volume [3] july ’07

perspectives in modern neurology and pain management

feature article
Diagnostic Tools for DPNP

David M. Simpson, MD
Alejandra Gonzalez-Duarte, MD
introduction

Dear Colleague:
Welcome back to Pathways, a journal for physicians who specialize in pain management. In this edition, David
M. Simpson, MD, Director of the Clinical Neurophysiology Laboratories and Neuro-AIDS Program at Mount
Sinai School of Medicine, and Alejandra Gonzalez-Duarte, MD, Neurologist, Mount Sinai School of Medicine,
discuss the clinical features of diabetic peripheral neuropathic pain (DPNP) and the tools that can aid physicians
in the diagnosis of this condition. The authors present an overview of simple diagnostic tools, such as a tuning
fork, as well as more complicated and recently developed tests, such as nerve conduction studies and skin biopsy,
that may be required in patients with atypical presentations of DPNP. In addition, the authors list key questions
that physicians should ask when evaluating patients with suspected DPNP.
In the accompanying case study, the authors present a patient with symptoms indicative of DPNP. The authors
walk through the examination findings that lead to the diagnosis of DPNP and describe an appropriate
treatment strategy.
We hope that you will find this information to be clinically relevant to your practice as you strive to improve the
pain and overall functioning of your patients with DPNP. Please send us your feedback on the enclosed reply card.

Sincerely,
Doug Williamson, MD
Associate Medical Director
US Neurosciences
Eli Lilly and Company

contents
2 Feature Article Diagnostic Tools for DPNP

7 Case Study Diagnosis of DPNP

 feature article
Alejandra Gonzalez-Duarte, MD David M. Simpson, MD Diagnostic Tools for DPNP
Neurologist Professor of Neurology
Mount Sinai School of Medicine, Director, Clinical Neurophysiology
New York City Laboratories
Director, Neuro-AIDS Program
Mount Sinai School of Medicine,
New York City

Diabetic peripheral neuropathic pain (DPNP) is a debilitating complication of diabetes, affecting 10% to
20% of patients with this disease.1 The prevalence of peripheral neuropathy approaches 50% in patients
who have had diabetes for more than 25 years.2,3 Neuropathic pain is often described as aching, burning,
stabbing, or shooting sensations in the feet.1,4 It is variable in severity and is often worst at night.1,4,5
DPNP can dramatically impact quality of life.5 Painful symptoms have been linked to worsening physical and
psychosocial functioning.5 DPNP also predisposes patients to foot ulceration, burns, infections, gangrene, and
Charcot’s neuroarthropathy.6 Thus, early diagnosis and treatment are essential to the care of patients with
DPNP. Key questions in the diagnosis of DPNP are listed in Table 1.

Table 1. Key Questions for the Diagnosis of DPNP

1. Is the patient diabetic?

2. Does the patient have burning pain in his or her feet?

3. Is the pain associated with tingling, pinprick sensations, or numbness?

4. Are the symptoms distributed symmetrically?

5. Are the examination findings consistent with distal peripheral neuropathy (ie, decreased or absent ankle
reflexes, decreased sensation of temperature or vibration, decreased propioception)?

6. Have other, nondiabetic causes of neuropathy been ruled out (eg, neoplasm, infection, toxic substance abuse)?

continued on page 3

[2]
 continued...

Features of DPNP
Neuropathic pain is defined as spontaneous pain or hypersensitivity to sensory stimuli in association with
damage to or a lesion of the nervous system.7 It is often chronic and unrelenting, and it does not respond
to treatment with common analgesics.8 Neuropathic pain can be diagnosed clinically on the basis of
distinct features that help differentiate it from other types of pain (Table 2).1,6,8
The pathogenesis of diabetic neuropathy is complex. In hyperglycemia, elevated intracellular levels of
glucose drive secondary pathologic mechanisms, such as oxidative stress and protein glycation, in vascular
and nervous tissues.9 Diabetic neuropathy can affect both large and small nerve fibers to varying degrees,
resulting in mixed symptoms and sensory loss.10,11 More commonly, small-fiber neuropathy predominates
over large-fiber neuropathy. Large afferent nerve fibers transmit propioception (ie, spatial limb location)
and sensations of cold and vibration.10,12 Small afferent fibers conduct nociceptive stimuli and sensations
of touch and warmth.10,12,13
The diagnosis of DPNP is usually made based on the patient’s history and results of a physical and
neurologic examination. Neuropathic symptoms are often difficult for patients to describe. They may
consist of severe burning pain, paresthesias, and numbness and can fluctuate in intensity from mild
discomfort to severe pain. The classic presentation of DPNP is pain in the feet, often described as
“burning,” “shooting,” or “throbbing.” The pain may be spontaneous or stimulus-evoked and may be
associated with allodynia (pain resulting from a stimulus that ordinarily does not elicit a painful response,
such as contact with bedclothes, shoes, and socks) or with hyperalgesia (increased sensitivity to a painful
stimulus, such as pinprick).8,12 Tingling or “pins and needles” sensations are common. In addition to the

Table 2. Features of Neuropathic and Nociceptive Pain1,6,8

Neuropathic pain Nociceptive pain

Time course Chronic, unrelenting, and not self-limited; Usually acute and self-limited
can persist for years

Symptoms Sensations of burning or of electric, Sharp, aching, throbbing, or gnawing pain

tingling, or shooting pain

Treatment response Poor response to NSAIDS; usually responds Usually responds to nonspecific analgesics,
to anticonvulsants, antidepressants, opioids, NSAIDS, and opioids
and topical agents

Pathophysiology Produced by damage to or pathologic Caused by the stimulation of A-δ and

changes in the peripheral or central C-polymodal pain receptors and by
nervous system algogenic substances (eg, histamine,
bradykinin, substance P)

Source of pain Injury or malfunction in the peripheral or Protective biological function to warn of
central nervous system ongoing tissue damage

Examples Radiculopathy, trigeminal neuralgia, Postoperative pain, pain associated with

postherpetic neuralgia, phantom limb pain, trauma or arthritis
complex regional pain syndrome,
polyneuropathies (ie, DPNP, HIV infection)

DPNP, diabetic peripheral neuropathic pain; HIV, human immunodeficiency virus; NSAIDs, nonsteroidal anti-inflammatory drugs

[3]
painful (positive) symptoms of neuropathy, patients may experience nonpainful (negative) symptoms.
These include numbness, often described as an area that is “dead” or “asleep.” Other negative symptoms
include gait unsteadiness (ataxia) and, in late stages, distal muscle weakness.1,12,14 Patients often compare
this sensation to one of walking through sponges that make it impossible to feel the ground normally.
Excruciating pain is the most common identified symptom of diabetic neuropathy; however, the damage
typically develops insidiously as loss or changes of sensation that may be detected only by clinical tests.1,4
Typically, DPNP first affects the feet and lower limbs symmetrically and affects the upper extremities only
in late stages.1,12 The distribution resembles a “stocking and glove” pattern (Figure).12,15 Proximal motor
weakness or an asymmetric distribution should suggest other types of neuropathy.1,16

Figure. Neuropathies can be distinguished by signs, symptoms, and areas of the body that are affected.15

Inflammatory
Distal symmetric demyelinating Progressive Mononeuritis
polyneuropathy polyneuropathy polyradiculopathy multiplex

1 Hyperesthesia
2 Normal strength
3 Pain, paresthesia
4 Decreased ankle reflexes
5 Decreased response to
pinprick, temperature;
increased vibratory
thresholds
6 Contact sensitivity
1 Facial nerve paresis
2 Ascending weakness
3 Generalized areflexia
4 Mild sensory involvement
1 Radiating pain in cauda
equina distribution
2 Flaccid paraparesis
3 Mild sensory loss
4 Areflexia
5 Sphincter dysfuntion
1 Cranial nerve involvement
(eg, facial palsy); multiple
peripheral nerve
involvement
2 Medial nerve involvement
3 Meralgia paresthetica
4 Peroneal nerve
involvement
5 Ulnar nerve involvement

From Wulff EA, Simpson DM. HIV-associated peripheral nervous system complications. NeuroAIDS. 1999;2.
Reprinted with permission from the American Association for the Advancement of Science.

[4]
 continued...

Clinical Examination
Neurologic examination in DPNP reveals absent or depressed ankle reflexes relative to knee reflexes.
Because of the anatomic position of the Achilles tendon, assessment of the ankle reflex (S1 innervation) is
at times difficult to perform correctly. To obtain the Achilles tendon reflex, the foot should be flexed
upward to stretch the tendon. The tendon on the back of the leg at the height of the ankle bone is tapped,
and if the reflex is present, the foot will extend. Most physicians have experience with the knee reflex (L3
innervation) because it is accessible and easily palpated. However, to obtain this reflex, it is necessary to
bend the knee to stretch the patellar tendon and ensure that the leg is relaxed. The tendon must be
palpated to verify the location. When reflexes are present, the leg will extend when tapped. Normal
reflexes are usually graded as 2+. Hyperactive reflexes are graded 3+ and 4+, depending on the presence
of clonus (the rhythmic contraction and relaxation of a muscle group). Hypoactive reflexes are graded 1+
and absent reflexes 0.

Results of sensory examination are commonly abnormal in patients with DPNP. Proprioception and
sensations of light touch, vibration, and temperature are decreased or absent. A relative loss of
discrimination of sharp touch is noted over the distal lower extremities, and an area of gradual transition
where normal sensation returns. A broken tongue depressor is commonly used to test for sharp sensation,8
although more specific commercial sterile examination pins and nylon monofilaments are available.
Vibratory sensation is assessed by placing a 128-Hz tuning fork over the bony surface of the malleolus or
first distal phalanx. The threshold to vibratory sensation is usually elevated in the feet compared with that
in the knees. Data from one study suggest that the predictive value of testing with a 128-Hz tuning fork
in the diagnosis of DPNP is similar to that of national and international scoring systems.17 The study
authors concluded that the tuning fork should play a central role in the diagnosis of DPNP.17 Temperature
sensation may be assessed with a cool tuning fork or with test tubes that contain warm or cold water.8 Like
the thresholds to vibratory sensation, altered thresholds to thermal sensation have been well documented
in patients with DPNP, and their elevation has been associated with progression of neuropathy.1,18 Loss of
proprioception can impair gait and balance.1,14

Because the diagnosis of DPNP is usually evident based on results of the bedside examination, further
neurologic testing is unnecessary in most patients.8,19 However, other diagnostic tests may be helpful in
patients with atypical clinical presentations, or in the research setting. Several methods to assess
peripheral nerve function are available (Table 3):

• Nerve conduction studies (NCS) and electromyography (EMG) have long been considered the gold
standard for the assessment of peripheral neuropathy. However, in DPNP, which may affect
predominantly small nerve fibers, NCS and EMG may yield normal results or show only minor
abnormalities. NCS may differentiate DPNP from other neuropathies.4,8,20 Abnormal NCS results
frequently indicate more severe involvement, a less benign course, and a less favorable diagnosis. The
progressive loss of distal axons is the pathologic hallmark of peripheral neuropathies. This loss is
reflected in NCS by prolonged distal latencies, reduction in evoked potential amplitudes, and secondary
slowing of conduction velocity.

• Quantitative sensory tests (QSTs) are used mostly for research purposes, although they may also be
applied in the clinical setting. They are performed with devices, often computer-assisted, that make it
possible to assess somatosensory function, including the perception of vibration, temperature, light
touch, and pain.8,12,20 QSTs can be used to identify the sensory modalities affected and to estimate the
magnitude of the deficit. In patients with diabetes, QSTs have proved valuable in the detection of
subclinical neuropathy.1,12

[5]
 Table 3. Diagnostic Tests for Diabetic Peripheral Neuropathic Pain

NCS/EMG Measures the speed and amplitude of
sensory and motor conduction
QST Detects sensory thresholds for vibration,
heat, and pain
Skin biopsy Measures density of intraepidermal nerve
fiber at various sites in the leg
Objective, parametric, noninvasive, and
reproducible
Insensitive in acute and small-fiber neuropathy
Useful in tracking the progression of neuropathy
in large cohorts and efficacy of treatment end
points in multicenter clinical trials
Loss of nerve fibers is associated with increased
neuropathic pain
Although test is invasive, it requires only a 3-mm
skin biopsy specimen and enables a direct study
of small nerve fibers

NCS/EMG, nerve conduction studies/electromyography; QST, quantitative sensory tests

• Skin biopsy is a newer technique that is sensitive in the detection of small-fiber neuropathies.12,21 A skin
biopsy is a procedure in which a small piece of the patient’s skin is removed for examination under a
microscope. It is a useful tool that requires basic medical skills and is easy to learn. Specimens are
obtained by performing skin-punch biopsies at various sites in the leg, usually in the distal portion of the
leg above the ankle and in the thigh. Full-thickness skin specimens are needed. After sterilizing and
numbing the area, a circular blade is rotated down through the epidermis and dermis and into the
subcutaneous fat, yielding a 3 to 4 mm cylindrical core of tissue. Samples are fixed and sent to the
pathology laboratory, where morphometric and immunohistochemical methods are used to examine the
thinly myelinated and unmyelinated nerve fibers. Integrity, density, and distribution of these fibers is
assessed. Skin biopsy is the most sensitive measure of neuropathic changes. Significant inverse
correlations between the density of nerve fibers and the severity of neuropathy have been documented.21
Moreover, changes in nerve fiber density over time correlates with decreased neuropathic pain.22

The first step in the approach to diabetic patients with pain is to establish the diagnosis of neuropathic
pain and determine the form of neuropathy. A simple key question to ask patients with diabetes might be,
“Do you feel burning pain, tingling, or numbness on your feet?”8 If the answer is positive, the distribution
may differentiate DPNP from other conditions. A distal and symmetric distribution of symptoms and
signs is suggestive of DPNP.1,8 A nerve root distribution suggests radiculopathy, whereas a nerve trunk
distribution may indicate mononeuropathy simplex or multiplex. Sensory function should be assessed on
both sides of the feet and hands to distinguish DPNP from entrapment syndromes (eg, carpal or tarsal
tunnel syndrome). Additional symptoms such as weakness are more suggestive of large-fiber dysfunction,
such as diabetic amyotrophy or motor neuropathies. The diagnostic studies previously discussed provide
valuable data in differentiating these forms of neuropathy.

Conclusion
DPNP is predominantly a clinical diagnosis. Patients usually present with burning pain, tingling, and
numbness in a symmetrical distribution over the feet and occasionally the hands. Physical examination
reveals decreased or absent ankle reflexes, sensations of pinprick and vibration, and propioception. NCS,
QSTs, and skin biopsy are helpful in differentiating DPNP from other forms of neuropathy and in
assessing the progression of neuropathy over time.

[6]
 case study
Diagnosis of DPNP Alejandra Gonzalez-Duarte, MD David M. Simpson, MD
Neurologist Professor of Neurology
Mount Sinai School of Medicine, Director, Clinical Neurophysiology
New York City Laboratories
Director, Neuro-AIDS Program
Mount Sinai School of Medicine,
New York City

A 50-year-old woman with type 2 diabetes is referred with a 6-month history of burning pain and a “pins
and needles” sensation in her feet. The symptoms have progressed such that she is finding it difficult to
walk because of pain and has required a cane for 2 months. She is kept awake for much of the night with
pain. She rates her average pain intensity at an 8 (on a scale of 0-10) during the day, with a worst pain score
of 10 at night. She has been taking naproxen 250 mg every 6 to 8 hours as needed without any
improvement during the previous 3 months. She has no significant past medical history or family history
of neurologic disease. She was formerly an avid golfer but can no longer play, and she does not engage in
the physical activities she once enjoyed. She has difficulty sleeping, feels
frustrated, and wants something that can help her promptly.

Examination
Examination reveals shiny skin of the distal lower extremities.
Her feet are cool to touch. Strength is normal. Deep tendon
reflexes are diminished at the ankles (1 on a scale of 0-4)
relative to the knees (2/4) bilaterally. Distal reduction in
pinprick and temperature sensation is noted bilaterally in a
stocking distribution. Vibration sensation is reduced in the
feet. Results of nerve conduction studies are normal, as are
results of the rest of her neurologic and general examination.

Diagnosis and Treatment

Fasting serum glucose is 240 mg/dL, and the patient is diagnosed with
diabetic peripheral neuropathic pain (DPNP). Naproxen is stopped, and
Cymbalta® (duloxetine HCl) 60 mg once daily is started. The patient is instructed to take the medication
at night and to monitor her symptoms daily using a pain diary. She experiences minor nausea and
dizziness for the first 3 days, but these symptoms then abate. At her next visit, her pain diary indicates an
improvement in painful symptoms beginning at 1 week. Her average pain score has dropped to 4, and her
worst pain score to 6. She is able to play golf again and no longer is kept awake at night because of pain.
She starts a diet and exercise program after consulting a physician, and follow-up with a nutritionist and
an endocrinologist is arranged.

[7]
Discussion
This patient has classic signs and symptoms of a painful peripheral neuropathy. The symptoms of DPNP
often appear after periods of poor metabolic control or sudden changes in glycemic control.1-3 Nerve
conduction studies can yield normal results or show only minor abnormalities because small nerve fibers
are more frequently damaged in sensory neuropathies. DPNP does not generally respond to the treatments
effectively used for inflammatory pain, such as nonsteroidal anti-inflammatory drugs.1
The patient experienced a significant reduction of pain as a result of treatment with the dual serotonin and
norepinephrine reuptake inhibitor Cymbalta. Side effects developed in this patient but fortunately these
were mild and resolved within several days.
Diabetic neuropathy is a common complication of diabetes and is a leading risk factor for nontraumatic
amputation.4,5 Therefore, measurement of the fasting serum glucose or a glucose tolerance test is indicated
in patients with a new onset of distal neuropathic pain. On the other hand, many patients with diabetes do
not report symptoms of neuropathy until the complications are severe. These patients may benefit from a
complete neurologic examination despite being asymptomatic. The examination can reveal distal areas of
numbness or decreased sensibility to pinprick or light touch. Abnormal ankle reflexes with diminished
vibration and temperature sensation fulfill the diagnosis of diabetic neuropathy. In this setting, rigorous
glycemic control may halt the progression of neuropathy.6

Conclusion
DPNP primarily affects small nerve fibers and accounts for decreased perception of temperature and
vibration and for paresthesias. Early institution of optimal glycemic control is the only method that has
been shown to prevent or slow the progression of diabetic neuropathy.6

Important Safety Information for Cymbalta:

• Antidepressants increased the risk of suicidal thinking and behavior

(suicidality) in short-term studies in children, adolescents, and young
adults with major depressive disorder (MDD) and other psychiatric
disorders.
• Patients of all ages started on therapy should be monitored
appropriately and observed closely for clinical worsening, suicidality,
or unusual changes in behavior.
• Cymbalta is not approved for use in pediatric patients.

See Important Safety Information, including Boxed Warning, on page 9 and full Prescribing
Information enclosed.

[8]
 Important Safety Information on Cymbalta® (duloxetine HCl)
Cymbalta is indicated in adults for:
• The treatment of major depressive disorder (MDD)
• The management of diabetic peripheral neuropathic pain (DPNP)
• The treatment of generalized anxiety disorder (GAD)
Suicidality and Antidepressant Drugs—Antidepressants increased the risk compared to placebo of suicidal thinking and
behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD)
and other psychiatric disorders. Anyone considering the use of Cymbalta or any other antidepressant in a child,
adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in
the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk
with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders
are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant
therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in
behavior. Families and caregivers should be advised of the need for close observation and communication with the
prescriber. Cymbalta is not approved for use in pediatric patients.

Contraindications Blood pressure should be measured prior to initiating

• Cymbalta is contraindicated in patients with a known
hypersensitivity to duloxetine or any of the inactive
ingredients.
• Cymbalta should not be used in combination with MAOIs and
is contraindicated for at least 14 days after discontinuation of
an MAOI. After stopping therapy on Cymbalta, at least 5 days
should be allowed before starting an MAOI.
• Cymbalta was associated with an increased risk of mydriasis;
therefore, it should not be used in patients with uncontrolled
narrow-angle glaucoma and used cautiously in patients with
controlled narrow-angle glaucoma.
Warnings
• Clinical Worsening and Suicide Risk
All patients being treated with antidepressants for
any indication should be monitored appropriately and
observed closely for clinical worsening, suicidality, and
unusual changes in behavior, especially when initiating
drug therapy and when increasing or decreasing the dose.
Consider changing the therapeutic regimen, including possibly
discontinuing the medication in patients whose depression is
persistently worse or includes symptoms of anxiety, agitation,
panic attacks, insomnia, irritability, hostility, aggressiveness,
impulsivity, akathisia (psychomotor restlessness), hypomania,
mania, or suicidality that are severe, abrupt in onset, or were
not part of the patient’s presenting symptoms.
• If discontinuing treatment, the medication should be tapered.
• Development of a potentially life-threatening serotonin
syndrome may occur with SNRIs and SSRIs, including
Cymbalta treatment, particularly with concomitant use of
serotonergic drugs, including triptans. Concomitant use is not
recommended.
Precautions
• Cymbalta and thioridazine should not be co-administered.
• Cymbalta should not be administered to patients with any
hepatic insufficiency or patients with end-stage renal disease
(requiring dialysis) or severe renal impairment (creatinine
clearance <30 mL/min).
• Postmarketing, cases of severe elevations of liver enzymes or
liver injury with a hepatocellular, cholestatic or mixed pattern
have been reported.
• Because it is possible that Cymbalta and alcohol may interact
to cause liver injury or that Cymbalta may aggravate pre-
existing liver disease, Cymbalta should ordinarily not be
prescribed to patients with substantial alcohol use or evidence
of chronic liver disease.
• Orthostatic hypotension and syncope have been reported with
therapeutic doses of Cymbalta. Consideration should be given
to discontinuing Cymbalta in patients who experience
symptomatic orthostatic hypotension and/or syncope.
• In clinical trials across indications relative to placebo,
treatment with Cymbalta was associated with mean increases
of up to 2.3 mm Hg systolic and diastolic blood pressure.
There was no significant difference in the frequency of
[9] sustained (3 consecutive visits) elevated blood pressure.
treatment and periodically measured throughout treatment.
• As observed in DPNP trials, Cymbalta treatment worsens
glycemic control in some patients with diabetes. In the
extension phases (up to 52 weeks) of the DPNP studies, an
increase in HbA1c in both the Cymbalta (0.5%) and the
routine care groups (0.2%) was noted.
• Safety and effectiveness not established in pediatric patients.
See Boxed Warning.
• As with many antidepressants, Cymbalta should be used
cautiously in patients with a history of mania or with a history
of a seizure disorder.
• As with other antidepressants, Cymbalta has been associated
with cases of clinically significant hyponatremia that appeared
to be reversible when Cymbalta was discontinued.
• On abrupt discontinuation, spontaneous reports of adverse
events, some of which may be serious, have been reported
during the marketing of other SSRIs and SNRIs. A gradual
reduction in dose rather than abrupt cessation is
recommended when possible.
• There are no adequate and well-controlled studies of Cymbalta
in pregnant women. Cymbalta should be used during
pregnancy only if the potential benefit justifies the potential
risk to the fetus.
• Neonates exposed to SSRIs or SNRIs late in the third
trimester have developed complications requiring prolonged
hospitalization, respiratory support, and tube feeding.
Nursing while taking Cymbalta is not recommended.
Adverse Events
• The most commonly observed adverse events (≥5% and at
least twice placebo) for Cymbalta vs placebo in premarketing
clinical trials were:
MDD (40-120 mg/day): (N=1139 vs 777) nausea (20% vs 7%),
dry mouth (15% vs 6%), constipation (11% vs 4%), fatigue
(8% vs 4%), decreased appetite (8% vs 2%), somnolence
(7% vs 3%), and increased sweating (6% vs 2%).
DPNP (20-120 mg/day): (N=568 vs 223) nausea (24% vs 9%),
somnolence (16% vs 5%), dizziness (13% vs 6%), constipation
(11% vs 3%), dry mouth (9% vs 4%), increased sweating
(7% vs 2%), decreased appetite (6% vs <1%), and asthenia
(5% vs 1%). GAD (60-120 mg/day): (N=668 vs 495) nausea
(38% vs 10%), fatigue (13% vs 5%), dry mouth (12% vs 4%),
somnolence (12% vs 3%), constipation (10% vs 3%), insomnia
(9% vs 4%), appetite decreased (8% vs 3%), increased
sweating (7% vs 2%), libido decreased (7% vs 2%), vomiting
(5% vs 2%), ejaculation delayed (5% vs 1%), and erectile
dysfunction (5% vs 1%).
• In premarketing placebo-controlled clinical trials, the overall
discontinuation rates due to adverse events were:
MDD: 10% vs 4%; DPNP: 14% vs 7%; GAD: 16% vs 4%.
The common adverse events reported as a reason for
discontinuation and considered to be drug related were:
MDD: nausea (1.4% vs 0.1%). DPNP: nausea (3.5% vs 0.4%),
dizziness (1.6% vs 0.4%), somnolence (1.6% vs 0%), fatigue
(1.1% vs 0%). GAD: nausea (3.7% vs 0.2%), vomiting
(1.4% vs 0%), dizziness (1.2% vs 0.2%).
REFERENCES: FEATURE ARTICLE
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diagnosis and staged severity. Neurology. 1992;42:1164-1170.
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REFERENCES: CASE STUDY

1. Argoff CE, Cole BE, Fishbain DA, Irving GA. Diabetic peripheral neuropathic pain: clinical and quality-of-life issues. Mayo Clin Proc. 2006;81:S3-11.
2. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28:956-962.
3. Oyibo SO, Prasad YD, Jackson NJ, Jude EB, Boulton AJ. The relationship between blood glucose excursions and painful diabetic peripheral neuropathy:
a pilot stud. Diabet Med. 2002;19:870-873.
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