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Review

Neuropathic Pain in Type 2 Diabetes Mellitus Patients


Shin-Yi Tsao1

Hui-Chuan Hsu1

Chih-Chung Liu2

Hsiao-Lun Sun 2,3,*

Background and purpose: The definition, clinical presentation, and treatment of diabetic
neuropathic pain were reviewed. Results: The estimated prevalence of diabetic neuropathic pain
is up to 22% based on a population of 270 million in the US. Diabetic neuropathy is one of the most
common complications of type 2 diabetes mellitus (T2DM). Diabetic neuropathic pain is a
sensorimotor neuropathy, or a distal symmetrical polyneuropathy, which is the most common type
of excruciating, refractory pain in T2DM patients. Positive symptoms include pain and
paresthesia. Patients complain about burning, tingling, aching, cold sensation, lancinating pain,
numbness, or pain from normal touch. Painful symptoms occur in a part (11%-32%) of neuropathic
patients with diabetes and do not correlate with diminished nerve conduction velocity. Thus
electrophysiological testing is rarely needed according to the recommendations of the American
Diabetes Association in 2010. The multifactorial pathogenesis of diabetic neuropathy suggested by
recent research includes the polyol pathway, oxidative stress, advanced glycation end products,
and protein kinase C. Medications for relief of diabetic neuropathic pain are recommended to
improve the quality of life. For neuropathic pain control, the efficacy of tricyclic antidepressants,
gabapentin, pregabalin, opioids, and tramadol is documented. Selective serotonin noradrenaline
reuptake inhibitors, topical lidocaine, and transcutaneous electrical stimulation are therapies with
some evidence of efficacy. Conclusions: Treatment is a great challenge, and has to be
individualized to each patient, by taking into account side effects, pain type, comorbidities, and
drug interactions. As poor glycemic control may worsen diabetic neuropathic pain, it is important
to achieve a glucose target as rapidly as possible. ( FJJM 2010; 8 (1) : 39-47 )
Key words: diabetic neuropathic pain, distal symmetric polyneuropathy, diabetic
peripheral neuropathic pain, type 2 diabetes mellitus

INTRODUCTION
Diabetic neuropathy is the most common
complication of type 2 diabetes mellitus (T2DM).
Diabetic neuropathic pain is a sensorimotor
neuropathy or a distal symmetrical polyneuropathy
(DPN), whichis the most common type of neuropathy,

with excruciating, refractory pain[1]. Approximately


50% of patients with diabetes develop a peripheral
neuropathy in their lifetime[2]. The estimated
prevalence of diabetic neuropathic pain is up to
22% out of 270 million in US[3-5]. Approximately
1/3 of all diabetic patients with DPN exhibit diabetic
peripheral neuropathic pain (DPNP)[18]. Glycemic

Division of Endocrinology and Metabolism, Department of Internal Medicine, Sijhih Cathay General Hospital1
Anesthesiology, Sijhih Cathay General Hospital2 Department of Medicine, Fu-Jen Catholic University3
Submitted March, 8, 2010; final version accepted March, 31, 2010.
*Correspondence author: hlsun@cgh.org.tw

8 1 2010

Department of

39

Shin-Yi Tsao

Hui-Chuan Hsu

Chih-Chung Liu

Hsiao-Lun Sun

control has the most important role in managing


diabetic neuropathic pain, for in prevention as well
as reduction. However, medical therapy is always
needed for patients with diabetic neuropathic pain.
The risk factors for diabetic neuropathy include
hyperglycemia, patient age, cigarette smoking,
alcoholconsumption,hypertension,hypercholesterolemia,
and height[6-8]. This article reviews the symptoms,
classification, mechanisms, and treatment of diabetic
neuropathic pain.
Symptoms of diabetic neuropathic pain
The diagnosis of neuropathic pain secondary
to diabetic neuropathy requires a comprehensive
history-taking, as well as physical and neurological
examinations[9]. Pain typically occurs symmetrically
in the feet and ankles (i.e., glove and stocking
distribution)[10]. Patients should be asked about
the quality (e.g., burning, shooting, or electric),
intensity, and duration of spontaneous pain as well
as its location[11]. The symptoms are pain and
paresthesia, and patients ussually complain of
burning, tingling, aching, a cold sensation, lancinating
pain, numbness, allodynia[12-15], or a persistent,
achy feeling in the feet and cramp-like sensations
in the legs[16]. The pain can involve the feet with
extension to the legs, and it can also involve the
upper limbs. Sensory loss is also found. Diabetic
neuropathic pain is more severe at night, and it
often induces poor sleep[17]. Some patients may
experience chronic fatigue syndrome because of
sleep deprivation[17]. Others are unable to maintain
full employment. Severe painful neuropathy can
occasionally cause a marked reduction in the
exercise threshold, so as to interfere with daily
activities[18]. This is particularly the case when
there is associated severe, disabling postural
hypotension due to autonomic involvement[18].
Depression and anxiety are major negative impacts
on the quality of life (QOL)[17]. There is also

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decreased physical activity and mobility[19].The


pain quality and intensity can be estimated with
the Neuropathic Pain Scale, the Neuropathic Pain
Questionnaire, and other scales[11]. Global function,
sleep, psychological comorbidity, and other issues
should be assessed to determine the effect of diabetic
neuropathic pain on the QOL, using a neuropathyspecific tool such as the Norfolk QOL-DN[20].
A diagnosis of diabetic neuropathic pain
requires a T2DM patient with neuropathy after
exclusion of other possible etiologies for the
neuropathy. The differential diagnoses include
alcoholic, idiopathic, nutritional, and many other
types of neuropathies, such as claudication, Morton's
neuroma, osteoarthritis, radiculopathy, Charcot's
neuroarthropathy, plantar fasciitis, or tarsal tunnel
syndrome[21]. Painful symptoms occur in a part
(11%-32%) of neuropathy patients with diabetes
and are not correlated with diminished nerve
conduction velocity (NCV) or functions[12,13,15].
Nerve conduction studies and electromyography
can assist in describing and confirming the
neuropathy. Electrophysiological nerve conduction
testing is useful to rule out other neuropathies and
identify atypical symptoms[21]. A nerve biopsy can
reveal the involvement of unmyelinated fibers,
which are not routinely evaluated and not required
by electrophysiological tests[22].Neuropathy associated
with changes in the intraepidermal nerve fiber
density and dendritic length was demonstrated in
patients with impaired glucose tolerance, a history
of T2DM for more than 5 years, and metabolic
syndrome[23-25].
Classification
Diabetic neuropathy affects sensory, autonomic,
and motor neurons of the peripheral nervous system
[1]
. Approximately, 1/3 of T2DM patients with DPN
exhibit DPNP[18]. Clinical symptoms of T2DM
patients include dysfunction of almost all segments

Fu-Jen Journal of Medicine Vol.8 No.1 2010

Diabetic neuropathic pain

of the somatic peripheral focally or diffusely, and


the autonomic nervous system[26]. The onset of
neuropathic pain may be acute or insidious, with
chronic pain as well as mixed sensorimotor
dysfunction. Diabetic neuropathic pain may result
from several varieties of diabetic neuropathies, the
most common of which is DPN. DPN can be further
divided into acute and chronic and into stimulusindependent and stimulus-evoked types[21]. Acute
diabetic neuropathic pain includes acute distal
sensory, acute thoracic radiculopathy, acute lumbar
radiculoplexopathy, and insulin neuritis[21]. Chronic
diabetic neuropathic pain include distal large fiber,
distal small fiber, proximal diabetic neuropathies
(chronic
inflammatory
demyelinating
polyradiculoneuropathy), andentrapmentneuropathies
(e.g., carpal tunnel syndrome)[21]. The acute sensory
neuropathy syndrome presents within the first 6
months of the diagnosis of diabetes[21]. It can be
sporadic, induced by periods of metabolic instability
such as ketoacidosis, poor glycemic control, or
fluctuating blood glucose levels, and is also commonly
seen with the introduction of insulin to improve
glycemic control[21]. Although symptoms can be
severe and are similar to those of the chronic variety,
it generally resolves spontaneously [21]. In acute
neuropathic pain, there is complete resolution of
symptoms within a year[27]. In contrast, the chronic
variety increases and decreases in intensity, but
remains for years[21]. The symptoms are usually
patient specific, but some are common to all patients,
such as hyperesthesia, a burning pain, stabbing or
shooting electric-type pains, and allodynia[21].
Mechanism of diabetic neuropathic pain in
T2DM
The exact pathophysiological mechanisms of
neuropathic pain in diabetes remain unknown
althoughseveralmechanismsincludingneurostructural
correlates for painful neuropathy were postulated

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[28]

. Peripheral mechanisms include changes in the


sodium channel distribution and expression, altered
neuropeptide expression, sympathetic sprouting,
peripheral sensitization, altered peripheral blood
flow, axonal atrophy, degeneration, or regeneration,
damage to small fibers, and glycemic flux[28]. Central
mechanisms are central sensitization, A fiber
sprouting into lamina II of the dorsal horn, and
reduced inhibition of descending pathways[28]. The
most common type of diabetic neuropathy is DPN,
which may affect large and/or small fibers and may
be either sensory or motor[21]. The major
neurotransmitter in small unmyelinated C fibers
is substance P as well as A fibers. Capsaicin
depletes substance P, and is usually effective for
C fiber pain[21]. Painful diabetic neuropathy is
caused by the involvement of small nerve fibers,
which may be affected without objective clinical
findings, such as decreased peripheral reflexes or
abnormalities on electrophysiological testing[21].
Small fiber neuropathies may manifest different
clinical symptoms, including allodynia, a burning
pain, defective warm thermal sensation, and defective
autonomic function, e.g., decreased sweating, dry
skin, and impaired vasomotor control[21]. In-vivo
studies showed an increase in sural nerve epineural
blood flow in individuals with diabetic neuropathic
pain compared to those with painless diabetic
peripheral neuropathy[29]. That study suggested
that nerve blood flow may be important in the
pathogenesis of neuropathic pain and treatments.
Diabetic neuropathic pain is differentiated from
other types of pain by injury or loss of primary
afferent nerve fibers (i.e., deafferentation)[11].
Allodynia, hyperalgesia, and spontaneous pain may
be related to ectopic nerve impulses or abnormal
expression of neurotransmitters and their receptors
and ion channels[11]. Insulin resistance is a risk
factor for chronic inflammation with atherosclerosis,
and neuropathy may develop through microvascular

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Shin-Yi Tsao

Hui-Chuan Hsu

Chih-Chung Liu

Hsiao-Lun Sun

degeneration. C-peptide and insulin deficiencies


can produce a self-limiting insulin neuritis that is
painful, but intensive insulin treatment of critically
ill patients reduces the development of neuropathy
[30,31]
. These chemical substances, which sensitize
nociceptors, may include prostaglandins, bradykinin,
serotonin, and histamine[32]. Sensitized nociceptors
become more responsive to previously effective
stimulation by increasing in discharge and lowering
the threshold [32]. The multifactorial pathogenesis
of diabetic neuropathy suggested by recent research
includes the polyol pathway, oxidative stress,
advanced glycation end products, and protein kinase
C[1]. Functional MRI showed a greater response in
the diabetic peripheral neuropathic pain group
include the primary somatosensory cortex, lateral
frontal, and cerebellar regions[33].
Treatment of diabetic neuropathic pain
Management of diabetic neuropathic pain is
a challenge for physicians. Careful history-taking
and peripheral neurological/vascular examinations
of patients are essential in order to exclude other
possible causes of leg pain such as peripheral
vascular disease, prolapsed intervertebral discs,
spinal-canal stenosis, etc.[18] Unilateral leg pain
should arouse suspicion that the pain may be due
to lumbar-sacral nerve root compression [18]. MRI
is needed to identify nerve root compression. The
quality and severity of the pain should be assessed
by a suitable pain rating scale, such as a visual
analogue scale (VAS) or numeric rating scale (NRS).
Glycemic control plays the most important role in
managing diabetic neuropathic pain, in both its
prevention and reduction. However, tight glycemic
control is not only based on medicine but is also
affected by a patient's diet, exercise, life modifications,
and underlying diseases. In addition to glucose,
risk factors include the patient's age, cigarette
smoking, alcohol consumption, hypertension,

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hypercholesterolemia, and height. Medical treatment


may benefit patients with diabetic neuropathic
pain due to improvements in the QOL. Many agents
are efficient in treating diabetic neuropathic pain,
and some agents are approved by the US Food and
Drug Administration (FDA).
Pharmacological treatment of diabetic
peripheral neuropathy
Tricyclic antidepressants (TCAs)
Severalrandomizedcontrolledtrialsdemonstrated
the efficacy of TCAs in diabetic neuropathic pain
[34-36]
. TCAs have many side effects including
anticholinergic effects such as a dry mouth, sweating,
sedation, and dizziness. Due to the exacerbation
of painful symptoms at bedtime, treatment is ideally
begun with a small dose of either amitripyline or
imipramine (10~25 mg) for pain control. The dose
initially needs to be low and gradually titrated
according to adverse events and efficacy. Recent
data from a retrospective study including 58,956
individuals after a year of follow-up on TCA therapy
indicated an increased risk of sudden cardiac death
associated with TCA doses in excess of 100 mg/
day[36]. Care should be taken for patients with
autonomic neuropathy and cardiovascular disease
so as not to exacerbate symptoms of postural
hypotensionwithTCAs. Treatingdiabeticneuropathic
pain with TCAs is an off-label use.
Selective serotonin noradrenaline reuptake
inhibitors (SNRIs)
SNRIs such as duloxetine relieve pain by
increasingsynapticavailability of5-hydroxytryptamine
and noradrenaline in the descending pathways that
are inhibitory to pain impulses. The efficacy of
duloxetine in painful DPN was investigated in
three identical trials[37-39]. The recommended dose
is 60~120 mg/day and is effective in relieving painful
symptoms. FDA has approved duloxetine to treat

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Diabetic neuropathic pain

diabetic neuropathic pain. It is efficient in 1 week,


and when maintained throughout a treatment
period of 12 weeks, about 45%~55% of patients
achieved at least 50% pain reduction.
Anticonvulsants
Gabapentin and pregabalin are calcium channel
modulators, which bind to the 2- ligand of the
calcium channel and thus reduce calcium flux, and
then results in reduced neurotransmitter release
in the hyperexcited neurons[18]. Gabapentin plays
a role in pain transmission and modulation, and is
titrated at 300~1200 mg/day tid. Pregabalin is a
more-specific 2- ligand with a 6-fold higher
binding affinity than gabapentin[40].In a recent
study included 67% of patients who received the
highest dose of gabapentin (3600 mg) in 4 weeks
achieved at least a 50% reduction in pain compared
to 32.9% with the placebo[41]. The recommended
dose is 100mg tid according to the FDA. The efficacy
of pregabalin for DPNP was also demonstrated
[41,42]
. Carbamazepine is also suggested by
recommendationofthe American DiabetesAssociation
(ADA) in 2010, and the suggested dose is 200~400
mg tid.
Opioid agonists
Tramadol, an opiate derivative, is efficient in
controling diabetic neuropathic pain[43]. Oxycodone,
in a slow-release form, is efficient in managing
neuropathic pain[44], and prolonged-release oxycodone
intensifies gabapentin therapy in patients with
diabetic neuropathic pain[46]. In 1 crossover study,
a low-dose combination therapy of gabapentin and
morphine was significantly more effective than
either monotherapy at a higher dose[45]. However,
there were more adverse effects with the combination
treatment than monotherapy [45].

Substance P inhibitor
Topical capsaicin (0.075%) applied sparingly
3 or 4 times per day to the affected area was found
to relieve neuropathic pain by depleting substance
Pfromnerveterminals[47].IntheADArecommendations
of 2010, the dose of capsaicin was 0.025%~0.075%
in cream applied tid to qid.
-Lipoic acid
-Lipoic acid is pathogenetically oriented
treatment with 600mg by intravenous infusion for
at least 3 weeks. -Lipoic acid reduces oxygen free
radicals and improves oxidative stress. A metaanalysis including 1258 patients from four prospective
trials showed that treatment with -lipoic acid
(600 mg/day intravenously) for 3 weeks was
associated with significant improvement in diabetic
neuropathic pain[48]. Oral -lipoic acid takes about
5 weeks to improve diabetic neuropathic pain[49].
Nonpharmacological treatments
Physical therapy is an alternative therapy for
patients who suffer from side effects or, and it may
co-exist with medicine to relieve diabetic neuropathic
pain. There are many alternative therapies such as
balneotherapy, relaxation therapy[40], acupuncture
[50]
, near-infrared phototherapy[51], low-intensity
laser therapy[52], magnetic field therapies[16],
transcutaneous electrical nerve stimulation[53],
frequency-modulated electromagnetic neural
stimulation therapy[54,55], high-frequency external
muscle stimulation[56], and even psychological
support. However, the efficacy of these alternative
treatments is inconclusive and depends on the
individual.

CONCLUSIONS
Painful diabetic neuropathy is a common cause
of neuropathic pain and produces significant

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Shin-Yi Tsao

Hui-Chuan Hsu

Chih-Chung Liu

Hsiao-Lun Sun

morbidity. Successful treatment can be difficult


and relies on modification of the underlying disease
with maintenance of euglycemia, a normal body
weight, and lipid levels as well as a multitude of
symptomatic therapies. Good glucose control
without fluctuation is important. TCAs remain the
mainstay of therapy for many patients although
there is no FDA approval. Only pregabalin and
duloxetine have FDA approval for treatment of
diabetic neuropathic pain. The physician's choice
of medicine must be individualized with attention
to a particular patient's susceptibility to side effects
such as hepatic and renal function, and potential
drug-drug interactions, especially with TCAs and
anticonvulsants. Although some efficacy was noted
with combination therapy, further studies are
required to determine drug safety. Pain relief is
important to improve the QOL, and physicians
should pay more attention to T2DM patients.
Diabetic neuropathic pain can induce poor sleep,
anxiety, and depression, and increase the risk of
cardiovascular disease. Both pharmacological and
non-pharmacologicaltherapies play roles in controlling
diabetic neuropathic pain.

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1 1

2,3,*

( 20108 (1)39-47)

1 2
2010 03 08 2010 03 31
*: : hlsun@cgh.org.tw

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