S P E C I A L F E A T U R E

A p p r o a c h t o t h e P a t i e n t

The Approach to the Management of the

Accreditation and Credit Designation Statements
Patient with Neuropathic Pain
The Endocrine Society is accredited by the Accreditation
Council for Continuing Medical Education to provide con-
tinuing medical education for physicians. The Endocrine So-
ciety has achieved Accreditation with Commendation. Aaron Vinik
The Endocrine Society designates this educational activity
for a maximum of 1 AMA PRA Category 1 Credit(s)™.
Physicians should only claim credit commensurate with the Department of Internal Medicine, Eastern Virginia Medical School, Strelitz Diabetes
extent of their participation in the activity. Center and Neuroendocrine Unit at Norfolk, Norfolk, Virginia, 23510
Learning Objectives
Upon completion of this educational activity, participants
should be able to
• Perform differential diagnosis of painful diabetic
neuropathy. Neuropathic pain occurs in about 6 –7% of the general population and in 15–20%
• Make informed decisions based on the numbers needed to of people with diabetes. It is defined as a disease or disorder of the sensorimotor
treat vs. the numbers needed to harm as well as the like-
lihood of success or failure of treatment. system and must be distinguished from nociceptive pain, which is a consequence
• Understand pathogenesis-based management.
Target Audience of trauma, injury, or inflammation. A host of other conditions can masquerade as
This continuing medical education activity should be of sub-
stantial interest to endocrinologists.
neuropathy including entrapments, fasciitis, and claudication. Pain can derive
Disclosure Policy from damage to unmyelinated C-fibers, A␦ fibers in the periphery, or from mech-
Authors, editors, and Endocrine Society staff involved in
planning this CME activity are required to disclose to learn- anisms within the spinal cord, brainstem, and cerebral cortex. A variety of exci-
ers any relevant financial relationship(s) that have occurred
within the last 12 months with any commercial interest(s) tatory and inhibitory neurotransmitters are involved and form the basis for tar-
whose products or services are discussed in the CME con- geted drug therapy. More important, however, is the pathogenesis of damage to
tent. The Endocrine Society has reviewed all disclosures and
resolved or managed all identified conflicts of interest, as the pain mechanism, which is multifactorial and includes metabolic disturbances
applicable.
The following individual reported relevant financial such as hyperglycemia, even impaired glucose tolerance, dyslipidemia, oxidative
relationships:
Aaron Vinik, M.D., has served as a consultant for Ansar,
and nitrosative stress, growth factor deficiencies, microvascular insufficiency, and
AstraZeneca, Eli Lilly, KV Pharmaceuticals, Merck, Novar- autoimmune damage to nerve fibers. The approach to managing the patient with
tis Pharmaceuticals, R.W. Johnson Pharmaceutical Re-
search Institute, sanofi-aventis, Takeda, and Tercica; and neuropathic pain is first to understand and recognize the cause of pain in a
has served on speaker’s bureaus for Abbott, Ansar, Astra-
Zeneca, Bristol Meyer Squibb, Eli Lilly, GlaxoSmith Kline particular patient and to use monotherapies or drug combinations directed at the
Beecham, Merck, Novartis Pharmaceuticals, Pfizer, Inc., different types and sources of pain. Ultimately, therapy directed at the underlying
sanofi-aventis, and Takeda. He has received grant funding
from Takeda Pharmaceuticals, Abbot, GlaxoSmithKline, pathogenesis of neuropathy is needed. The case presented in this report illus-
sanofi-aventis, Arcion Therapeutics, Inc., Eli Lilly & Company,
and Merck Research Labs. trates the complexity of resolution of pain in an individual and the need for a
Disclosures for JCEM Editors are found at http://www.
endo-society.org/journals/Other/faculty_jcem.cfm.
holistic approach to medicine, employing empathy, compassion, and understand-
The following individual reported NO relevant financial ing in the relationship between the doctor and the patient to succeed in allevi-
relationships:
Leonard Wartofsky, M.D., reported no relevant financial ating pain. (J Clin Endocrinol Metab 95: 4802– 4811, 2010)
relationships.
Endocrine Society staff associated with the development of
content for this activity reported no relevant financial
relationships.
ain is the reason for 40% of patient visits in a primary
P
Acknowledgement of Commercial Support
This activity is not supported by grants, other funds, or in-
kind contributions from commercial supporters. care setting, and about 20% of these patients have
Privacy and Confidentiality Statement
The Endocrine Society will record learner’s personal infor- had pain for longer than 6 months (1). Chronic pain may
mation as provided on CME evaluations to allow for issu-
ance and tracking of CME certificates. No individual per- be nociceptive, which occurs as a result of disease or dam-
formance data or any other personal information collected
from evaluations will be shared with third parties. age to tissue wherein there is no abnormality in the ner-
Method of Participation
This Journal CME activity is available in print and online as vous system or there may be no somatic abnormality. In
full text HTML and as a PDF that can be viewed and/or
printed using Adobe Acrobat Reader. To receive CME contrast, experts in the neurology and pain community
credit, participants should review the learning objectives
and disclosure information; read the article and reflect on its define neuropathic pain as “pain arising as a direct con-
content; then go to http://jcem.endojournals.org and find
the article, click on CME for Readers, and follow the in- sequence of a lesion or disease affecting the somatosensory
structions to access and complete the post-activity test ques-
tions and evaluation. The estimated time to complete this
system” (2). Persistent neuropathic pain interferes signif-
activity, including review of material, is 1 hour. If you have
questions about this CME activity, please direct them to
icantly with quality of life, impairing sleep and recreation,
education@endo-society.org.
Activity release date: November 2010
and it significantly impacts emotional well-being of such
Activity expiration date: November 2011 patients, predisposing them to depression and noncom-

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: AED, Antiepileptic drug; BID, twice daily; DPN, diabetic peripheral neurop-
Printed in U.S.A. athy; HS, at bedtime; NMDA, N-methyl-D-aspartate; QD, daily; SNRI, serotonin norepi-
Copyright © 2010 by The Endocrine Society nephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic
doi: 10.1210/jc.2010-0892 Received April 19, 2010. Accepted July 6, 2010. antidepressants; TID, three times daily.

4802 jcem.endojournals.org J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811

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 J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811
pliance with treatment resulting in a general worsening of
the condition. Patients with chronic neuropathic pain re-
port poor physical health and mental conditions com-
pared with those with other causes of chronic pain even
adjusting for pain intensity (3). Diabetic neuropathy pain
is a difficult-to-manage clinical problem. It is often asso-
ciated with mood and sleep disturbances, and patients
with diabetic neuropathy pain are more apt to seek med-
ical attention than those with other types of diabetic neu-
ropathy. Two population-based studies showed that neu-
ropathic pain is associated with a greater psychological
burden than nociceptive pain (4) and is considered to be
more severe than other pain types. Early recognition of
psychological problems is critical to the management of
pain, and physicians need to go beyond the management
of pain per se if they are to achieve success. Patients may
also complain of decreased physical activity and mobility,
increased fatigue, and negative effects on their social lives.
Providing significant pain relief markedly improves qual-
ity-of-life measures, including sleep and vitality (5). Be-
cause of its complexity, the presentation of pain poses a
diagnostic dilemma for the clinician who needs to distin-
guish between neuropathic pain arising as a direct conse-
quence of a lesion or disease of the somatosensory system
and nociceptive pain that is due to trauma, inflammation,
or injury. It is imperative to try to establish the nature of
any predisposing factor, including the pathogenesis of the
pain, if one is to be successful in its management. Man-
agement of neuropathic pain requires a sound relationship
between patient and physician, with an emphasis on a
positive outlook and encouragement that there is a solu-
tion, using patience and targeted pain-centered strategies
that deal with the underlying disorder rather than the
usual “Band-aid” prescription of drugs approved for gen-
eral pain, which do not address the disease process. The
inciting injury may be focal or diffuse and may involve
single, or more likely, multiple mechanisms such as meta-
bolic disturbances encompassing hyperglycemia, dyslipide-
mia, glucose fluctuations, or intensification of therapy with
insulin. On the other hand, the injury might embrace auto-
immune mechanisms, neurovascular insufficiency, deficient
neurotrophism, oxidative and nitrosative stress, and inflam-
mation (6). Because pain syndromes in diabetes may be focal
or diffuse, proximal or distal, acute or chronic, each has its
own pathogenesis, and the treatment must be tailored to the
underlying disorder if the outcome is to be successful.
The Case
We first saw the patient—a 24-yr-old female with poorly
controlled type 1 diabetes for the past 6 yr and an eating
disorder with anorexia/bulimia syndrome— on May 19,
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2009. She had been admitted to an eating disorder clinic
from February 2009 through April 10, 2009. She had been
on an insulin pump that she had manipulated to control
her weight and was subsequently placed on an injectable
combination of short- and long-acting insulin, Lantus (40
U in the morning) and NovoLog (1 U for every 15 g of
carbohydrate for meals and snacks and 1 U for every 50
mg/dl of her blood glucose greater than 100 mg/dl). On
this regimen, her blood glucose levels averaged 100 to 220
mg/dl without hypoglycemic episodes. Within 2–3 months
of this therapy, she developed intractable pain and was
referred for consultation. The pain was burning and ach-
ing with tenderness bilaterally in the feet and the legs, as
well as in the hips. A rheumatologist had diagnosed fibro-
myalgia and prescribed Gabapentin [100 mg twice daily
(BID), 200 mg at bedtime (HS) for 2 wk, increased to 200 mg
three times a day for 1 week, and then increased to 300 mg
BID and 600 mg at bedtime]. This had no real impact on the
pain. She was very distressed and tearful, was confined to
bed, and was unable to sleep. Advil two to three times per day
eased the pain slightly. Her last hemoglobin A1c was 9.0.
She had exercised regularly, including Pilates, before
the pain occurred, but she stopped because of pain. She
had an eye exam in the fall of 2008, and there was no
evidence of retinopathy. Her urine specimen contained no
protein and was negative for ketones. She had developed
grand mal seizures controlled with lamotrigine 150 mg
daily (QD). She denied stress or phobia, although she had
some difficulty with heights. She attended college and
lived at home with her parents. Her family history revealed
an older sister who suffered from some degree of anxiety;
her mother had Hashimoto thyroiditis and also had rheu-
matoid arthritis, for which she was treated with Enbrel and
methotrexate in small doses. Her father is disease free. Her
maternal grandmother had Hashimoto thyroiditis with di-
abetes, and her grandfather had a myocardial infarction. On
the paternal side, there was a history of lung cancer. The
patient smoked a pack of cigarettes a day for 5 yr, but quit in
November 2008. She did not consume alcohol or use illegal
drugs. She had not been exposed to heavy metals, organo-
toxins, or other toxins. She was not intolerant to cold or
constipated and had no voice change or hair loss.
Physical examination
Physical exam revealed an alert and oriented individual
who, although tearful, communicated well. She had no pig-
mentation change and no dry or brittle hair. She had a few
psoriatic lesions at the back of her head, but not elsewhere.
Head, eyes, ears, nose, and throat were within normal
limits. She had no lymphadenopathy. Her chest and lungs
were clear. There were no breast masses. Her heart was
normal without murmurs. Her abdomen was soft, non-
 4804 Vinik Approach to Pain Management in Diabetes
TABLE 1. Examination: bedside sensory tests
Sensory modality Nerve fiber
Vibration A␤ (large)
Pain (pin prick) C (small)
Pressure A␤, A␣ (large)
Light touch A␤, A␣ (large)
Cold A␦ (small)
tender, and without masses. Her musculoskeletal system
was intact. She had good dorsalis pedis and posterior tibial
pulses. Application of pressure to her feet caused her to
scream in agony. She weighed 120.4 pounds and was 5 feet
11 inches tall. Her body mass index was 16.7 kg/m2. Her
waist was 26 inches and hip measurement was 34 in, with a
waist-hip ratio of 0.766. Supine blood pressure was 119/78
mm Hg with a pulse of 94 bpm, sitting blood pressure was
125/82 mm Hg with a pulse of 107 bpm, and standing blood
pressure was 109/78 mm Hg with a pulse of 81 bpm.
Neurological examination
Cranial nerves were intact. Her pupils were large, re-
acted to light, and accommodated poorly suggesting au-
tonomic dysfunction. She had no evidence of muscle
weakness. Handgrip dynamometry was at the 10th per-
centile bilaterally. All her reflexes were present, and upper
limb sensation was entirely intact. In the lower limb, she
had a reduction of prickling pain perception to 15 cm on
the right and 22 cm on the left, but she had marked hy-
peralgesic and hyperesthetic soles of her feet. Vibration
perception was intact, there was some slight loss of joint
position, but perception of 1- and 10-g monofilament was
intact. Her total neuropathy scores were 5 on the right and
6 on the left, which indicated a mild degree of peripheral
neuropathy (7). The use of simple clinical tools is illus-
trated in Table 1.
Laboratory studies
A quantitative sensory test done on May 12, 2009,
showed normal vibration perception, touch/pressure,
warm and cold thermal perception, indicating that her
somatic nervous system was intact.
A cardiac autonomic function test revealed an expira-
tion/inspiration ratio of 1.14, a Valsalva ratio of 1.05, and
a 30:15 ratio of 1.05. This very abnormal result indicated
autonomic nerve dysfunction. The QTc interval was
425 msec on electrocardiogram, which was normal. She
had a sinus tachycardia syndrome of 100 bpm and ap-
peared to have slight left atrial enlargement, but no
other abnormalities.
Vitamin D level was 10.7 ng/ml, which is inordinately
low. The remainder of the biochemistries were: urine pro-
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Instrument Associated sensory receptors
128-Hz tuning fork Ruffini corpuscle mechanoreceptors
Neuro-tips Nociceptors for pain and warmth
1 and 10 g monofilament Pacinian corpuscle
Wisp of cotton Meissner’s corpuscle
Cold tuning fork Cold thermoreceptors
tein microalbumin, 12.8 ␮g/ml; TSH, 1.329 ␮U/ml; glu-
cose, 253 mg/dl (elevated); blood urea nitrogen, 18 mg/dl;
creatinine, 0.5 mg/dl; electrolytes, within normal limits;
serum glutamic oxaloacetic transaminase, 19; serum glu-
tamic pyruvic transaminase, 25; alkaline phosphatase, 64;
calcium and magnesium, within normal limits; estimated
glomerular filtration rate, 59 ml/min; antinuclear factor
antibodies, negative; C-reactive protein, 0.1; sedimenta-
tion rate, 12; glutamic acid decarboxylase antibody, 4.7
(elevated); and gastric parietal cell antibodies, 1.6. Serum
protein electrophoresis revealed no gammopathy, and no
motor or sensory nerve antibodies were detected; acetyl-
choline receptor antibodies in serum and antinuclear fac-
tor were negative. Serum folate and B12 were normal.
Urine porphyrins and urine heavy metals were negative.
Serum angiotensin-converting enzyme was normal. Lyme,
HIV, and hepatitis screening tests were all negative.
Neuronal cells were incubated in culture with her se-
rum. With control pooled human serum, 100,000 cells
increased to 871,250 by the fourth day; with her serum,
100,000 cells fell to 11,250 by the second day and fell
further to zero by the third and fourth days. There was no
recovery of these cells, indicating that her serum was
highly toxic to neuronal cells in culture and indicative of
an autoimmune response (8).
Clinical Considerations
My impressions were that this young woman had type 1
diabetes for 6 yr, a seizure disorder, and anxiety, with
claustrophobic panic disorder. She was an anorexic bu-
limic and was using an insulin pump to allow her to adjust
the insulin doses down so that she could lose weight. When
placed on a regular insulin regimen, monitored in an in-
stitution, she could no longer do this and within a few
weeks of the intensification of insulin developed a severe,
highly sensory form of neuropathy with autonomic man-
ifestations, classic of the insulin neuritis syndrome. She
had a long family history of autoimmune disease, and her
serum was highly toxic to neurons in culture, suggesting
the possibility of autoimmune disease. Neuropathic pain
is not uncommon. A population-based survey of 6000
patients treated in family practice in the United Kingdom
 J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811
reported 6% prevalence of pain predominantly of neuro-
pathic origin (9). Similarly, a large population-based study
in France showed that 6.9% of the population had neu-
ropathic pain (4). Interestingly, in a Dutch population sur-
vey of more than 362,000 people, younger people with
pain tended to be mostly women, but with advancing age
the gender differences disappeared. Perhaps a little recog-
nized fact is that mononeuritis and entrapments were three
times as common as diabetic peripheral neuropathy
(DPN), and fully one third of the diabetic population has
some form of entrapment (10), which when recognized is
readily amenable to intervention (11). Even more salutary
is the mounting evidence that even with impaired glucose
tolerance, patients may experience pain (12–14). As a cor-
ollary, patients presenting with painful neuropathy have
impaired fasting glucose or impaired glucose tolerance,
and about 50% of the time, they are overweight and have
autonomic dysfunction (12). Even in the absence of ele-
vated fasting blood glucose (⬍100 mg/dl), pain may be the
presenting feature of the metabolic syndrome and coseg-
regates with elevated triglycerides and a low high-density
lipoprotein-cholesterol (15). Indeed, a risk factor for neu-
ropathic pain in diabetic and nondiabetic populations is
an impairment of peripheral vascular function (14, 16).
The Clinical History
History taking is becoming an obsolete art. Without it, ar-
riving at the correct diagnosis can be hazardous. Pain asso-
ciated with a peripheral nerve injury has several distinct clin-
ical characteristics. Neuropathic pain derived from small
nerve fibers is often burning, lancinating, or shooting in qual-
ity with unusual, tingling, or crawling sensations referred to
as formication. Some describe bees stinging through the
socks, whereas others talk of walking on hot coals. The pain,
worse at night, keeps the patient awake and is associated with
sleep deprivation (17). Patients volunteer that they have al-
lodynia or pain from normal stimuli, such as the touch of
bedclothes, and may have hyperesthesias, increased sensitiv-
ity to touch, or hyperalgesia with increased sensitivity to
painful stimuli or even altered sensation to cold or heat.
These may be paradoxical with differences in sensation to
one or other modality of stimulation. Unlike animal models
of DPN, the pain is spontaneous and does not need provo-
cation such as a hot plate or laser heat. It is a glove and
stocking distribution. Small fiber neuropathies usually
present with pain in the feet or hands, do not have abnor-
malities in sensation, lack weakness or loss of reflexes, are
electrophysiologically silent, and often lead to the erroneous
diagnosis of hysteria or conversion reactions.
Large fiber neuropathy presents with characteristic
weakness, ataxia, loss of reflexes, and impaired nerve con-
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duction. Pain is deep seated and gnawing in quality, “like
a toothache” in the foot, or “a dog gnawing at the bones
of the feet,” or “feet feel as if they are encased in concrete.”
In contrast, the nociceptive pain of arthritis does not
have these qualities. It is localized to the joints; fasciitis is
localized to the fascia; entrapment produces pain in a der-
matome, and claudication is made worse by walking. Ar-
thritic pain starts with morning stiffness and improves as
the day wears on (18).
It is noteworthy that one third of patients with diabetes
have some form of entrapment. In contrast with the
mononeuropathies, the condition begins gradually and is
made worse with repeated minor trauma or history of
occupational exposure. The sensory disturbance often
does not reflect the nerve distribution, and the pain can
exceed the area of sensory innervation leading to incorrect
diagnosis. Nerve conduction velocity is required to show
impairment of conduction across the site of entrapment.
Evaluation of pain intensity is essential for monitoring
response to therapy. There are a number of symptom-
based screening tools, such as: Nerve Total Symptom
Score-6, Brief Pain Inventory, Quality of Life Diabetic
Neuropathy, Short Form-36, Visual Analog Scale for Pain
Intensity, Neuro-QOL, and Norfolk Neuropathy Symp-
toms Score (7). With the visual analog scale, the patient
marks the intensity of their pain on a scale from 0 –10, al-
lowing an assessment of the response to intervention. Simul-
taneously, the patient should complete a quality of life tool
such as the Norfolk QOL-DN (17), which permits evalua-
tion of the impact of the pain on quality of life, anxiety, and
depression, known to be accompanying features of DPN.
The Clinical Examination
A careful evaluation of the nature of pain and its exact
location and a detailed examination of the lower limbs are
mandatory to ascertain alternate causes of pain (Table 1).
Laboratory Tests
These tests usually done for research: laser-evoked poten-
tials; contact heat-evoked potentials, whereby brain sig-
nals evoked by peripheral heat stimulation can be quan-
tified and amplitudes and conduction velocities of the slow
conducting fibers measured; and quantitative sensory tests
that measure the thresholds for various sensory modali-
ties, such as vibration and heat and cold perception, and
can be adapted to identifying hypoalgesia and hypoes-
thesia. Also included are 3-mm skin biopsies to quan-
titatively assess the number of nerve fibers present in the
epidermis. Paradoxically, these are reduced in number
in DPN (19 –21).
 4806 Vinik Approach to Pain Management in Diabetes J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811

Conditions Mimicking Diabetic Neuropathy
There are a number of conditions that can be mistaken for
painful diabetic neuropathy: intermittent claudication, in
which the pain is exacerbated by walking; Morton’s neu-
roma, in which the pain and tenderness are localized to the
intertarsal space, elicited by applying pressure with the
thumb in the appropriate intertarsal space; osteoarthritis,
in which the pain is confined to the joints and made worse
with joint movement or exercise and is associated with
morning stiffness that improves with ambulation; radic-
ulopathy, in which the pain originates in the shoulder,
arm, thorax, and back and radiates into the legs and feet;
Charcot neuropathy, in which the pain is localized to the
site of the collapse of the bones of the foot and the foot is
hot rather than cold, as occurs in neuropathy; plantar fas-
ciitis, in which there is shooting or burning in the heel with
each step and there is exquisite tenderness in the sole of
the foot; and tarsal tunnel syndrome, in which the pain
and numbness radiate from beneath the medial malle-
olus to the sole and are localized to the inner side of the
foot. These contrast with the pain of DPN, which is
bilateral, symmetrical, covering the whole foot and par-
ticularly the dorsum, and worse at night, interfering
with sleep.
Therapeutic Modalities for
Neuropathic Pain
The growing knowledge about the neural and pharmaco-
logical basis of neuropathic pain is likely to have impor-
tant treatment implications, including development and
refinement of a symptom/mechanism-based approach to
neuropathic pain and implementation of novel treatment
strategies using the newer antiepileptic agents, which may
address the underlying neurophysiological aberrations in
neuropathic pain, allowing the clinician to increase the
likelihood of effective management (Table 2). The neuro-
pharmacology of pain is also becoming better understood.
For example, recent data suggest that ␥-aminobutyric
acid, voltage-gated sodium channels, and glutamate re-
ceptors may be involved in the pathophysiology of neu-
ropathic pain. Many of the newer agents have significant
effects on these neurophysiological mechanisms. Hyper-
glycemia may be a factor in lowering the pain threshold.
Pain is often worse with wide glycemic excursions. Para-
doxically, acute onset of pain may appear soon after ini-
tiation of therapy with insulin or oral agents (22). In con-
trast, it has been reported that a striking amelioration of
symptoms can occur with continuous sc insulin adminis-
tration, which may reduce the amplitudes of excursion of
blood glucose (22). This dichotomy is not well explained.
There is a sequence in diabetic neuropathy, beginning
when A, ␤, and C nerve fiber function is intact and there
is no pain. With damage to C-fibers, there is sympathetic
sensitization, and peripheral autonomic symptoms are in-
terpreted as painful. Topical application of clonidine
causes antinociception by blocking emerging pain signals
at the peripheral terminals via ␣-2 adrenoreceptors (23), in
contrast with the central actions of clonidine on blood
pressure control. With the death of C-fibers, there is no-
ciceptor sensitization. A␤ fibers conduct all varieties of
peripheral stimuli such as touch and these are interpreted
as painful, e.g. allodynia. With time there is reorganization
at the cord level and the patient experiences cold hyper-
algesia and ultimately, even with the death of all fibers,
pain is registered in the cerebral cortex, whereupon the
syndrome becomes chronic without the need for periph-

TABLE 2. Treatments for symptomatic diabetic polyneuropathy: dosing and side effects
Drug class Drug Dose (mg) Side effects
Tricyclics Amitryptyline 50 –150 HS Somnolence, dizziness, dry mouth, tachycardia
Nortriptyline 50 –150 HS Constipation, urinary retention, blurred vision
Imipramine 25–150 HS Confusion
Desipramine 25–150 HS
SSRIs Paroxetine 40 QD Somnolence, dizziness, sweating, nausea, anorexia
Citalopram 40 QD Diarrhea, impotence, tremor
SNRIs Duloxetine 60 QD Nausea, somnolence, dizziness, anorexia
Anticonvulsants Gabapentin 300 –1200 TID Somnolence, dizziness, confusion, ataxia
Pregabalin 50 –150 TID Somnolence, confusion, edema, weight gain
Carbamazepine/oxcarbezepine Up to 200 QID Dizziness, somnolence, nausea, leukopenia
Topiramate Up to 400 QD Somnolence, dizziness, ataxia, tremor
Opiods Tramadol 50 –100 BID Nausea, constipation, HA somnolence
Oxycodone CR 10 –30 BID Somnolence, nausea, constipation, HA
Topical Capsaicin 0.075% QID Local irritation
Lidocaine 0.04% QD Local irritation
Injection Botulinum toxin None
QID, Four times daily.

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 J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811
eral stimulation. Disappearance of pain may not neces-
sarily reflect nerve recovery but rather nerve death. When
patients volunteer the loss of pain, progression of the neu-
ropathy must be excluded by careful examination.
Adrenergic blockers
Initially, when there is ongoing damage to the nerves,
the patient experiences pain of the burning, lancinating,
dysesthetic type often accompanied by hyperalgesia and
allodynia. Because the peripheral sympathetic nerve fibers
are also small unmyelinated C-fibers, sympathetic block-
ing agents (clonidine) may improve the pain.
Topical capsaicin
C-fibers use the neuropeptide substance P as their neu-
rotransmitter, and depletion of axonal substance P
(through the use of capsaicin) will often lead to amelio-
ration of the pain. Prolonged application of capsaicin de-
pletes stores of substance P, and possibly other neuro-
transmitters, from sensory nerve endings. This reduces or
abolishes the transmission of painful stimuli from the pe-
ripheral nerve fibers to the higher centers (24). Recent
analysis of randomized and controlled studies revealed
that either a repeated application of low doses of capsaicin
or single application of high doses affords pain relief (25).
Lidocaine
A multicenter randomized, open-label, parallel-group
study of lidocaine vs. pregabalin with a drug washout
phase of up to 2 wk and a comparative phase of 4-wk
treatment periods of 5% lidocaine (n ⫽ 99 vs. pregabalin,
n ⫽ 94) showed that lidocaine was as effective as pregaba-
lin in reducing pain and was free of side effects (26). This
form of therapy may be of most use in self-limited forms
of neuropathy. If successful, therapy can be continued
with oral mexiletine. This class of compounds targets the
pain caused by hyperexcitability of superficial, free nerve
endings (27).
Tramadol and N-methyl-D-aspartate (NMDA)
receptor antagonists
There are two possible targeted therapies. Tramadol is
a centrally acting weak opioid analgesic for use in treating
moderate to severe pain. Tramadol was shown to be better
than placebo in a randomized controlled trial (28) of only
6-wk duration, but a subsequent follow-up study sug-
gested that symptomatic relief could be maintained for at
least 6 months (29). Side effects are, however, relatively
common and are similar to other opioid-like drugs. An-
other spinal cord target for pain relief is the excitatory
glutaminergic NMDA receptor. Blockade of NMDA re-
ceptors is believed to be one mechanism by which dextro-
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methorphan exerts analgesic efficacy (30). The NMDA
receptors play an important role in central sensitization of
neuropathic pain. Their use, however, has not been wide-
spread due in part to dose-limiting side effects (31).
Antidepressants
Antidepressants are now emerging as the first line of
agents in the treatment of chronic neuropathic pain (32).
Clinical trials have focused on interrupting pain trans-
mission using antidepressant drugs that inhibit the re-
uptake of norepinephrine or serotonin. This central ac-
tion accentuates the effects of these neurotransmitters
in activation of endogenous pain-inhibitory systems in
the brain that modulate pain-transmission cells in the
spinal cord (33).
Tricyclic antidepressants (TCA)
With the development of newer agents, this class is now
being used less frequently due to cholinergic side effects of
dysautonomia, dry mouth, and fatigue that can be trou-
blesome. Caution needs to be exercised in patients with
ischemic heart disease and arrhythmias. Amitriptyline
and imipramine should be avoided in elderly patients
because they can exacerbate cognitive impairment and
gait disturbances, predisposing them to falls. Switching
to nortriptyline or desipramine may lessen some of the
anticholinergic effects of amitriptyline. The advantages
of TCA are that they can be administered once daily and
are inexpensive.
Selective serotonin reuptake inhibitors (SSRIs)
SSRIs inhibit presynaptic reuptake of serotonin but not
norepinephrine, but are not effective.
Selective serotonin norepinephrine reuptake
inhibitors (SNRIs)
There has been much focus on this group of drugs lately
in treatment of diabetic neuropathic pain. Duloxetine has
been studied in two doses of 60 and 120 mg for its effects
of reducing diabetic neuropathic pain and for pain in fi-
bromyalgia. To achieve an outcome of 50% pain relief
over 12–13 wk, the number needed to treat was 6 (Table
3). Adverse effects include nausea, constipation, somno-
lence, decreased appetite, some increase in fasting blood
sugar, and dry mouth (34, 35). There do not appear to be
any significant cardiovascular risks. Venlafaxine is an-
other SNRI that has mixed action on catecholamine up-
take. At lower doses, it inhibits serotonin uptake, and at
higher doses it inhibits norepinephrine uptake (36). The
extended-release version of venlafaxine was found to be
superior to placebo in diabetic neuropathic pain in non-
depressed patients at doses of 150 –225 mg/d, and when
 4808 Vinik Approach to Pain Management in Diabetes
TABLE 3. Odds ratios for efficacy and withdrawal, numbers needed to treat (NNT) and numbers needed to harm (NNH)
Drug class Efficacy
Tricyclics 22.2 (5.8 – 84.7)
Duloxetine 2.6 (1.6 – 4.8)
Traditional anticonvulsants 5.3 (1.8 –16.0)
Newer generation anticonvulsants 3.3 (2.3– 4.7)
Opioids 4.3 (2.3–7.8)
added to gabapentin there was improved pain, mood, and
quality of life (37).
Antiepileptic Drugs (AEDs)
Antiepileptic drugs (AEDs) have a long history of effec-
tiveness in the treatment of neuropathic pain, dating back
to case studies of the treatment of trigeminal neuralgia
with phenytoin in 1942 and carbamazepine in 1962 (38).
Principal mechanisms of action include sodium channel
blockade (felbamate, lamotrigine, oxcarbazepine, topira-
mate, zonisamide), potentiation of ␥-aminobutyric acid
activity (tiagabine, topiramate), calcium channel blockade
(felbamate, lamotrigine, topiramate, zonisamide), an-
tagonism of glutamate at NMDA receptors (felbamate)
or ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic
acid (felbamate, topiramate), and mechanisms of action
as yet to be fully determined (gabapentin, pregabalin,
levetiracetam) (39). An understanding of the mecha-
nisms of action of the various drugs leads to the concept
of “rational polytherapy,” where drugs with comple-
mentary mechanisms of action can be combined for syn-
ergistic effect. For example, one might choose a sodium
channel blocker such as lamotrigine to be used with a
glutamate antagonist such as felbamate. Furthermore, a
single drug may possess multiple mechanisms of action,
perhaps increasing its likelihood of success (e.g. topi-
ramate). If pain is divided according to its derivation
from different nerve fiber types (e.g. A␦ vs. C-fiber),
spinal cord or cortical, then different types of pain
should respond to different therapies.
In addition to providing efficacy against epilepsy, these
new AEDs may also be effective in neuropathic pain. For
example, spontaneous activity in regenerating small-cal-
iber primary afferent nerve fibers may be quelled by so-
dium channel blockade, and hyperexcitability in dorsal
horn spinal neurons may be decreased by the inhibition of
glutamate release—two mechanisms of action possessed
by the AED lamotrigine (40, 41). Clinical trials, how-
ever, have not been salutary (5). This was evident in our
patient who was being treated with lamotrigine for sei-
zures, and lamotrigine was ineffective in relieving pain.
In addition, the “wind-up” phenomenon caused by
nerve injury and the kindling that occurs in hippocam-
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Odds ratio
Withdrawal due to adverse effect NNT NNH
2.3 (0.6 –9.7) 1.5–3.5 2.7–17.0
2.4 (1.1–5.4) 5.7–5.8 15.0
1.5 (0.3–7.0) 2.1–3.2 2.7–3.0
3.0 (1.75–5.1) 2.9 – 4.3 26.1
4.1 (1.2–14.2) 2.6 –3.9 9.0
pal neurons in patients with mesial temporal sclerosis
both enlist activation of NMDA receptors (42, 43),
which can be affected by felbamate (39). The evidence
supporting the use of AEDs for the treatment of DPN
continues to evolve (36). Patients who have failed to
respond to one AED may respond to another or to two
or more drugs in combination (44).
Sodium Channel Blockers
Voltage-gated sodium channels are crucial determinants
of neuronal excitability and signaling. After nerve injury,
hyperexcitability and spontaneous firing develop at the
site of injury and also in the dorsal root ganglion cell bod-
ies. This hyperexcitability results at least partly from ac-
cumulation of sodium channels at the site of injury (45).
Carbamazepine and oxcarbazepine are most effective
against “lightning” pain (46).
Calcium Channel Modulators
Five types of voltage-gated calcium channels have been iden-
tified, and the L- and N-types of channels have a role to play
in the neuromodulation in the sensory neurons of the spinal
cord. Gabapentin and pregabalin are medications that bind
at the ␣ 2 ␦ subunits of the channels. Unlike traditional cal-
cium channel antagonists, they do not block calcium chan-
nels but modulate their activity and sites of expression. The
exact mechanism of action of this group of agents on neu-
romodulation has yet to be clearly defined.
Gabapentin
Gabapentin was significantly superior to placebo in pain
control, beginning at wk 2 and continuing through wk 8, and
it significantly reduced sleep interference beginning at wk 1
and continuing through wk 8. The most common adverse
events with gabapentin were dizziness and somnolence (47).
Gabapentin has the additional benefit of improving
sleep (47), which is often compromised in patients with
chronic pain (44). Over the long term, it is known to pro-
duce weight gain, which may complicate diabetes man-
agement (48). Combination therapy has been examined
using gabapentin and morphine, indicating slight superi-
ority of the combination (49).
 J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811
Pregabalin
Several randomized, double-blind, placebo-controlled, mul-
ticenter studies have evaluated the effectiveness of pregabalin
in a fixed dose with an open-label extension in alleviating
pain associated with DPN. Forty percent of patients receiving
pregabalin reported at least a 50% reduction in pain, com-
pared with 14.5% of the placebo group (P ⫽ 0.001) (50).
Secondary measures that improved included a reduc-
tion in mean sleep interference scores on the SF-36 Bodily
Pain subscale (P ⬍ 0.0001), total SF-MPQ score (P ⬍
0.05), and total mood disturbance and tension-anxiety
components of the Profile of Mood States (P ⬍ 0.03) (50).
In this respect, the data appear to be not unlike the early
reports on gabapentin.
Topiramate
Although topiramate failed in three clinical trials, due to
the use of the wrong endpoint (51), it has been shown to
successfully reduce pain and induce nerve regeneration
(52), and has the added advantage of causing weight loss
and improving the lipoprotein profile particularly useful
in overweight type 2 diabetic patients.
Botulinum Toxin
Botulinum toxin has been tried for trigeminal neuralgia
(53) and has been shown to have long-lasting antinoci-
ceptive effects in carpal tunnel syndrome with no electro-
physiological restoration (54).
Guidelines
Figure 1 is an algorithm that we propose for the manage-
ment of painful neuropathy in diabetes. This starts with
identification of neuropathic pain being focal or diffuse.
FIG. 1. Treatment algorithm: neuropathic pain after exclusion of
nondiabetic etiologies and stabilization of glycemic control.
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Focal neuropathic pain is best treated with diuretics to
reduce edema in the canal, splinting, and surgery to release
entrapment. Diffuse neuropathies are treated with medi-
cal therapy and in a majority of cases, need multidrug
therapy. Immune-mediated neuropathies are treated with
iv Ig, steroid, or other immunomodulators.
Back to the Patient
Having reviewed the treatment options we return to the
patient.
If this was insulin neuritis syndrome, it would simply be
a matter of time and would recover spontaneously. How-
ever, the patient clearly had an eating disorder, anxiety/
depression, evidence of autoimmunity, and autonomic
nerve dysfunction. She was started on topiramate 15 mg
QD for 1 month, increased to 25 mg, and then to 50 mg/d.
Topiramate has been shown to induce nerve regeneration
and also reduces body weight in contrast with gabapentin,
which causes weight gain. We added NutriNerve (an over-
the-counter combination of antioxidants) at a dose of
two tablets BID because this contains ␣-lipoic acid,
which has been shown to improve autonomic dysfunc-
tion (55). Thirdly, she was placed on topical lidoderm
to reduce the allodynia and hyperalgesia. Because of the
seizure disorder, we endorsed the use of gabapentin and
lamotrigine.
June 16, 2009
Her legs and feet still hurt very badly. She was very weepy,
and one could not touch her toes. She had a magnetic reso-
nance image done bilaterally of the feet, and this was found
to be negative for impending Charcot neuropathy. Her heart
rate had returned toward normal, about 80 bpm.
Our impression of the effects of topiramate (25 mg/d),
NutriNerve (two pills BID), and a 5% lidoderm patch was
that the pain has lessened some, but was still bad at night. In
light of the very intense autoimmune response with the ap-
optosis of neuronal cells in culture, we resolved to do the
following: 1) give her a course of iv Ig at 1.0 g/kg䡠d on con-
secutive days (two per week) for 3 wk; 2) increase the dose of
topiramate to 50 mg/d and possibly to 100 mg/d; and 3)
replace the vitamin D with 50,000 U ergocalciferol every
month.
July to November 2009
We were making slow progress and decided to give her a
course of botulinum toxin into her feet. The pain soon started
to improve, and a second course was given in December.
October 19, 2009
Her Lantus was changed to 13 U in the morning and 26
U in the evening. She was also to use Novolog coverage (1
 4810 Vinik Approach to Pain Management in Diabetes
U for every 12 g of carbohydrate for meals and snacks,
along with 1 U for every 50 mg/dl of blood sugar ⬎200
mg/dl). She is currently covering with 1 U for 10 g of
carbohydrate and 1 U for every 50 mg/dl blood sugar
greater than 150 mg/dl.
She checks her blood sugar “too much”—about 10 –15
times daily. The range is usually 70 –140 mg/dl. For the
past couple of days, the results have been higher and she
is upset. For anxiety/depression, Ativan 1 mg BID was
increased to three times daily (TID). Ambien was also in-
creased from 10 to 12.5 mg HS.
November 16, 2009
She was feeling better. Her hemoglobin A1c was 5.5,
down from 8.8 in May 2009.
January 2010
Pain had resolved completely. Diabetes control remained
superb. The patient had started to reduce the dosages of the
medications, and she had returned to doing a full exercise
program including Pilates and yoga! Repeat autonomic func-
tion tests showed improvement in the autonomic function,
and the neuronal apoptosis assay had become negative.
Conclusions
Painful neuropathy is an important complication of dia-
betes, and our patient illustrates that pathogenesis is mul-
tifactorial and requires attention to detail of management
if one is to achieve success. Two drugs have been approved
for neuropathic pain in the United States, pregabalin and
duloxetine, but neither of these afforded relief, even when
used in combination. If we had neglected the evidence for
an eating disorder, manipulation of insulin dosing, the
presence of significant autoimmunity and autonomic dys-
function, as well as the huge psychological disturbance
and not used a holistic positive approach to the patient we
might have failed. Indeed, a sobering view is that few drugs
achieve a greater than 30% reduction in pain in more than
50% of patients, dictating a need to use more than one
drug with different mechanisms of action. Even in the class
of AEDs, not all are created equal as shown here. There is
a great need to understand pathogenic mechanisms more
fully, particularly the differences in origin of peripheral
and central pain. Our patient, when subject to traditional
measures of nerve function, would have been labeled as
hysterical because all nerve function studies are often nor-
mal with severe painful syndromes. A holistic approach is
essential, and the doctor and patient need to generate trust
and a positive attitude. One needs to be aware of the con-
ditions that masquerade as painful neuropathy and the
treatment directed toward the underlying disorder as sug-
gested in the algorithm provided. As Winston Churchill
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said, “We need to go from failure to failure without losing
our enthusiasm and ultimately we will succeed….”
Acknowledgments
Address all correspondence and requests for reprints to: Aaron
Vinik, Department of Internal Medicine, Eastern Virginia Med-
ical School, Strelitz Diabetes Center and Neuroendocrine Unit at
Norfolk, Norfolk, Virginia 23510. E-mail: vinikai@evms.edu.
Disclosure Summary: A.V. is a consultant for Ansar,
AstraZeneca, Eli Lilly, KV Pharmaceuticals, Merck, Novartis
Pharmaceuticals, R.W. Johnson Pharmaceutical Research Insti-
tute, Sanofi-Aventis, Takeda, and Tercica; and is on the speakers
bureau for Abbott, Ansar, AstraZeneca, Bristol Meyer Squibb,
Eli Lilly, GlaxoSmith Kline Beecham, Merck, Novartis Pharma-
ceuticals, Pfizer Inc., Sanofi-Aventis, and Takeda.
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