active-controlled trials were included in this
analysis (National Institute for Health & Clinical Excellence).
3.5. Differences in treatment rankings between guidelines
Four agents, pregabalin, gabapentin, duloxetine, and venlafaxine, are
designated as rst-line treatment in at least one of the ve guidelines
under review. Pregabalin was the only agent to meet the threshold for
level A recommendation (three class 1 and one class 2 studies) in the
AAN guidelines and is the only drug to achieve rst-line status in all ve
guidelines (Table 1), while duloxetine and gabapentin are each
recommended for rst-line treatment in four of the ve guidelines.
Duloxetine is recommended as rst-line therapy in the NICE, AACE,
Toronto, and EFNS guidelines (with four class 1 studies) (Attal et al.,
2010; Handelsman et al., 2011; National Institute for Health & Clinical
Excellence; Tesfaye et al., 2011); however, only one duloxetine trial
was rated as class 1 according to the AAN criteria (primarily due to
completion rates of b 80% in the class 2 studies) (Bril et al., 2011). The
EFNS guidelines were alone in recommending venlafaxine ER as rst-line
treatment, based on one class 1 study (Attal et al., 2010). In contrast, NICE
guideline recommends against its use by nonspecialist providers
(National Institute for Health & Clinical Excellence).
TCAs as a class are recommended as rst-line therapy in three
guidelines: AACE, EFNS, Toronto (Attal et al., 2010; Handelsman et al.,
2011; Tesfaye et al., 2011). TCAs met these guidelines' criteria for the
highest level of evidence, although the limitationseg, that the
positive studies were small, crossover trialsof existing TCA data
were acknowledged. Amitriptyline is generally the preferred TCA. The
NICE guideline recommends amitriptyline as a rst-line therapy and
does not recommend the use of other TCAs (National Institute for

Health & Clinical Excellence). The Toronto guidelines state a

preference for amitriptyline and imipraminewhich inhibit both
serotonin and noradrenalineover desipramine and nortriptyline,
which are primarily noradrenergic. The AAN guidelines also differentiate among the TCAs; level B evidence was demonstrated for
amitriptyline (similar to venlafaxine and duloxetine), while level U
evidence (insufcient evidence to support or refute use) was
demonstrated for the other TCAs (Bril et al., 2011). EFNS and AACE
guidelines do not distinguish between the different TCAs.
Indications and dosing for rst-line treatments are presented in
Table 2. Agents ranked no higher than second-line in recent
international guidelines are described in Table 3.
4. Choosing initial treatment
4.1. Comparisons between rst-line agents: little guidance
from guidelines
Taken as a whole, these guidelines offer limited support for choosing
one rst-line over another in the overall DPN population. These
guidelines found no signicant differences in terms of efcacy between
antidepressants (TCA or SNRIs) and anticonvulsants (including 2-
ligands). Recent studies support a lack of clear differentiation based on
overall efcacy between duloxetine and pregabalin. Pooled analyses in
painful DPN trials showed that 45 to 55% of duloxetine-treated patients
had N50% pain reduction vs. 25 to 28% with PBO, while 46% of patients
treated with pregabalin 600 mg/day had N50% pain reduction vs. 22%
with PBO (Pluijms et al., 2010). In AAN class 1 studies, the effect size for
relief of pain was also not markedly different between duloxetine,
pregabalin, and gabapentin, ranging from 8 to 13% (Bril et al., 2011).
Quilici et al. (2009) performed a meta-analysis comparing duloxetine vs.
pregabalin and duloxetine vs. gabapentin in the treatment of painful
DPN: no signicant differences in pain scores were noted between
duloxetine and either pregabalin or gabapentin. More recently, Boyle et
al. (2012) reported results from a short (2-week low dose, 2-week
higher dose) double-blind, parallel-group trial of duloxetine, pregabalin,
and amitriptyline that enrolled and randomized 83 patients with painful
Table 2
Drugs considered rst-line treatment in at least 1 recent international guideline.
Class/drug
2- ligands
Gabapentin

Pregabalin

SNRIs
Duloxetine
Venlafaxine
XR

NeP indications,
US

NeP indications,
EU

Recommended dosing
for painful DPNa

PHN

Peripheral NeP

EU: 900 to 3600 mg/day

in 3 divided doses
US: 900 to 1800 mg/day
in 3 divided doses
EU: 150 to 600 mg/day
in 2 or 3 divided doses
US: 150 to 300 mg/day
in 3 divided doses

Painful DPN, PHN, Peripheral and

central NeP
NeP associated
with SCI

Painful DPN

Painful DPN

Not approved for NeP indications

TCAs
Amitriptyline Not approved for NeP indications

EU: 60 to 120 mg QD
US: 60 mg QD
EU: 75 mg to 375 mg QD
US: 75 mg to 225 mg
QD
EU: 50 to 200 mg/day
in 2 divided doses or
1 at bedtime
US: 75 to 150 mg/day in
2 divided doses or 1
at bedtime

DPN, diabetic peripheral neuropathy; FM, bromyalgia; GAD, generalized anxiety

disorder; NeP, neuropathic pain; PHN, postherpetic neuralgia; SAD, social anxiety
disorder; SCI, spinal cord injury.
a
Dosing for gabapentin (US) is based on dosing for PHN, and dosing for venlafaxine
and amitriptyline are based on dosing for MDD.

D. Ziegler, V. Fonseca / Journal of Diabetes and Its Complications 29 (2015) 146156

149

Table 3
Treatments recommended no higher than second-line.

Local treatments
Capsaicin
Lidocaine

-receptor agonists
Morphine
Oxycodone
Tramadol
Na+ channel blockers
Valproate
Carbamazepine
Lamotrigine

Uses

Considerations

Low systemic side effects, few if any drug interactions

Skin lesions, dermatitis, and vascular insufciency may proscribe topical

treatments (Guastella & Mick, 2009)

Capsaicin 8% patch is approved in US to treat PHN and in Europe to

treat NeP in non-diabetic patients. It is not approved to treat painful
DPN (Derry et al., 2013)

Capsaicin causes pain on initial use that may be intolerable, though this
generally subsides within 2 weeks (Derry & Moore, 2012; Derry et al.,
2013)

Lidocaine has few local side effects

Potential harms (eg, GI side effects, cognitive impairment, sedation and

others) often outweigh benets when used non-selectively to treat DPN
(Guastella & Mick, 2009)

Shown at best marginal improvement, or in the case of carbamazepine,

positive results have been seen only in a limited number of small, lowquality studies (Wiffen, Derry & Moore, 2013; Wiffen et al., 2014)

Useful in patients unable to take oral medications

Capsaicin cream 0.075% is OTC in US and is approved for DPN and PHN
in Europe

5% lidocaine patch is approved in US and Europe for treatment of PHN

Recommended for intermittent breakthrough pain and pain during

up-titration phase of rst-line treatment (Dworkin et al., 2007)

Should generally be reserved for patients who cannot tolerate or who

do not respond adequately to rst- and second-line medications
(O'Connor, 2009)

Rapid onset of action

Lidocaine blood levels are minimal when 4 patches/day are applied for
18 hours (Dworkin et al., 2007)

DPN, diabetic peripheral neuropathy; GI, gastrointestinal; OTC, over-the-counter; PHN, postherpetic neuralgia.

DPN. They found no signicant difference in analgesic effect between

the treatments (Boyle et al., 2012). The short duration of treatment
makes overall assessment difcult, particularly to dene the balance of
benet versus risk of side effects.
Two of the guidelinesToronto and AANstated a preference for
pregabalin over gabapentin: the Toronto guidelines, because gabapentin doses used in clinical trials are higher than those commonly
used in clinical practice (Tesfaye et al., 2011), and the AAN guidelines,
because of a higher level of evidence for pregabalin (level A) than for
gabapentin (level B) (Bril et al., 2011). In contrast, the EFNS guidelines
found that the two agents were similar in terms of efcacy and
tolerability, and a recent double-blind, open-label comparative trial
supports this conclusion. Patients with moderately painful DPN
(baseline pain, 40/100 on VAS) were treated for 12 weeks with
duloxetine (up to 120 mg/day), pregabalin (up to 300 mg/day), or
gabapentin (up to 1800 mg/day) (Attal et al., 2010; Devi et al., 2012).
All three agents signicantly reduced key endpoints, but there were
no signicant between-treatment differences.
These guidelines also found no signicant differences in terms of
efcacy between antidepressant class (SNRIs vs. TCAs) or between
different TCAs. Duloxetine was the preferred SNRI in the AACE, NICE, and
Toronto guidelines, and amitriptyline was generally the preferred TCA,
primarily because most studies of TCAs in NeP involved amitriptyline.
4.2. Indirect comparison of efcacy
Number needed to treat (NNT)the number of patients that must
be treated with a particular therapy to observe a clinically relevant
effect in one patientcan be used as a summary measure of efcacy to
help differentiate treatment options. In chronic pain trials, a 50%
reduction from baseline in pain intensity is considered to be a
substantial improvement, while a 30% decrease represents a
moderately important improvement (Dworkin et al., 2008). Determinations of NNT based on the proportion of patients that achieve
30 and 50% pain relief are recommended by the Neuropathic Pain
Special Interest Group (NeuPSIG) of the International Association for
the Study of Pain (IASP) (Haanp et al., 2011). NNT has also been
determined for the Patient Global Impression of Change (PGIC) scale,
another core efcacy domain recommended by the Initiative on
Methods, Measurement, and Pain Assessment in Clinical Trials
(IMMPACT) (Moore et al., 2009).
The Cochrane group has published meta-analyses that evaluated
the efcacyincluding calculation of NNTand safety of pregabalin
(Moore et al., 2009; Wiffen, Derry, Moore, Aldington, et al., 2013),

gabapentin (Moore et al., 2014; Wiffen, Derry, Moore, Aldington, et al.,

2013), and duloxetine (Lunn et al., 2014) in neuropathic pain. Only
double-blind, randomized, controlled trials that employed validated
pain scales (consistent with IMMPACT guidelines) were included in
these analyses. There were eight trials of duloxetine in painful DPN
(n = 2728), seven of pregabalin (n = 2086), and nine of gabapentin
(n = 1604) that met Cochrane inclusion criteria. Duloxetine was
dosed at 20, 40, 60 mg/day, or 60 mg twice daily: 20 mg/day was
found to be ineffective, and 60 mg twice daily was not more effective
than 60 mg/day. Change in PGIC was statistically signicant but was
less than the 1-point difference considered to be a clinically
meaningful change (Dworkin et al., 2008). Dosing of pregabalin
ranged from 150 to 600 mg/day, and there was a signicant dose
response relationship for efcacy and incidence of adverse events
(AEs). The 150 mg/day dose was generally ineffective, while dosing at
300 and 600 mg/day was associated with meaningful benets in
patients with painful DPN. Gabapentin in dosages greater than
1200 mg/day was more effective than placebo for some people with
painful DPN. Based on NNT values, there appears to be little to
differentiate these agents. Number needed to treat and risk ratio for
duloxetine, pregabalin, and gabapentin are shown in Table 4.
The size and quality of the trials that provide evidence for the use
of TCAs are not impressive. In a 2012 Cochrane review of amitriptyline
in NeP, four studies in painful DPN that included a total of 286 patients
treated with amitriptyline were evaluated. In each of the four trials,
there was an active comparator (topical capsaicin, lamotrigine,
pregabalin, or desipramine or uoxetine). None of the studies showed
a difference between amitriptyline and the other treatments, while in
the two trials that also included a placebo comparator, there was only
some support for amitriptyline being any better than placebo. The
authors emphasized that amitriptyline has been a rst-line treatment
for neuropathic pain for many years. The fact that there is no
supportive unbiased evidence for a benecial effect is disappointing,
but has to be balanced against decades of successful treatment in
many patients with neuropathic pain. There is no good evidence of a
lack of effect; rather our concern should be of overestimation of
treatment effect (Moore et al., 2012).
A second TCA, imipramine, was evaluated in a 2014 Cochrane
review (Hearn et al., 2014). Five trials including a total of 168
participants, 90% of whom had painful DPN, were evaluated. None of
these trials provided rst or second tier evidence for efcacy, although
low-quality third-tier (small, short studies in which the likelihood of
meaningful bias is high) evidence suggested some improvement with
imipramine in painful DPN.

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D. Ziegler, V. Fonseca / Journal of Diabetes and Its Complications 29 (2015) 146156

Table 4
Number needed to treat for substantial and for moderately important improvementa.
Outcome
50% pain relief
Duloxetine 60 mg/day (Lunn et al., 2014)
Pregabalin 600 mg/day (Moore et al., 2009)
Pregabalin 300 mg/day (Moore et al., 2009)
Gabapentin 1200 mg/day (Moore et al., 2014)
30% pain relief
Duloxetine 60 mg/day (Lunn et al., 2014)
Pregabalin 600 mg/day (Moore et al., 2009)
Pregabalin 300 mg/day (Moore et al., 2009)
Gabapentin 1200 mg/day (Moore et al., 2014)
PGIC very much improved
Gabapentin 1200 mg/day
(Wiffen, Derry, Moore, Aldington, et al., 2013)
PGIC much/very much improved
Pregabalin 600 mg/day (Moore et al., 2009)
Pregabalin 300 mg/day (Moore et al., 2009)
Gabapentin 1200 mg/day
(Wiffen, Derry, Moore, Aldington, et al., 2013)

Studies

Subjects

Active vs. PBO % with outcome

NNT (95% CI)

4
6
4
6

908
1360
823
1277

46
45
40
38

vs.
vs.
vs.
vs.

26%
25%
26%
21%

5.0 (4.07.0)
5.0 (4.06.6)
7.5 (5.114)
5.9 (4.68.3)

4
3
2
2

799
819
482
744

64
63
59
54

vs.
vs.
vs.
vs.

41%
43%
45%
43%

5.0 (3.07.0)
5.1 (3.87.8)
6.8 (4.317)
9.4 (5.629)

408

24 vs. 14%

9.6 (5.535)

4
2
5

875
359
695

56 vs. 33%
48 vs. 30%
50 vs. 30%

4.2 (3.35.8)
5.6 (3.613)
4.9 (3.67.6)

CI, condence interval; NNT, number needed to treat; NR, not rated; PBO, placebo; PGIC, patient global impression of change; RR, risk ratio.
a
Following IMMPACT guidelines, a 50% reduction from baseline in pain intensity is considered to be a substantial improvement, while a 30% decrease represents a moderately
important improvement (Dworkin et al., 2008).

The conclusions of these two recent Cochrane reviews are

pregured in the guidelines themselves: Two of the three guidelines
that recommend TCAs as rst-line treatment for painful DPN mention
methodologic issues with the supporting studies, ie, reliance on data
from small, crossover studies (Attal et al., 2010; Tesfaye et al., 2011).
Indeed, the largest of the trials included in the amitriptyline review
had 87 patients treated with amitriptyline, while among the ve trials
included in the Cochrane review of imipramine, the total number of
patients treated in each trial ranged from 15 to 59, with treatment
lasting for 2 to 5 weeks in four of the studies and for 12 weeks in one
of the studies.
4.3. Quality of life
Health-related quality of life (QoL) is substantially impaired in
patients with NeP (O'Connor, 2009), and QoL is signicantly more
impaired in those with diabetes and NeP compared to those with
diabetes only or those with DPN but no painful symptoms (Van Acker
et al., 2009). Recent guidelines recommend assessing health-related
QoL with the SF-36, a generic QoL instrument, or EQ-5D, which
incorporates patient opinion of the utility value of a particular health
state (Haanp et al., 2011).
Pain severity correlates with all domains of the SF-36 and appears
to be the primary driver of QoL impairment in patients with NeP
(Cocito et al., 2006). Yet, relief of pain does not always improve QoL.
Haanp et al. (2011) identied 39 published studies in which change
in NeP and QoL was measured. Of the 26 trials in which clinically
meaningful reduction in pain was demonstrated, only 11 reported a
robust improvement in QoL. Superior improvements vs. placebo in
EQ-5D were seen in studies of pregabalin (Tlle et al., 2008) and
duloxetine (Goldstein et al., 2005; Wernicke et al., 2006). Studies of
duloxetine (Goldstein et al., 2005), pregabalin (Lesser et al., 2004;
Richter et al., 2005; Rosenstock et al., 2004), and gabapentin
(Backonja et al., 1998; Gilron et al., 2005) that assessed SF-36 have
consistently reported signicant improvement in the bodily pain
domain. Gabapentin appears to provide benets in the domains of
vitality and mental health (Backonja et al., 1998; Gilron et al., 2005),
and a pooled analysis of three duloxetine trials showed signicant
improvement in all SF-36 domains (Armstrong et al., 2007). Among
other medications, one study in patients with NeP showed signicant
improvement with imipramine in two SF-36 domains but not in
bodily pain (Otto et al., 2007). There seems to be little meaningful

difference between the treatments considered to be rst- or secondline options for painful DPN in terms of impact on QoL.
5. First-line treatment choice informed by patient characteristics
Results from recent, high-quality trials demonstrate a lack of clear
differentiation between rst-line agents in terms of reduction in
painful symptoms. As a result, patient-specic variables such as
comorbidities, contraindications, and interactions with concomitant
treatments may be important in determining optimal therapy, a
decision-making process that is formally endorsed by some guidelines
(Attal et al., 2010; National Institute for Health & Clinical Excellence;
Tesfaye et al., 2011). Table 5 summarizes the impact of treatments for
painful DPN on key patient characteristics.
5.1. Comorbidities: sleep disturbance, depression, anxiety, and obesity
Patients with NeP often complain of sleep disturbance (Attal et al.,
2010; O'Connor, 2009). Benecial effects on sleep quality and
interference with sleep have been reported in individual trials involving
pregabalin, gabapentin, duloxetine, amitriptyline, and opioids (Freeman
et al., 2007; Harati et al., 1998; Turkington, 1980; Wernicke et al., 2006;
Zin et al., 2010). The most consistent effects have been reported with

Table 5
Characterization of effect of treatment on patient characteristics.
Duloxetine
Depression
Obesity
Generalized anxiety disorder
Sleep disturbances
Coronary heart disease
Autonomic neuropathy
Fasting glucose
Hepatic failure
Renal failure
Drug interactions
Elderly

Pregabalin

Adapt dose

Effect: , favorable; , unfavorable; , depends on specic agent.

Table adapted from Ziegler D. Curr Diabet Rev. 2011;7:208-220.
Improvement in heart rate variability in one study.

TCAs

Opioids

D. Ziegler, V. Fonseca / Journal of Diabetes and Its Complications 29 (2015) 146156

pregabalin and gabapentin (Attal et al., 2010). Freeman et al. (2008)

described a pooled analysis of 7 double-blind, placebo-controlled trials
of pregabalin in painful DPN. Pregabalin at all dosages (150, 300,
600 mg/day) was found to signicantly improve sleep in a dosedependent manner (Freeman et al., 2008). Boyle et al. (2012) recently
reported results from a small study showing that while pregabalin was
associated with signicant improvement in sleep continuity in patients
with painful DPN, duloxetine was associated with greater sleep
fragmentation, including signicantly reduced sleep efciency, a
signicant reduction in sleep time, and signicantly increased wake
after sleep onset. For patients in whom sleep disturbance is prominent,
and for whom there are no contraindications, pregabalin may be a good
choice for rst-line treatment.
The prevalence of depression is increased 2-fold in patients with
diabetes (Chapman et al.). TCAs improve pain and depressive
symptoms and appear to have equivalent analgesic benets in
depressed and nondepressed patients with NeP (O'Connor, 2009).
To differentiate analgesic effects from effects on mood, clinical trials of
duloxetine in painful DPN have excluded patients with comorbid
mood disorders (Raskin et al., 2005; Wernicke et al., 2006). However,
patients with depression who were treated with duloxetine demonstrated improvements in somatic pain symptoms (Detke et al., 2002;
Goldstein et al., 2004). SNRIs and TCAs may be good options for
patients with comorbid painful DPN and depression (Ziegler, 2011).
Similarly, multiple RCTs have shown pregabalin and duloxetine to be
effective in the treatment of generalized anxiety disorder (GAD), and
they may be appropriate for patients with comorbid GAD (Khan &
Macaluso, 2009).
Given the incidence of overweight and obesity among patients
with diabetes, weight gain is among the more problematic long-term
side effects of treatment for painful DPN. Pregabalin, gabapentin, and
TCAs are associated with weight gain, as edema and as adipose tissue
(Attal et al., 2010). While published studies have not reported their
long-term effects on weight in patients with painful DPN, profound
effects were seen in other conditions. In patients with seizure disorder
treated with gabapentin for more than 12 months, 34% had N 5%
weight gain (DeToledo et al., 1997). In pregabalin-treated bromyalgia patients, there was a 2-fold increased risk of signicant weight
gain (N 7% increase in body weight), regardless of dose. In contrast,
duloxetine has been shown to be weight-neutral with up to
15 months of treatment in patients with painful DPN (Gaynor et al.,
2011). Meta-analyses showed modest increases in fasting plasma
glucose with no meaningful changes in HbA1c (Dworkin et al., 2007).
5.2. Safety and tolerability
There are clear differences in the safety and tolerability proles of
agents used to treat painful DPN, primarily between classes but also
within classes. Table 6 summarizes adverse events and safety
considerations typical of recommended treatments for painful DPN.
Autonomic manifestations of DPN may increase the incidence and
severity of known side effects. For example, additive effects on nausea
and constipation associated with duloxetine and opioids, anticholinergic effects common with TCAs, and impairment of sexual function
seen across all painful DPN treatments are factors that should be
considered when making individualized treatment decisions (Hovaguimian & Gibbons, 2011; Pluijms et al., 2010). Orthostasis, which is
not uncommon in patients who have diabetes, may contribute to or
amplify the side effects of dizziness and gait disturbances seen with
2- agents, thus increasing risk of falls and injuries related to falls,
including traumatic brain injury, fractures, and lacerations. Some
trials excluded subjects with autonomic neuropathy or gastrointestinal dysfunction, therefore underestimating the real-world occurrence of side effects (Gimbel et al., 2003). Worsening of gastroparesis
has been reported as a potential problem with TCAs and opiates
(Wood & Galligan, 2004), although a recent Cochrane review of

151

opiates made no mention of gastroparesis as an adverse event in 10

studies analyzed (McNicol et al., 2013).

5.3. Drugdrug interactions

The metabolism of TCAs, SNRIs, and tramadol is dependent on CYP
450 2D6. Concurrent use of CYP2D6 inhibitorsincluding SSRIs, SNRIs,
TCAs, quinidine, terbinane, and phenothiazinesmay lead to
increased duloxetine levels and to toxic levels of TCAs. On the other
hand, when tramadol is co-administered with CYP2D6 inhibitors,
patients will not achieve adequate analgesia despite tramadol dose
escalations (Hovaguimian & Gibbons, 2011). Drug interactions that
increase serotonergic activity can lead to a potentially lethal
serotonin syndrome. Coadministration of serotonergic drugs (eg,
SNRIs, SSRIs, TCAs, tramadol, lithium, sympathomimetics) and
nutraceuticals (eg, St John's wort, tryptophan) may increase the risk
of serotonin syndrome and should be avoided (Cushing & Benzer;
Dworkin et al., 2007). Monoamine oxidase inhibitors are contraindicated with both duloxetine and TCAs. TCAs and SNRIs may increase
the risk of bleeding in patients also receiving warfarin, nonsteroidal
anti-inammatory drugs, or aspirin (Sansone & Sansone, 2009).
Pregabalin and gabapentin appear to have no clinically meaningful
drug interactions and may, thus, be good choices for patients on
polypharmacy (Dworkin et al., 2007).

5.4. Long-term safety

The long-term safety of most agents used to treat painful DPN has
not been well-established. Safety and efcacy data from studies of
more than 14 weeks specic to patients with painful DPN have not
been published for TCAs, pregabalin, gabapentin, or opioids. Two
open-label safety extension studies of duloxetine found no apparent
adverse effects on lipid proles after 1 year. Small but statistically
signicant increases in HbA1c were observed in some studies but not
others (Raskin, et al., 2006; Wernicke et al., 2007).

5.5. Considerations in the elderly population

Age itself is not a primary factor in determining treatment. In a
post hoc analysis of duloxetine studies, patients 65 years in both
active treatment and control groups were more likely to withdraw
due to AEs. However, efcacy responder rates were similar between
age groups (Wasan et al., 2009). Similarly, Semel et al. (2010) grouped
patients from 11 pregabalin studies in painful DPN or PHN into three
age groups1864, 6574, and 75 yearsand found no signicant
differences in efcacy or responder rates between the age groups. In
the subgroup of painful DPN patients, AE rates, with the exception of
dry mouth, were similar across age groups at the 300 mg/day dose.
However, distinct increases in dizziness, somnolence, and asthenia
were seen in the older age groups at the 600 mg/day dose, suggesting
use of higher pregabalin doses should be carefully considered in the
elderly (Semel et al., 2010).
Elderly patients may be more susceptible to cognitive or gait
impairment associated with TCAs and, less commonly, with pregabalin, gabapentin, and tramadol (Dworkin et al., 2007), potentially
predisposing elderly patients to falls and injuries related to falls,
including traumatic brain injury, fractures, and lacerations. Cardiac
risks with TCAs are higher in older patients, and anticholinergic
symptoms may be a greater burden for older patients in whom
autonomic symptoms, such as dry mouth and orthostasis, are
common. Accidental fatal overdose is a concern in elderly patients
who may be taking multiple medications; amitriptyline in particular
should be avoided in elderly patients (Dworkin et al., 2007).

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Table 6
Adverse events typical of drug classes used to treat painful diabetic peripheral neuropathy.
Drug class

Common AEs

Potentially serious AEs

Contraindications

Considerations

TCAs (Boulton, 2011;

Dworkin et al., 2007;
Gimbel et al., 2003;
Watson et al., 2005)

Anticholinergic and antimuscarinic effects in up to 84%

of patients

Cardiac conduction
effects

Up to 1 in 3 patients do not
tolerate even the lowest dosage

Sudden cardiac death

Weight gain

Secondary amines typically better

tolerated than tertiary amines

Screening ECG recommended in

patients N40 years old

Commonly implicated in accidental

or intentional overdose

Avoid use in elderly patients

Duloxetine may have additive effects

when coadministered with narcotics

Incidence of AEs typically increase

with dose

15 to 20% of duloxetine-treated
subjects discontinued due to AEs

Duloxetine has been associated with

small changes in heart rate and cardiac
conduction, but these changes are not
felt to be clinically meaningful

AEs are typically dose dependent

Comparatively low risk of

life-threatening toxicity at high doses

Renal clearance requires

dose adjustment
in renal insufciency (CrCl 30)

In painful DPN trials, 15% of

patients receiving 600 mg/day
pregabalin discontinuations
due to AEs

In 1 published trial of gabapentin in

painful DPN,
8% of discontinuations were due to AEs

Similar incidence of AEs with

immediate- and extendedrelease formulations

AEs of similar nature but less frequent

with tramadol than with opioids

In head-to-head comparisons, opioids

have produced side effects more
frequently than TCAs and gabapentin

Renal clearance requires dose adjustment in renal insufciency (CrCl 30)

Orthostatic hypotension

SNRIs (Allgulander et al., 2008;

Dworkin et al., 2007;
Gahimer et al., 2007;
Khan & Macaluso, 2009;
Montgomery, 2008;
Moore et al., 2014;
Perahia et al., 2008;
Raskin, Wang, Pritchett &
Goldstein, 2006;
Robinson-Papp & Simpson, 2007;
Rowbotham et al., 2004;
Sultan et al., 2008;
Wernicke et al., 2007)

Nausea in up to 25% of
patients in duloxetine trials

Clinically important ECG

changes (venlafaxine)

Diarrhea, vomiting,
abdominal pain

Anticholinergic effects
(sweating, dry
mouth, constipation)

Dose-dependent
increases in
blood pressure

2- anticonvulsants
(Dworkin et al., 2007;
Freeman, 2013;
Gilron et al., 2005;
Sansone & Sansone, 2009)

Opioids and tramadol

(Dworkin et al., 2007;
Freeman et al., 2007;
Gaskell et al., 2014;
McNicol et al., 2013;
Wood & Galligan, 2004)

Cardiac disease,
including unstable
angina, recent
myocardial infarction,
heart failure, and
abnormal
cardiac conduction

Glaucoma

Liver or renal disease

(duloxetine)

Anxiety, insomnia

Somnolence
Dizziness
Peripheral edema

Edema in patients
with CHF

There have been postmarketing reports of CHF

in some, mostly elderly
CV-compromised,
patients. Pregabalin
should be used with
caution in these patients

Weight gain 7% in 5%
of patients

Nausea, constipation in N30%

of patients

Tramadol may potentiate

seizure disorder

Drowsiness in N30% of patients

Risk of opioid
dependence

Risk of suicide and

driving impairment

Liver or renal disease

(extended-release
formulations)

Nausea associated with duloxetine

may be reduced if titrated over
1 week

No clear tolerability advantages

between pregabalin and gabapentin

AE, adverse event; CrCl, creatinine clearance; DPN, diabetic peripheral neuropathy; SNRI, serotoninnorepinephrine reuptake inhibitor; TCA, tricyclic antidepressant.

6. Options after rst-line treatment

In the majority of painful DPN patients, rst-line monotherapy
does not provide satisfactory relief at maximally tolerated doses
(Dworkin et al., 2007; Pluijms et al., 2010). In such cases, options
include switching to a different agent within the same class, switching
to a new class, or adding a second agent (combination therapy)
(Fig. 1).
6.1. Switching agents
When switching treatment, one should consider overlapping both
agents and then tapering the rst to avoid deterioration in pain
control and onset of discontinuation symptoms. There is scarce
evidence to support switching from one to another agent in the same
therapeutic category (ie, gabapentin to pregabalin; TCAs to SNRIs).

Freynhagen et al. (2007) reported a trend toward improvement in a

small (n = 15) sample of patients switched from unsuccessful
treatment with gabapentin (1200 to 3600 mg/day) to pregabalin,
but this improvement was not signicant. Switching from gabapentin
to duloxetine is also not supported by the literature. In an open-label
trial of DPN patients who had previously inadequate pain relief on
gabapentin and then were treated for 12 weeks with duloxetine,
pregabalin, or gabapentin + duloxetine, Tanenberg et al. (2011)
reported reductions in pain from baseline for each treatment group
but no signicant differences between treatment groups in pain
reduction or proportion of responders.
The NICE guideline suggests switching to one of the 3 remaining
drugs of the 4 it recommends as rst-line choices for patients who have
an inadequate response or cannot tolerate their initial therapy. A second
treatment failure should trigger another switch among the 4 rst-line
treatments. While acknowledging that combination therapy may be

D. Ziegler, V. Fonseca / Journal of Diabetes and Its Complications 29 (2015) 146156

153

Fig. 1. Treatment of painful diabetic peripheral neuropathy.

useful, the guideline stopped short of recommending the use of

combination therapies, because data are insufcient to support such a
recommendation (National Institute for Health & Clinical Excellence).
6.2. Adding a second agent
The use of combination therapy is common in clinical practice, and
guidelines recommend combination regimens when rst-line treatment is insufcient. Adding a second agent may allow down-titration
of the initial agent, which may have advantages for tolerability
(National Institute for Health & Clinical Excellence). All of the
guidelines, with the exception of AACE and NICE, provide recommendations on adding a second agent, provided there is at least some
response to the rst-line agent. The Toronto guidelines provide the
most rudimentary guidance, recommending the addition of an agent
of another class if pain control is inadequate (Tesfaye et al., 2011).
Tramadol-containing combinations are reserved for third-line use in
these guidelines, and opioid-containing regimens are not recommended in the primary care setting (their use is to be restricted to
specialist practitioners).
The AAN guidelines recommended, with level C evidence (one
class 2 study), adding venlafaxine to gabapentin in patients with
inadequate pain relief on gabapentin monotherapy. In a placebocontrolled study, patients on venlafaxine + gabapentin combination
therapy demonstrated a signicant improvement from baseline in
pain score (2.0 decrease on an 11-point Likert scale; P b 0.001),
compared to a 0.5-point decrease in the gabapentin plus placebo
group (Simpson, 2001). These results are in contrast with the above
study by Tanenberg et al (2011), which found that in patients with
inadequate response to gabapentin, the addition of duloxetine did not
provide signicant advantages over maintaining gabapentin monotherapy. More recently, the COMBO-DN studywhich investigated
whether combining duloxetine and pregabalin in 339 nonresponders

to standard dosages of either drug alone was superior to increasing

either drug alone to its maximum dosageshowed that there was no
signicant difference between duloxetinepregabalin combination
therapy (at 60 and 300 mg/day, respectively) and maximum-dosage
monotherapy (120 mg/day duloxetine or 600 mg/day pregabalin) in
patients initially unresponsive to standard dosages. Combination
therapy did, however, trend toward numerically greater efcacy on
the primary endpoint (Brief Pain Inventory Modied Short Form) and
on multiple secondary endpoints, including 50% response rates (52.1%
on combination therapy vs. 39.3% on high-dose monotherapy)
(Tesfaye et al., 2013).
The EFNS guidelines reported level A evidence of efcacy for
combining gabapentin with TCAs in patients with partial but
insufcient response to either monotherapy, based on one class 1
study (National Institute for Health & Clinical Excellence). Gilron et al.
(2009) compared gabapentin and nortriptyline, alone or in combination, in a double-blind, crossover study in patients with painful DPN or
PHN. In the subset of 33 painful DPN patients who completed 2
treatment arms, pain scores were signicantly lower at the end of
combination therapy (2.2) vs. either nortriptyline (2.9) or gabapentin
(3.1) alone. Maximal doses of gabapentin and nortriptyline were also
signicantly lower in the combination group than in either monotherapy group. The incidence of somnolence was notably higher with
combination treatment (8%) compared with monotherapy (2% for
gabapentin and nortriptyline). For the other AEs, incidence rates
generally fell between the 2 monotherapy arms, suggesting that AEs
are not additive with this combination.
Level A evidence was also demonstrated for combining gabapentin
with an opioid based on two class 1 studies. In a crossover study, 57
patients (35 with painful DPN, 22 with PHN) were treated for 5 weeks
with active placebo (lorazepam), morphine ER, gabapentin, or
morphine + gabapentin (Gilron et al., 2005). Pain scores were
signicantly improved with combination therapy vs. either

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monotherapy. Mean maximal doses of morphine and gabapentin

were lower in the combination arm vs. the monotherapy arms. In the
second study, patients with DPN and moderate to severe pain (5 out
of 10) despite maximally tolerated gabapentin treatment received
add-on treatment with oxycodone ER or placebo for up to 12 weeks
(Hanna et al., 2008). Patients who received add-on oxycodone had
signicantly better pain relief compared with those who remained on
gabapentin monotherapy. Additional benets included less use of
rescue medication and improved sleep. Combination therapy was
associated with more frequent treatment-emergent AEs and more
withdrawals due to AEs than gabapentin.
In a study that can be interpreted as an assessment of oxycodone ER
as add-on therapy, patients with painful DPN (baseline pain: 6.9/10)
were treated with oxycodone ER or placebo in a double-blind fashion for
6 weeks (Gimbel et al., 2003). Approximately 60% of enrolled subjects
were on stable regimens of non-narcotic analgesics, primarily anticonvulsant and antidepressants. Twenty-two of 24 patients who took
anticonvulsants were taking gabapentin, and 27 of 35 subjects who took
TCAs were taking amitriptyline. Published data only included results
from weeks 4 to 6, after the initial titration period. During this interval,
pain scores were signicantly lower in the oxycodone group (4.1) than
in the placebo group (5.3).
Yet, a recent Cochrane review (Gaskell et al., 2014), which
included the study by Gimbel described above (Gimbel et al., 2003)
as well as two placebo-controlled trials of oxycodone controlled
release monotherapy reported by Watson et al, concluded there is no
convincing, unbiased evidence that oxycodone controlled release is of
value in treating patients who have painful DPN. Consistent with the
extant guidelines, controlled release oxycodone is best reserved for
use as add-on only in specialty pain treatment settings for select
patients who are at little risk of opioid abuse and dependence.
6.3. Drug-sparing effect
An important question is whether low-dose combinations yield
more benet than high-dose monotherapy. Studies that compared
gabapentin + morphine and gabapentin + nortriptyline combination regimens with their respective monotherapies appear to support
this hypothesis (Gilron et al., 2005; Gilron et al., 2009). A drug-sparing
effect has also been seen with oxycodone-containing combination
regimens (Hanna et al., 2008). It remains to be addressed whether
combination therapy should be used only after reaching maximum
tolerable dose of a single agent or if earlier use of combination therapy
may provide advantages.
7. Discussion
Painful DPN exacts a heavy toll on patients, including impaired QoL,
sleep disturbances, and effects on depression and anxiety. In randomized controlled trials, a number of agents have been shown to improve
pain and other outcomes in DPN patients. Yet less than half of patients
will achieve meaningful improvements in pain and global outcomes.
Recent treatment guidelines provide up to six rst-line treatment
options for painful DPN. Direct and indirect comparisons suggest
similar efcacies among rst-line treatment options. In reporting a
recent systematic review and meta-analysis of pharmacologic
therapies for painful DPN that included 58 studies and 11,883
patients, Snedecor et al. (2014) observed that despite the large
number of treatments available, the relative equivalence of their
treatment effects means that the best treatment is only slightly
better than the worst. Therefore, based solely on efcacy, it is difcult
to choose one option over another. As such, other factors must inform
the choice of treatment, and treatment should be tailored to the
characteristics and needs of individual patients (Brix Finnerup et al.,
2013). The presence of comorbiditiessuch as sleep disturbance,
mood disorders, body weight, and cardiovascular risk factors and

diseasescan help guide treatment, and addressing such comorbidities as they manifest with pain is essential to successful management
of pain (Vinik & Casellini, 2013).
Also, dose-limiting side effects are often an obstacle to maximally
effective treatment of painful DPN, and the likelihoodand ramicationsof such side effects in a given patient should be considered
when selecting treatment for painful DPN. Signicant weight gain
occurs in a large proportion of patients treated with 2- ligands and
TCAs. TCAs, and to a lesser degree duloxetine, may have adverse
effects on glucose control. Cardiac safety is an issue with both TCAs
and some SNRIs (venlafaxine). In addition, the risk of drug toxicity
due to DDI and hepatic and renal disease may restrict treatment
options. Safety and tolerability issues are especially important in
elderly patients.
As noted by Bril et al. (2012) in a recent review and comparison of
guidelines, there are noticeable gaps in the care of patients with
painful DPN. These gaps include consistent guidance around switching therapies or using combination therapies when treatment effect is
lost or insufcient. Also, the safety and efcacy of medications for
treating painful DPN over time are poorly understood, as is how long
treatment should be maintained or under what conditions it should
be discontinued. Data are needed that provide guidance for more
effective individualization of treatment. Initiatives are underway that
may facilitate such individualized treatment in the future.
8. Author contributions
DZ and VF contributed equally to the development of this paper by
making substantial contributions to the conception of this review and
to the interpretation of the material discussed; by revising it critically
for important intellectual content; and by giving nal approval of the
version to be published.
Acknowledgments
Medical writing support for this paper was provided by Karl
Torbey, MD and Gregory Bezkorovainy, MA, both of Adelphi
Communications, New York. This support was funded by Daiichi
Sankyo, Inc.
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