DIABETES/METABOLISM RESEARCH AND REVIEWS REVI EW ARTI CLE

Diabetes Metab Res Rev 2008; 24(Suppl 1): S52S57.

Published online 8 April 2008 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/dmrr.817
Painful diabetic neuropathy: treatment and future
aspects
Dan Ziegler*
Institute of Clinical Diabetes
Research, German Diabetes Center,
Leibniz Center at the Heinrich Heine
University, D usseldorf, Germany
*Correspondence to: Dan Ziegler,
Institute of Clinical Diabetes
Research, German Diabetes Center,
Leibniz Center at the Heinrich Heine
University, D usseldorf, Germany.
E-mail:
dan.ziegler@ddz.uni-duesseldorf.de
Received: 9 October 2007
Revised: 14 November 2007
Accepted: 6 December 2007
Summary
Around one of three diabetic patients is affected by distal symmetric
polyneuropathy (DSP) which represents a major health problem, as it
may present with partly excruciating neuropathic pain and is responsible
for substantial morbidity and increased mortality. Treatment is based
on four cornerstones: (1) multifactorial intervention aimed at (near)-
normoglycaemia and reduction in cardiovascular risk factors, (2) treatment
based on pathogenetic mechanisms, (3) symptomatic treatment, and
(4) avoidance of risk factors and complications. Among the pathogenetic
treatments only -lipoic acid and epalrestat are available for treatment in
several countries. Neuropathic pain, which is present in 826% of diabetic
patients, exerts a substantial impact on the quality of life, particularly
by causing considerable interference in sleep and enjoyment of life. Non-
pharmacologic options such as nerve or muscle stimulation should always
be given consideration. Among the centrally acting analgesic drugs for many
years mainly the tricyclic antidepressants (TCA), carbamazepine, gabapentin,
and opioids have been used to treat neuropathic pain. More recently,
signicant pain relief has been reported in clinical trials of painful diabetic
neuropathy using agents such as the dual selective serotonin noradrenaline
reuptake inhibitor (SNRI), duloxetine and the anticonvulsant pregabalin,
a specic modulator of the
2
subunit of the voltage-dependent calcium
channels. A promising new anticonvulsant is lacosamide. In future, drug
combinations might also include those aimed at symptomatic pain relief and
quality of life on one hand and improvement or slowing the progression of
the underlying neuropathic process on the other hand. Copyright 2008
John Wiley & Sons, Ltd.
Keywords neuropathic pain; treatment; diabetic neuropathy
Clinical impact and epidemiology
Diabetic neuropathy has been dened as a demonstrable disorder, either
clinically evident or subclinical, that occurs in the setting of diabetes mellitus
without other causes for peripheral neuropathy. It includes manifestations in
the somatic and/or autonomic parts of the peripheral nervous system [1],
which are being classied along clinical criteria. However, because of the
variety of the clinical syndromes with possible overlaps, there is no univer-
sally accepted classication. The most widely used classication differentiates
between rapidly reversible, persistent symmetric polyneuropathies, and focal
or multifocal neuropathies [2]. The distal symmetric sensory or sensorimotor
polyneuropathy (DSP) represents the most relevant clinical manifestation
affecting approximately 30% of the hospital-based population and 25% of
community-based samples of diabetic patients [3]. The incidence of DSP is
Copyright 2008 John Wiley & Sons, Ltd.
Treatment of Painful Neuropathy S53
approximately 2% per year. The most important aetiolog-
ical factors that have been associated with DSP are poor
glycaemic control, diabetes duration and height, with
possible roles for hypertension, age, smoking, hypoinsuli-
naemia, and dyslipidaemia [3]. There is accumulating
evidence suggesting that not only surrogate markers of
microangiopathy such as albuminuria but also those used
for polyneuropathy such as nerve conduction velocity
(NCV) and vibration perception threshold (VPT) may pre-
dict mortality in diabetic patients [4,5]. Elevated VPT also
predicts the development of neuropathic foot ulceration,
one of the most common causes for hospital admission
and lower limb amputations among diabetic patients [6].
Pain is a subjective symptom of major clinical importance
as it is often this complaint that motivates patients to seek
health care. Chronic neuropathic pain has been observed
in 826% of diabetic patients, respectively [3,7,8]. Pain
associated with diabetic neuropathy exerts a substantial
impact on the quality of life, particularly by causing con-
siderable interference in sleep and enjoyment of life [9].
Despite this signicant impact, in one survey 39% of the
diabetic patients had no treatment for their neuropathic
pain [7].
Distal symmetric polyneuropathy
The term hyperglycaemic neuropathy has been used to
describe sensory symptoms in poorly controlled diabetic
patients, which are rapidly reversible following institution
of near-normoglycaemia [2]. The most frequent form is
the DSP commonly associated with autonomic involve-
ment. The onset is insidious, and, in the absence of
intervention, the course is chronic and progressive. The
reduction or loss of small bre-mediated sensation results
in loss of pain sensation (heat pain, pin-prick) and tem-
perature perception to cold (A) and warm (C) stimuli.
Large bre involvement leads to nerve conduction slow-
ing and reduction or loss of touch, pressure, two-point
discrimination, and vibration sensation that may lead to
sensory ataxia (atactic gait) in severe cases. Sensory bre
involvement causes positive sensory symptoms such as
paraesthesiae, dysaesthesiae, and pain, as well as nega-
tive symptoms such as reduced sensation.
Persistent or episodic pain that typically may worsen
at night and improve during walking is localized pre-
dominantly in the feet. The pain is often described as a
deep-seated aching, but there may be superimposed lan-
cinating stabs, or it may have a burning thermal quality.
Evoked pain such as allodynia (pain due to a stimulus that
does not normally cause pain, e.g. stroking) and hyperal-
gesia (severe pain due to a stimulus that normally causes
slight pain, e.g. pin-prick) may be present. The symptoms
may be accompanied by sensory loss, but patients with
severe pain may have few clinical signs. Pain may per-
sist over several years causing considerable disability and
impaired quality of life in some patients, whereas it remits
partially or completely in others, despite further deterio-
ration in small bre function. Pain remission tends to be
associated with sudden metabolic change, short duration
of pain or diabetes, preceding weight loss, and less severe
sensory loss [10].
Treatment based on pathogenetic
concepts
Recent experimental studies suggest a multifactorial
pathogenesis of diabetic neuropathy [1115]. From the
clinical point of view, it is important to note that, based
on the various pathogenetic mechanisms, therapeutic
approaches could be derived, some of which have been
evaluated in randomized clinical trials. These drugs have
been designed to favourably inuence the underlying
neuropathic process rather than for symptomatic pain
treatment. For clinical use, -lipoic acid is licensed
and used for treatment of symptomatic DSP in several
countries worldwide, while epalrestat is marketed in
Japan and India. According to a recent meta-analysis
comprising 1258 patients, infusions of -lipoic acid
(600 mg i.v./day) ameliorated neuropathic symptoms and
decits after 3 weeks, while the ALADIN III Study showed
oral treatment with 600 mg t.i.d. resulted in a favourable
effect on neuropathic decits after 6 months [16,17].
Moreover, the SYDNEY 2 Trial suggests that treatment
for 5 weeks using 600 mg of -lipoic acid orally q.d.
reduces the chief symptoms of diabetic polyneuropathy
including pain, paraesthesias, and numbness to a clinically
meaningful degree [18]. Clinical and post-marketing
surveillance studies have revealed a highly favourable
safety prole of this drug. Results from a phase III
trial of the PKC inhibitor ruboxistaurin have been
disappointing after encouraging data fromphase II studies
had been reported [19]. The aldose reductase inhibitor
ranirestat [20], C-peptide [21], and other compounds
seem promising [22]. Since in the foreseeable future
normoglycaemia will not be achievable in most diabetic
patients, the advantage of the aforementioned treatment
approaches is that they may exert their effects despite
prevailing hyperglycaemia. Experimental studies of low-
dose combined drug treatment suggest enhanced drug
efcacy mediated by facilitatory interactions between
drugs. In the future, combinations of drugs that produce
synergistic effects could be a therapeutic option.
Symptomatic treatment of painful
neuropathy
Pain associated with diabetic neuropathy exerts a
substantial impact on the quality of life, particularly by
causing considerable interference in sleep and enjoyment
of life. Pain is a subjective symptom of major clinical
importance as it is often this complaint that motivates
patients to seek health care. Painful symptoms in
diabetic polyneuropathy may constitute a considerable
management problem. The efcacy of a single therapeutic
Copyright 2008 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2008; 24(Suppl 1): S52S57.
DOI: 10.1002/dmrr
S54 D. Ziegler
Table 1. Treatment options for painful diabetic neuropathy
Approach Compound/measure Dose per day Remarks NNT
Optimal diabetes control Diet, OAD, insulin Individual adaptation Aim: HbA
1c
6.5%
Pathogenetically oriented
treatment
-Lipoic acid (thioctic acid)
a
600 mg i.v. infusion
12001800 mg orally
Duration: 3 weeks
Good safety prole
6.3
c
Symptomatic treatment Tricyclic antidepressants (TCA)
Amitriptyline (10) 25150 mg NNMH: 15 2.1
Desipramine (10) 25150 mg NNMH: 24 2.2/3.2
Imipramine (10) 25150 mg CRR 1.3/2.4/3.0
Clomipramine (10) 25150 mg NNMH: 8.7 2.1
Nortriptyline (10) 25150 mg plus Fluphenazine 1.2
d
SSNR
Duloxetine
b
60120 mg NNT 120 mg, 60 mg 5.3, 4.9
Anticonvulsants
Gabapentin 9003600 mg High dose 3.8/4.0
Pregabalin
b
300600 mg NNT 600 mg, 300 mg 5.9, 4.2
Weak opioids
Tramadol 50400 mg NNMH: 7.8 3.1/4.3
Local treatment
Capsaicin (0,025%) cream q.i.d. topically Max. duration:
68 weeks
8.1
Strong opioids
Pain resistant to standard
pharmacotherapy
Oxycodone Add-on treatment 2.6
Electrical spinal cord stimulation
(ESCS)
Invasive, specialist
required
Physical therapy TENS, medical gymnastics,
Balneotherapy,relaxation therapy
No AE
Acupuncture No AE
Psychological support Uncontrolled study
a
Available only in some countries.
b
Licensed in USA and EU.
c
50% symptom relief after 3 weeks.
d
Combined with uphenazine.
OAD, oral antidiabetic drugs; CRR, concentrationresponse relationship; NNMH, number needed for major harm; TENS, transcutaneous
electrical nerve stimulation; AE, adverse events; SSNRI, selective serotonin norepinephrine reuptake inhibitors.
agent is not the rule, and simple analgesics are usually
inadequate to control the pain. Therefore, various
therapeutic schemes have been previously proposed, but
none of them has been validated. Nonetheless, there is
agreement that patients should be offered the available
therapies in a stepwise fashion. Effective pain treatment
considers a favourable balance between pain relief and
side effects without implying a maximum effect. The
possible treatment options are summarized in Table 1.
The relative benet of an active treatment over a control
in clinical trials is usually expressed as the relative risk,
the relative risk reduction, or the odds ratio. However,
to estimate the extent of a therapeutic effect (i.e. pain
relief) that can be translated into clinical practice, it is
useful to apply a simple measure that serves the physician
to select the appropriate treatment for the individual
patient. Such a practical measure is the number needed
to treat (NNT), i.e. the number of patients that need
to be treated with a particular therapy to observe a
clinically relevant effect or adverse event in one patient.
This measure is expressed as the reciprocal of the absolute
risk reduction, i.e. the difference between the proportion
of events in the control group (Pc) and the proportion
of events in the intervention group (Pi): NNT = 1/(Pc-
Pi). The 95% condence interval (CI) of NNT can be
obtained from the reciprocal value of the 95% CI for the
absolute risk reduction. The NNT and NNMH (number
needed for major harm) for the individual agents used
in the treatment of painful diabetic neuropathy are given
in Table 1. The pros and cons for the different drugs,
considering some important comorbidities of diabetes and
neuropathic pain are summarized in Table 2.
Antidepressants
For more than 30 years psychotropic agents, among which
antidepressants have been evaluated most extensively,
constitute an important component in the treatment of
chronic pain syndromes. Several authors consider the
tricyclic antidepressants (TCA) to be the drug treatment
of choice for neuropathic pain [2325]. However, their
Table 2. Differential treatment of painful diabetic neuropathy
considering frequent comorbidities
Duloxe
tine
Pre
gabalin
Tri
cyclics
Opi
oids
-Lipoic
acid
Depression +
a
n
a
+ n n
Obesity n n n
Sleep disturbances + + + + na
Coronary heart disease n n n n
Autonomic neuropathy na na +
Effect: + = favourable; = unfavourable; n = neutral; nu = not avail-
able.
a
Anxiolytic effect in generalized anxiety disorder (GAD).
Copyright 2008 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2008; 24(Suppl 1): S52S57.
DOI: 10.1002/dmrr
Treatment of Painful Neuropathy S55
use is limited by relative high rates of adverse events
and several contraindications. Thus, there is a need for
agents that exert efcacy equal to or better than that
achieved with TCAs but have a more favourable side-effect
prole. Because selective serotonin reuptake inhibitors
(SSRIs) have been found to be less effective than TCAs
[23], recent interest has focussed on antidepressants with
dual selective inhibition of serotonin and noradrenaline
(SSNRI) such as duloxetine and venlafaxine. The efcacy
and safety of duloxetine was evaluated in three controlled
studies using a dose of 60 and 120 mg/Tag over 12 weeks
[2628]. In all three studies the average 24 h pain
intensity was signicantly reduced with both doses as
compared to placebo treatment, the difference between
active and placebo being achievement of statistical
signicance after 1 week. The response rates dened
as 50% pain reduction were 48.2% (120 mg/day),
47.2% (60 mg/day), and 27.9% (placebo), giving an
NNT of 4.9 (95% CI: 3.67.6) for 120 mg/day and
5.3 (3.88.3) for 60 mg/day. Initial pain intensity, but
not metabolic variables such as glycaemic control or
duration of diabetes were predictors of response [29]. The
most frequent side effects of duloxetine (60/120 mg/day)
include nausea (16.7/27.4%), somnolence (20.2/28.3%),
dizziness (9.6/23%), constipation 14.9/10.6%), dry
mouth (7.1/15%), and reduced appetite (2.6/12.4%).
These adverse events are usually mild to moderate and
transient. To minimize them the starting dose should be
30 mg/day for 45 days. In contrast with TCAs and some
anticonvulsants, duloxetine does not cause weight gain.
Calcium channel modulators
Gabapentin is an anticonvulsant structurally related to
-aminobutyric acid (GABA), a neurotransmitter that
plays a role in pain transmission and modulation. The
exact mechanisms of action of this drug in neuropathic
pain are not fully elucidated. Among others, they involve
an interaction with the system L-amino acid transporter
and high afnity binding to the
2
- subunit of voltage-
activated calcium channels. In an 8week multicentre
dose-escalation trial including 165 diabetic patients with
painful neuropathy, 60% of the patients on gabapentin
(3600 mg/day achieved in 67%) had at least moderate
pain relief compared to 33% on placebo. Dizziness and
somnolence were the most frequent adverse events in
about 23% of the patients each [30]. Pregabalin is a more
specic
2
- ligand with a six-fold higher binding afnity
than gabapentin. The efcacy and safety of pregabalin
was reported in a pooled analysis of eleven studies
over 513 weeks in 1510 diabetic patients with painful
neuropathy. The response rates dened as 50% pain
reduction were 47% (600 mg/day), 39% (300 mg/day),
27% (150 mg/day), and 22% (placebo), giving an NNT
of 4.0, 5.9, and 12.0 [31]. The most frequent side effects
for 150600 mg/day are dizziness (22.0%), somnolence
(12.1%), peripheral edema (10.0%), headache (7.2%),
and weight gain (5.4%). The evidence supporting a
favourable effect in painful diabetic neuropathy is
more solid and dose titration is considerably easier for
pregabalin than gabapentin. Although carbamazepine has
been widely used for treating neuropathic pain, it cannot
be recommended in painful diabetic neuropathy due to
very limited data.
Sodium channel blockers
Sodium channel blockers such as carbamazepine can-
not be recommended because of inadequate evidence in
painful diabetic neuropathy. The successor drug oxcar-
bazepine has been withdrawn from clinical trials [32].
Trials of other anticonvulsants such as topiramate [33]
and lamotrigine [34] have also produced disappointing
results, while lacosamide is being evaluated in phase III
trials.
Opioids
The weak opioid tramadol is effective in painful DSP,
but most severe pain requires administration of strong
opioids such as oxycodone. Although there is little data
available on combination treatment, combinations of
different substance classes have to be used in patients
with pain resistant to monotherapy. Two trials over 4
and 6 weeks have demonstrated signicant pain relief
and improvement in quality of life following treatment
with controlled-release oxycodone, a pure -agonist,
in a dose range of 10100 mg (mean 40 mg/day) in
patients with painful diabetic neuropathy whose pain
was not adequately controlled on standard treatment
with antidepressants and anticonvulsants that were not
discontinued throughout the trial [35,36]. As expected,
adverse events were frequent and typical of opioid-related
side effects. A recent study examined the maximum
tolerable dose of a combination treatment of gabapentin
and morphine as compared to monotherapy of each drug.
The maximum tolerable dose was signicantly lower and
efcacy was better during combination therapy than
with monotherapy, suggesting an additive interaction
between the two drugs [37]. The results of these
studies suggest that opioids should be included among
the therapeutic options for painful diabetic neuropathy,
provided that careful selection of patients unresponsive
to standard treatments, regular monitoring, appropriate
dose titration, and management of side effects are
ensured. Combination therapy using antidepressants
and anticonvulsants may also be useful, particularly if
monotherapy is not tolerated due to side effects.
Non-pharmacological treatment
Because there is no entirely satisfactory pharmacother-
apy of painful diabetic neuropathy, non-pharmacological
Copyright 2008 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2008; 24(Suppl 1): S52S57.
DOI: 10.1002/dmrr
S56 D. Ziegler
treatment options such as psychological support, tran-
scutaneous electrical nerve stimulation (TENS), or phys-
ical measures (e.g. cold water immersion) have been
tried. As for the pharmacological treatment, considerable
effort must also be made to develop effective non-
pharmacological approaches. We recently showed a better
effect of high frequency muscle stimulation than TENS on
neuropathic symptoms after 3 days [38]. A frequency-
modulated electromagnetic nerve stimulation (FREMS)
applied during ten sessions over 3 weeks resulted in a
signicant pain reduction as compared to placebo stimu-
lation [39]. Monochromatic infrared energy (MIRE) has
been shown to reduce neuropathic symptoms and signs
in diabetic patients in uncontrolled studies [40]. How-
ever, 30 min of active MIRE applied 3 days per week for
4 weeks was no more effective than placebo in increasing
sensation in subjects with diabetic peripheral neuropathy
[41], emphasizing the need for controlled studies in this
area to allow an evidence-based treatment decision.
Future aspects
Advanced knowledge in neurobiology of neuropathic pain
and an increasing perception of the commercial value
of analgesic agents have led to a burst of research
into novel pharmaceutical approaches. According to
a recent review, at least 50 new molecular entities
have reached clinical stage of development, including
glutamate antagonists, cytokine inhibitors, vanilloid-
receptor agonists, catecholamine modulators, ion-channel
blockers, anticonvulsants, opioids, cannabinoids, COX
inhibitors, acetylcholine modulators, adenosine receptor
agonists, and several miscellaneous drugs. Eight drugs
are in phase III trials at present. Strategies that may
show promise over existing treatments include topical
therapies, analgesic combinations, and, in future, gene-
related therapies [42].
Conclusions
Although considerable improvement in the quality of
controlled trials has recently been achieved, no major
breakthrough in slowing the progression of diabetic
neuropathy in the long run has been achieved with drugs
used on the basis of present pathogenetic concepts. Some
of the newer drugs have shown promising results in
phase II trials that require conrmation from large phase
III trials. It is conceivable that drugs interfering with
the pathogenesis of diabetic neuropathy may be most
effective in terms of prevention, rather than intervention.
Although several novel analgesic drugs have recently
been introduced into clinical practice, the pharmacologic
treatment of chronic painful diabetic neuropathy remains
a challenge for the physician. Individual tolerability
remains a major aspect in any treatment decision. Almost
no information is available from controlled trials on long-
term analgesic efcacy, and only a few studies have used
drug combinations. Combination drug use or the addition
of a new drug to a therapeutic regimen may lead to
increased efcacy. In future, drug combinations may also
include those aimed at symptomatic pain relief and quality
of life on the one hand, and improvement or slowing of
the progression of the underlying neuropathic process on
the other hand.
Conflict of interest
Dan Ziegler has received honoraria, research grants, or
consulting fees fromLilly (duloxetine), Pzer (pregabalin,
gabapentin), Meda (alpha-lipoic acid), Schwarz-Pharma
(lacosamide), and Gr unenthal (tramadol).
References
1. Consensus statement. Report and recommendations of the San
Antonio conference on diabetic neuropathy. Diabetes Care 1988;
11: 592597.
2. Sima AAF, Thomas PK, Ishii D, Vinik A. Diabetic neuropathies.
Diabetologia 1997; 40: B74B77.
3. Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A,
KORA Study Group. Prevalence of polyneuropathy in pre-
diabetes and diabetes is associated with abdominal obesity
and macroangiopathy: the MONICA/KORA Augsburg Surveys
S2 and S3. Diabetes Care 2008; 31: 464469.
4. Forsblom CM, Sane T, Groop PH, et al. Risk factors for mortality
in Type II (non-insulin-dependent) diabetes: evidence of a role
for neuropathy and a protective effect of HLA-DR4. Diabetologia
1998; 4: 12531262.
5. Coppini DV, Bowtell PA, Weng C, Young PJ, S onksen PH.
Showing neuropathy is related to increased mortality in diabetic
patientsa survival analysis using an accelerated failure time
model. J Clin Epidemiol 2000; 53: 519523.
6. Abbott CA, Vileikyte L, Williamson S, Carrington AL, Boul-
ton AJM. Multicenter study of the incidence of and predictive
risk factors for diabetic neuropathic foot ulceration. Diabetes
Care 1998; 21: 10711075.
7. Daousi C, MacFarlane IA, Woodward A, Nurmikko TJ, Bun-
dred PE, Benbow SJ. Chronic painful peripheral neuropathy in
an urban community: a controlled comparison of people with
and without diabetes. Diabet Med 2004; 21: 976982.
8. Davies M, Brophy S, Williams R, Taylor A. The prevalence,
severity, and impact of painful diabetic peripheral neuropathy
in type 2 diabetes. Diabetes Care 2006; 29: 15181522.
9. Galer BS, Gianas A, Jensen MP. Painful diabetic neuropathy:
epidemiology, pain description, and quality of life. Diabetes Res
Clin Pract 2000; 47: 123128.
10. Benbow SJ, Chan AW, Bowsher D, MacFarlane IA, Williams G.
A prospective study of painful symptoms, small-bre function
and peripheral vascular disease in chronic painful diabetic
neuropathy. Diabet Med 1993; 11: 1721.
11. Boulton AJM, Malik RA, Arezzo JC, Sosenko JM. Diabetic
somatic neuropathies. Diabetes Care 2004; 27: 14581486.
12. Cameron NE, Eaton SE, Cotter MA, Tesfaye S. Vascular factors
and metabolic interactions in the pathogenesis of diabetic
neuropathy. Diabetologia 2001; 44: 19731988.
13. Ziegler D. Glycemic control. In Textbook of Diabetic Neuropathy,
Gries FA, Cameron NE, Low PA, Ziegler D (eds). Thieme:
Stuttgart, New York, 2003; 9196.
14. Martin CL, Albers J, Herman WH, et al., DCCT/EDIC Research
Group. Neuropathy among the diabetes control and
complications trial cohort 8 years after trial completion. Diabetes
Care 2006; 29(2): 340344.
15. The Diabetes Control and Complications Trial Research Group.
The absence of a glycemic threshold for the development of long-
term complications: the perspective of the Diabetes Control and
Complications Trial. Diabetes 1996; 45: 12891298.
Copyright 2008 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2008; 24(Suppl 1): S52S57.
DOI: 10.1002/dmrr
Treatment of Painful Neuropathy S57
16. Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment
of symptomatic diabetic polyneuropathy with the antioxidant
-lipoic acid: a meta-analysis. Diabet Med 2004; 21: 114121.
17. Ziegler D. Thioctic acid for patients with symptomatic diabetic
neuropathy. A critical review. Treat Endocrinol 2004; 3: 117.
18. Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-
lipoic acid improves symptomatic diabetic polyneuropathy: the
SYDNEY 2 trial. Diabetes Care 2006; 29: 23652370.
19. Vinik AI, Bril V, Kempler P, et al., The MBBQ Study Group.
Treatment of symptomatic diabetic peripheral neuropathy with
the protein kinase Cbeta-inhibitor ruboxistaurinmesylate during
a 1-year, randomized, placebo-controlled, double-blind clinical
trial. Clin Ther 2005; 27: 11641180.
20. Bril V, Buchanan RA. Long-term effects of Ranirestat (AS-
3201) on peripheral nerve function in patients with diabetic
sensorimotor polyneuropathy. Diabetes Care 2006; 29: 6872.
21. Ekberg K, Brismar T, Johansson BL, et al. C-Peptide replacement
therapy and sensory nerve function in type 1 diabetic
neuropathy. Diabetes Care 2007; 30: 7176.
22. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a
statement by the American diabetes association. Diabetes Care
2005; 28: 956962.
23. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH.
Algorithm for neuropathic pain treatment: an evidence based
proposal. Pain 2005; 118: 289305.
24. Finnerup NB, Jensen TS. Mechanisms of disease: mechanism-
based classication of neuropathic pain-a critical analysis. Nat
Clin Pract Neurol 2006; 2: 107115.
25. Jensen TS, Backonja MM, Hernandez Jimenez S, Tesfaye S,
Valensi P, Ziegler D. New perspectives on the management of
diabetic peripheral neuropathic pain. Diab Vasc Dis Res 2006; 3:
108119.
26. Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. Duloxetine vs.
placebo in patients with painful diabetic neuropathy. Pain 2005;
116: 109118.
27. Raskin J, Pritchett YL, Wang F, et al. A double-blind,
randomized multicenter trial comparing duloxetine with placebo
in the management of diabetic peripheral neuropathic pain. Pain
Med 2005; 6: 346356.
28. Wernicke JF, Pritchett YL, DSouza DN, et al. A randomized
controlled trial of duloxetine in diabetic peripheral neuropathic
pain. Neurology 2006; 67: 14111420.
29. Ziegler D, Pritchett YL, Wang F, et al. Impact of disease
characteristics on the efcacy of duloxetine in diabetic peripheral
neuropathic pain. Diabetes Care 2007; 30: 664669.
30. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the
symptomatic treatment of painful neuropathy in patients with
diabetes mellitus. JAMA 1998; 280: 18311836.
31. Freeman R, Rosenstock J, Emir B, Durso-Deeruz E. Pooled
analysis of 7 randomized, controlled trials of pregabalin for
the treatment of painful diabetic peripheral neuropathy (DPN):
efcacy, safety, tolerability. Diabetologia 2007; 50(Suppl. 1):
S62S63.
32. Dogra S, Beydoun S, Mazzola J, Hopwood M, Wan Y.
Oxcarbazepine in painful diabetic neuropathy: a randomized,
placebo-controlled study. Eur J Pain 2005; 9: 543554.
33. Thienel U, Neto W, Schwabe SK, Vijapurkar U, Topiramate
Diabetic Neuropathic Pain Study Group. Topiramate in
painful diabetic polyneuropathy: ndings from three double-
blind placebo-controlled trials. Acta Neurol Scand 2004; 110:
221231.
34. 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: 169170.
35. Watson CP, Moulin D, Watt-Watson J, Gordon A, Eisenhoffer J.
Controlled-release oxycodone relieves neuropathic pain: a
randomized controlled trial in painful diabetic neuropathy. Pain
2003; 105: 7178.
36. Gimbel JS, Richards P, Portenoy RK. Controlled-release
oxycodone for pain in diabetic neuropathy: a randomized
controlled trial. Neurology 2003; 60: 927934.
37. Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL.
Morphine, gabapentin, or their combination for neuropathic
pain. N Engl J Med 2005; 31(352): 13241334.
38. Reichstein L, Labrenz S, Ziegler D, Martin S. Effective treatment
of symptomatic diabetic polyneuropathy by high-frequency
external muscle stimulation. Diabetologia 2005; 48: 824828.
39. Bosi E, Conti M, Vermigli C, et al. Effectiveness of frequency-
modulated electromagnetic neural stimulation in the treatment
of painful diabetic neuropathy. Diabetologia 2005; 48: 817823.
40. Powell MW, Carnegie DH, Burke TJ. Reversal of diabetic
peripheral neuropathy with phototherapy (MIRE

) decreases
falls and the fear of falling and improves activities of daily living
in seniors. Age Ageing 2006; 35: 1116.
41. Clifft JK, Kasser RJ, Newton TS, Bush AJ. The effect of
monochromatic infrared energy on sensation in patients
with diabetic peripheral neuropathy: a double-blind, placebo-
controlled study. Diabetes Care 2005; 28: 28962900.
42. Gilron I, Coderre TJ. Emerging drugs in neuropathic pain. Expert
Opin Emerg Drugs 2007; 12: 113126.
Copyright 2008 John Wiley & Sons, Ltd. Diabetes Metab Res Rev 2008; 24(Suppl 1): S52S57.
DOI: 10.1002/dmrr