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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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pliance with treatment resulting in a general worsening of 2009. She had been admitted to an eating disorder clinic
the condition. Patients with chronic neuropathic pain re- from February 2009 through April 10, 2009. She had been
port poor physical health and mental conditions com- on an insulin pump that she had manipulated to control
pared with those with other causes of chronic pain even her weight and was subsequently placed on an injectable
adjusting for pain intensity (3). Diabetic neuropathy pain combination of short- and long-acting insulin, Lantus (40
is a difficult-to-manage clinical problem. It is often asso- U in the morning) and NovoLog (1 U for every 15 g of
ciated with mood and sleep disturbances, and patients carbohydrate for meals and snacks and 1 U for every 50
with diabetic neuropathy pain are more apt to seek med- mg/dl of her blood glucose greater than 100 mg/dl). On
ical attention than those with other types of diabetic neu- this regimen, her blood glucose levels averaged 100 to 220
ropathy. Two population-based studies showed that neu- mg/dl without hypoglycemic episodes. Within 2–3 months
ropathic pain is associated with a greater psychological of this therapy, she developed intractable pain and was
burden than nociceptive pain (4) and is considered to be referred for consultation. The pain was burning and ach-
more severe than other pain types. Early recognition of ing with tenderness bilaterally in the feet and the legs, as
psychological problems is critical to the management of well as in the hips. A rheumatologist had diagnosed fibro-
pain, and physicians need to go beyond the management myalgia and prescribed Gabapentin [100 mg twice daily
of pain per se if they are to achieve success. Patients may (BID), 200 mg at bedtime (HS) for 2 wk, increased to 200 mg
also complain of decreased physical activity and mobility, three times a day for 1 week, and then increased to 300 mg
increased fatigue, and negative effects on their social lives. BID and 600 mg at bedtime]. This had no real impact on the
Providing significant pain relief markedly improves qual- pain. She was very distressed and tearful, was confined to
ity-of-life measures, including sleep and vitality (5). Be- bed, and was unable to sleep. Advil two to three times per day
cause of its complexity, the presentation of pain poses a eased the pain slightly. Her last hemoglobin A1c was 9.0.
diagnostic dilemma for the clinician who needs to distin- She had exercised regularly, including Pilates, before
guish between neuropathic pain arising as a direct conse- the pain occurred, but she stopped because of pain. She
quence of a lesion or disease of the somatosensory system had an eye exam in the fall of 2008, and there was no
and nociceptive pain that is due to trauma, inflammation, evidence of retinopathy. Her urine specimen contained no
or injury. It is imperative to try to establish the nature of protein and was negative for ketones. She had developed
any predisposing factor, including the pathogenesis of the grand mal seizures controlled with lamotrigine 150 mg
pain, if one is to be successful in its management. Man- daily (QD). She denied stress or phobia, although she had
agement of neuropathic pain requires a sound relationship some difficulty with heights. She attended college and
between patient and physician, with an emphasis on a lived at home with her parents. Her family history revealed
positive outlook and encouragement that there is a solu- an older sister who suffered from some degree of anxiety;
tion, using patience and targeted pain-centered strategies her mother had Hashimoto thyroiditis and also had rheu-
that deal with the underlying disorder rather than the matoid arthritis, for which she was treated with Enbrel and
usual “Band-aid” prescription of drugs approved for gen- methotrexate in small doses. Her father is disease free. Her
eral pain, which do not address the disease process. The maternal grandmother had Hashimoto thyroiditis with di-
inciting injury may be focal or diffuse and may involve abetes, and her grandfather had a myocardial infarction. On
single, or more likely, multiple mechanisms such as meta- the paternal side, there was a history of lung cancer. The
bolic disturbances encompassing hyperglycemia, dyslipide- patient smoked a pack of cigarettes a day for 5 yr, but quit in
mia, glucose fluctuations, or intensification of therapy with November 2008. She did not consume alcohol or use illegal
insulin. On the other hand, the injury might embrace auto- drugs. She had not been exposed to heavy metals, organo-
immune mechanisms, neurovascular insufficiency, deficient toxins, or other toxins. She was not intolerant to cold or
neurotrophism, oxidative and nitrosative stress, and inflam- constipated and had no voice change or hair loss.
mation (6). Because pain syndromes in diabetes may be focal
or diffuse, proximal or distal, acute or chronic, each has its
Physical examination
own pathogenesis, and the treatment must be tailored to the
Physical exam revealed an alert and oriented individual
underlying disorder if the outcome is to be successful.
who, although tearful, communicated well. She had no pig-
mentation change and no dry or brittle hair. She had a few
The Case psoriatic lesions at the back of her head, but not elsewhere.
Head, eyes, ears, nose, and throat were within normal
We first saw the patient—a 24-yr-old female with poorly limits. She had no lymphadenopathy. Her chest and lungs
controlled type 1 diabetes for the past 6 yr and an eating were clear. There were no breast masses. Her heart was
disorder with anorexia/bulimia syndrome— on May 19, normal without murmurs. Her abdomen was soft, non-

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4804 Vinik Approach to Pain Management in Diabetes J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811

TABLE 1. Examination: bedside sensory tests


Sensory modality Nerve fiber Instrument Associated sensory receptors
Vibration A␤ (large) 128-Hz tuning fork Ruffini corpuscle mechanoreceptors
Pain (pin prick) C (small) Neuro-tips Nociceptors for pain and warmth
Pressure A␤, A␣ (large) 1 and 10 g monofilament Pacinian corpuscle
Light touch A␤, A␣ (large) Wisp of cotton Meissner’s corpuscle
Cold A␦ (small) Cold tuning fork Cold thermoreceptors

tender, and without masses. Her musculoskeletal system tein microalbumin, 12.8 ␮g/ml; TSH, 1.329 ␮U/ml; glu-
was intact. She had good dorsalis pedis and posterior tibial cose, 253 mg/dl (elevated); blood urea nitrogen, 18 mg/dl;
pulses. Application of pressure to her feet caused her to creatinine, 0.5 mg/dl; electrolytes, within normal limits;
scream in agony. She weighed 120.4 pounds and was 5 feet serum glutamic oxaloacetic transaminase, 19; serum glu-
11 inches tall. Her body mass index was 16.7 kg/m2. Her tamic pyruvic transaminase, 25; alkaline phosphatase, 64;
waist was 26 inches and hip measurement was 34 in, with a calcium and magnesium, within normal limits; estimated
waist-hip ratio of 0.766. Supine blood pressure was 119/78 glomerular filtration rate, 59 ml/min; antinuclear factor
mm Hg with a pulse of 94 bpm, sitting blood pressure was antibodies, negative; C-reactive protein, 0.1; sedimenta-
125/82 mm Hg with a pulse of 107 bpm, and standing blood tion rate, 12; glutamic acid decarboxylase antibody, 4.7
pressure was 109/78 mm Hg with a pulse of 81 bpm. (elevated); and gastric parietal cell antibodies, 1.6. Serum
protein electrophoresis revealed no gammopathy, and no
Neurological examination motor or sensory nerve antibodies were detected; acetyl-
Cranial nerves were intact. Her pupils were large, re- choline receptor antibodies in serum and antinuclear fac-
acted to light, and accommodated poorly suggesting au- tor were negative. Serum folate and B12 were normal.
tonomic dysfunction. She had no evidence of muscle Urine porphyrins and urine heavy metals were negative.
weakness. Handgrip dynamometry was at the 10th per- Serum angiotensin-converting enzyme was normal. Lyme,
centile bilaterally. All her reflexes were present, and upper HIV, and hepatitis screening tests were all negative.
limb sensation was entirely intact. In the lower limb, she Neuronal cells were incubated in culture with her se-
had a reduction of prickling pain perception to 15 cm on rum. With control pooled human serum, 100,000 cells
the right and 22 cm on the left, but she had marked hy- increased to 871,250 by the fourth day; with her serum,
peralgesic and hyperesthetic soles of her feet. Vibration 100,000 cells fell to 11,250 by the second day and fell
perception was intact, there was some slight loss of joint further to zero by the third and fourth days. There was no
position, but perception of 1- and 10-g monofilament was recovery of these cells, indicating that her serum was
intact. Her total neuropathy scores were 5 on the right and highly toxic to neuronal cells in culture and indicative of
6 on the left, which indicated a mild degree of peripheral an autoimmune response (8).
neuropathy (7). The use of simple clinical tools is illus-
trated in Table 1.
Clinical Considerations
Laboratory studies My impressions were that this young woman had type 1
A quantitative sensory test done on May 12, 2009, diabetes for 6 yr, a seizure disorder, and anxiety, with
showed normal vibration perception, touch/pressure, claustrophobic panic disorder. She was an anorexic bu-
warm and cold thermal perception, indicating that her limic and was using an insulin pump to allow her to adjust
somatic nervous system was intact. the insulin doses down so that she could lose weight. When
A cardiac autonomic function test revealed an expira- placed on a regular insulin regimen, monitored in an in-
tion/inspiration ratio of 1.14, a Valsalva ratio of 1.05, and stitution, she could no longer do this and within a few
a 30:15 ratio of 1.05. This very abnormal result indicated weeks of the intensification of insulin developed a severe,
autonomic nerve dysfunction. The QTc interval was highly sensory form of neuropathy with autonomic man-
425 msec on electrocardiogram, which was normal. She ifestations, classic of the insulin neuritis syndrome. She
had a sinus tachycardia syndrome of 100 bpm and ap- had a long family history of autoimmune disease, and her
peared to have slight left atrial enlargement, but no serum was highly toxic to neurons in culture, suggesting
other abnormalities. the possibility of autoimmune disease. Neuropathic pain
Vitamin D level was 10.7 ng/ml, which is inordinately is not uncommon. A population-based survey of 6000
low. The remainder of the biochemistries were: urine pro- patients treated in family practice in the United Kingdom

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reported 6% prevalence of pain predominantly of neuro- duction. Pain is deep seated and gnawing in quality, “like
pathic origin (9). Similarly, a large population-based study a toothache” in the foot, or “a dog gnawing at the bones
in France showed that 6.9% of the population had neu- of the feet,” or “feet feel as if they are encased in concrete.”
ropathic pain (4). Interestingly, in a Dutch population sur- In contrast, the nociceptive pain of arthritis does not
vey of more than 362,000 people, younger people with have these qualities. It is localized to the joints; fasciitis is
pain tended to be mostly women, but with advancing age localized to the fascia; entrapment produces pain in a der-
the gender differences disappeared. Perhaps a little recog- matome, and claudication is made worse by walking. Ar-
nized fact is that mononeuritis and entrapments were three thritic pain starts with morning stiffness and improves as
times as common as diabetic peripheral neuropathy the day wears on (18).
(DPN), and fully one third of the diabetic population has It is noteworthy that one third of patients with diabetes
some form of entrapment (10), which when recognized is have some form of entrapment. In contrast with the
readily amenable to intervention (11). Even more salutary mononeuropathies, the condition begins gradually and is
is the mounting evidence that even with impaired glucose made worse with repeated minor trauma or history of
tolerance, patients may experience pain (12–14). As a cor- occupational exposure. The sensory disturbance often
ollary, patients presenting with painful neuropathy have does not reflect the nerve distribution, and the pain can
impaired fasting glucose or impaired glucose tolerance, exceed the area of sensory innervation leading to incorrect
and about 50% of the time, they are overweight and have diagnosis. Nerve conduction velocity is required to show
autonomic dysfunction (12). Even in the absence of ele- impairment of conduction across the site of entrapment.
vated fasting blood glucose (⬍100 mg/dl), pain may be the Evaluation of pain intensity is essential for monitoring
presenting feature of the metabolic syndrome and coseg- response to therapy. There are a number of symptom-
regates with elevated triglycerides and a low high-density based screening tools, such as: Nerve Total Symptom
lipoprotein-cholesterol (15). Indeed, a risk factor for neu- Score-6, Brief Pain Inventory, Quality of Life Diabetic
ropathic pain in diabetic and nondiabetic populations is Neuropathy, Short Form-36, Visual Analog Scale for Pain
an impairment of peripheral vascular function (14, 16). 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-
The Clinical History lowing an assessment of the response to intervention. Simul-
taneously, the patient should complete a quality of life tool
History taking is becoming an obsolete art. Without it, ar-
such as the Norfolk QOL-DN (17), which permits evalua-
riving at the correct diagnosis can be hazardous. Pain asso-
tion of the impact of the pain on quality of life, anxiety, and
ciated with a peripheral nerve injury has several distinct clin-
depression, known to be accompanying features of DPN.
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 The Clinical Examination
as formication. Some describe bees stinging through the
socks, whereas others talk of walking on hot coals. The pain, A careful evaluation of the nature of pain and its exact
worse at night, keeps the patient awake and is associated with location and a detailed examination of the lower limbs are
sleep deprivation (17). Patients volunteer that they have al- mandatory to ascertain alternate causes of pain (Table 1).
lodynia or pain from normal stimuli, such as the touch of
bedclothes, and may have hyperesthesias, increased sensitiv- Laboratory Tests
ity to touch, or hyperalgesia with increased sensitivity to
painful stimuli or even altered sensation to cold or heat. These tests usually done for research: laser-evoked poten-
These may be paradoxical with differences in sensation to tials; contact heat-evoked potentials, whereby brain sig-
one or other modality of stimulation. Unlike animal models nals evoked by peripheral heat stimulation can be quan-
of DPN, the pain is spontaneous and does not need provo- tified and amplitudes and conduction velocities of the slow
cation such as a hot plate or laser heat. It is a glove and conducting fibers measured; and quantitative sensory tests
stocking distribution. Small fiber neuropathies usually that measure the thresholds for various sensory modali-
present with pain in the feet or hands, do not have abnor- ties, such as vibration and heat and cold perception, and
malities in sensation, lack weakness or loss of reflexes, are can be adapted to identifying hypoalgesia and hypoes-
electrophysiologically silent, and often lead to the erroneous thesia. Also included are 3-mm skin biopsies to quan-
diagnosis of hysteria or conversion reactions. titatively assess the number of nerve fibers present in the
Large fiber neuropathy presents with characteristic epidermis. Paradoxically, these are reduced in number
weakness, ataxia, loss of reflexes, and impaired nerve con- in DPN (19 –21).

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4806 Vinik Approach to Pain Management in Diabetes J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811

Conditions Mimicking Diabetic Neuropathy strategies using the newer antiepileptic agents, which may
address the underlying neurophysiological aberrations in
There are a number of conditions that can be mistaken for neuropathic pain, allowing the clinician to increase the
painful diabetic neuropathy: intermittent claudication, in likelihood of effective management (Table 2). The neuro-
which the pain is exacerbated by walking; Morton’s neu- pharmacology of pain is also becoming better understood.
roma, in which the pain and tenderness are localized to the For example, recent data suggest that ␥-aminobutyric
intertarsal space, elicited by applying pressure with the
acid, voltage-gated sodium channels, and glutamate re-
thumb in the appropriate intertarsal space; osteoarthritis,
ceptors may be involved in the pathophysiology of neu-
in which the pain is confined to the joints and made worse
ropathic pain. Many of the newer agents have significant
with joint movement or exercise and is associated with
effects on these neurophysiological mechanisms. Hyper-
morning stiffness that improves with ambulation; radic-
glycemia may be a factor in lowering the pain threshold.
ulopathy, in which the pain originates in the shoulder,
Pain is often worse with wide glycemic excursions. Para-
arm, thorax, and back and radiates into the legs and feet;
doxically, acute onset of pain may appear soon after ini-
Charcot neuropathy, in which the pain is localized to the
tiation of therapy with insulin or oral agents (22). In con-
site of the collapse of the bones of the foot and the foot is
trast, it has been reported that a striking amelioration of
hot rather than cold, as occurs in neuropathy; plantar fas-
symptoms can occur with continuous sc insulin adminis-
ciitis, in which there is shooting or burning in the heel with
tration, which may reduce the amplitudes of excursion of
each step and there is exquisite tenderness in the sole of
blood glucose (22). This dichotomy is not well explained.
the foot; and tarsal tunnel syndrome, in which the pain
There is a sequence in diabetic neuropathy, beginning
and numbness radiate from beneath the medial malle-
when A, ␤, and C nerve fiber function is intact and there
olus to the sole and are localized to the inner side of the
is no pain. With damage to C-fibers, there is sympathetic
foot. These contrast with the pain of DPN, which is
sensitization, and peripheral autonomic symptoms are in-
bilateral, symmetrical, covering the whole foot and par-
ticularly the dorsum, and worse at night, interfering terpreted as painful. Topical application of clonidine
with sleep. 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-
Therapeutic Modalities for
ciceptor sensitization. A␤ fibers conduct all varieties of
Neuropathic Pain
peripheral stimuli such as touch and these are interpreted
The growing knowledge about the neural and pharmaco- as painful, e.g. allodynia. With time there is reorganization
logical basis of neuropathic pain is likely to have impor- at the cord level and the patient experiences cold hyper-
tant treatment implications, including development and algesia and ultimately, even with the death of all fibers,
refinement of a symptom/mechanism-based approach to pain is registered in the cerebral cortex, whereupon the
neuropathic pain and implementation of novel treatment 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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eral stimulation. Disappearance of pain may not neces- methorphan exerts analgesic efficacy (30). The NMDA
sarily reflect nerve recovery but rather nerve death. When receptors play an important role in central sensitization of
patients volunteer the loss of pain, progression of the neu- neuropathic pain. Their use, however, has not been wide-
ropathy must be excluded by careful examination. spread due in part to dose-limiting side effects (31).

Adrenergic blockers Antidepressants


Initially, when there is ongoing damage to the nerves, Antidepressants are now emerging as the first line of
the patient experiences pain of the burning, lancinating, agents in the treatment of chronic neuropathic pain (32).
dysesthetic type often accompanied by hyperalgesia and Clinical trials have focused on interrupting pain trans-
allodynia. Because the peripheral sympathetic nerve fibers mission using antidepressant drugs that inhibit the re-
are also small unmyelinated C-fibers, sympathetic block- uptake of norepinephrine or serotonin. This central ac-
ing agents (clonidine) may improve the pain. tion accentuates the effects of these neurotransmitters
in activation of endogenous pain-inhibitory systems in
Topical capsaicin the brain that modulate pain-transmission cells in the
C-fibers use the neuropeptide substance P as their neu- spinal cord (33).
rotransmitter, and depletion of axonal substance P
(through the use of capsaicin) will often lead to amelio- Tricyclic antidepressants (TCA)
ration of the pain. Prolonged application of capsaicin de- With the development of newer agents, this class is now
pletes stores of substance P, and possibly other neuro- being used less frequently due to cholinergic side effects of
transmitters, from sensory nerve endings. This reduces or dysautonomia, dry mouth, and fatigue that can be trou-
abolishes the transmission of painful stimuli from the pe- blesome. Caution needs to be exercised in patients with
ripheral nerve fibers to the higher centers (24). Recent ischemic heart disease and arrhythmias. Amitriptyline
analysis of randomized and controlled studies revealed and imipramine should be avoided in elderly patients
that either a repeated application of low doses of capsaicin because they can exacerbate cognitive impairment and
or single application of high doses affords pain relief (25). gait disturbances, predisposing them to falls. Switching
to nortriptyline or desipramine may lessen some of the
Lidocaine anticholinergic effects of amitriptyline. The advantages
A multicenter randomized, open-label, parallel-group of TCA are that they can be administered once daily and
study of lidocaine vs. pregabalin with a drug washout are inexpensive.
phase of up to 2 wk and a comparative phase of 4-wk
treatment periods of 5% lidocaine (n ⫽ 99 vs. pregabalin, Selective serotonin reuptake inhibitors (SSRIs)
n ⫽ 94) showed that lidocaine was as effective as pregaba- SSRIs inhibit presynaptic reuptake of serotonin but not
lin in reducing pain and was free of side effects (26). This norepinephrine, but are not effective.
form of therapy may be of most use in self-limited forms
of neuropathy. If successful, therapy can be continued Selective serotonin norepinephrine reuptake
with oral mexiletine. This class of compounds targets the inhibitors (SNRIs)
pain caused by hyperexcitability of superficial, free nerve There has been much focus on this group of drugs lately
endings (27). in treatment of diabetic neuropathic pain. Duloxetine has
been studied in two doses of 60 and 120 mg for its effects
Tramadol and N-methyl-D-aspartate (NMDA) of reducing diabetic neuropathic pain and for pain in fi-
receptor antagonists bromyalgia. To achieve an outcome of 50% pain relief
There are two possible targeted therapies. Tramadol is over 12–13 wk, the number needed to treat was 6 (Table
a centrally acting weak opioid analgesic for use in treating 3). Adverse effects include nausea, constipation, somno-
moderate to severe pain. Tramadol was shown to be better lence, decreased appetite, some increase in fasting blood
than placebo in a randomized controlled trial (28) of only sugar, and dry mouth (34, 35). There do not appear to be
6-wk duration, but a subsequent follow-up study sug- any significant cardiovascular risks. Venlafaxine is an-
gested that symptomatic relief could be maintained for at other SNRI that has mixed action on catecholamine up-
least 6 months (29). Side effects are, however, relatively take. At lower doses, it inhibits serotonin uptake, and at
common and are similar to other opioid-like drugs. An- higher doses it inhibits norepinephrine uptake (36). The
other spinal cord target for pain relief is the excitatory extended-release version of venlafaxine was found to be
glutaminergic NMDA receptor. Blockade of NMDA re- superior to placebo in diabetic neuropathic pain in non-
ceptors is believed to be one mechanism by which dextro- depressed patients at doses of 150 –225 mg/d, and when

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4808 Vinik Approach to Pain Management in Diabetes J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811

TABLE 3. Odds ratios for efficacy and withdrawal, numbers needed to treat (NNT) and numbers needed to harm (NNH)
Odds ratio
Drug class Efficacy Withdrawal due to adverse effect NNT NNH
Tricyclics 22.2 (5.8 – 84.7) 2.3 (0.6 –9.7) 1.5–3.5 2.7–17.0
Duloxetine 2.6 (1.6 – 4.8) 2.4 (1.1–5.4) 5.7–5.8 15.0
Traditional anticonvulsants 5.3 (1.8 –16.0) 1.5 (0.3–7.0) 2.1–3.2 2.7–3.0
Newer generation anticonvulsants 3.3 (2.3– 4.7) 3.0 (1.75–5.1) 2.9 – 4.3 26.1
Opioids 4.3 (2.3–7.8) 4.1 (1.2–14.2) 2.6 –3.9 9.0

added to gabapentin there was improved pain, mood, and pal neurons in patients with mesial temporal sclerosis
quality of life (37). both enlist activation of NMDA receptors (42, 43),
which can be affected by felbamate (39). The evidence
Antiepileptic Drugs (AEDs) supporting the use of AEDs for the treatment of DPN
Antiepileptic drugs (AEDs) have a long history of effec- continues to evolve (36). Patients who have failed to
tiveness in the treatment of neuropathic pain, dating back respond to one AED may respond to another or to two
to case studies of the treatment of trigeminal neuralgia or more drugs in combination (44).
with phenytoin in 1942 and carbamazepine in 1962 (38).
Principal mechanisms of action include sodium channel Sodium Channel Blockers
blockade (felbamate, lamotrigine, oxcarbazepine, topira- Voltage-gated sodium channels are crucial determinants
mate, zonisamide), potentiation of ␥-aminobutyric acid of neuronal excitability and signaling. After nerve injury,
activity (tiagabine, topiramate), calcium channel blockade hyperexcitability and spontaneous firing develop at the
(felbamate, lamotrigine, topiramate, zonisamide), an- site of injury and also in the dorsal root ganglion cell bod-
tagonism of glutamate at NMDA receptors (felbamate) ies. This hyperexcitability results at least partly from ac-
or ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic cumulation of sodium channels at the site of injury (45).
acid (felbamate, topiramate), and mechanisms of action Carbamazepine and oxcarbazepine are most effective
as yet to be fully determined (gabapentin, pregabalin, against “lightning” pain (46).
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- Calcium Channel Modulators
mentary mechanisms of action can be combined for syn- Five types of voltage-gated calcium channels have been iden-
ergistic effect. For example, one might choose a sodium tified, and the L- and N-types of channels have a role to play
channel blocker such as lamotrigine to be used with a in the neuromodulation in the sensory neurons of the spinal
glutamate antagonist such as felbamate. Furthermore, a cord. Gabapentin and pregabalin are medications that bind
single drug may possess multiple mechanisms of action, at the ␣ 2 ␦ subunits of the channels. Unlike traditional cal-
perhaps increasing its likelihood of success (e.g. topi- cium channel antagonists, they do not block calcium chan-
ramate). If pain is divided according to its derivation nels but modulate their activity and sites of expression. The
from different nerve fiber types (e.g. A␦ vs. C-fiber), exact mechanism of action of this group of agents on neu-
spinal cord or cortical, then different types of pain romodulation has yet to be clearly defined.
should respond to different therapies.
In addition to providing efficacy against epilepsy, these Gabapentin
new AEDs may also be effective in neuropathic pain. For Gabapentin was significantly superior to placebo in pain
example, spontaneous activity in regenerating small-cal- control, beginning at wk 2 and continuing through wk 8, and
iber primary afferent nerve fibers may be quelled by so- it significantly reduced sleep interference beginning at wk 1
dium channel blockade, and hyperexcitability in dorsal and continuing through wk 8. The most common adverse
horn spinal neurons may be decreased by the inhibition of events with gabapentin were dizziness and somnolence (47).
glutamate release—two mechanisms of action possessed Gabapentin has the additional benefit of improving
by the AED lamotrigine (40, 41). Clinical trials, how- sleep (47), which is often compromised in patients with
ever, have not been salutary (5). This was evident in our chronic pain (44). Over the long term, it is known to pro-
patient who was being treated with lamotrigine for sei- duce weight gain, which may complicate diabetes man-
zures, and lamotrigine was ineffective in relieving pain. agement (48). Combination therapy has been examined
In addition, the “wind-up” phenomenon caused by using gabapentin and morphine, indicating slight superi-
nerve injury and the kindling that occurs in hippocam- ority of the combination (49).

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Pregabalin Focal neuropathic pain is best treated with diuretics to


Several randomized, double-blind, placebo-controlled, mul- reduce edema in the canal, splinting, and surgery to release
ticenter studies have evaluated the effectiveness of pregabalin entrapment. Diffuse neuropathies are treated with medi-
in a fixed dose with an open-label extension in alleviating cal therapy and in a majority of cases, need multidrug
pain associated with DPN. Forty percent of patients receiving therapy. Immune-mediated neuropathies are treated with
pregabalin reported at least a 50% reduction in pain, com- iv Ig, steroid, or other immunomodulators.
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 Back to the Patient
Pain subscale (P ⬍ 0.0001), total SF-MPQ score (P ⬍ Having reviewed the treatment options we return to the
0.05), and total mood disturbance and tension-anxiety patient.
components of the Profile of Mood States (P ⬍ 0.03) (50). If this was insulin neuritis syndrome, it would simply be
In this respect, the data appear to be not unlike the early a matter of time and would recover spontaneously. How-
reports on gabapentin. ever, the patient clearly had an eating disorder, anxiety/
depression, evidence of autoimmunity, and autonomic
Topiramate
nerve dysfunction. She was started on topiramate 15 mg
Although topiramate failed in three clinical trials, due to
QD for 1 month, increased to 25 mg, and then to 50 mg/d.
the use of the wrong endpoint (51), it has been shown to
Topiramate has been shown to induce nerve regeneration
successfully reduce pain and induce nerve regeneration
and also reduces body weight in contrast with gabapentin,
(52), and has the added advantage of causing weight loss
which causes weight gain. We added NutriNerve (an over-
and improving the lipoprotein profile particularly useful
the-counter combination of antioxidants) at a dose of
in overweight type 2 diabetic patients.
two tablets BID because this contains ␣-lipoic acid,
which has been shown to improve autonomic dysfunc-
Botulinum Toxin
tion (55). Thirdly, she was placed on topical lidoderm
Botulinum toxin has been tried for trigeminal neuralgia
to reduce the allodynia and hyperalgesia. Because of the
(53) and has been shown to have long-lasting antinoci-
seizure disorder, we endorsed the use of gabapentin and
ceptive effects in carpal tunnel syndrome with no electro-
lamotrigine.
physiological restoration (54).
June 16, 2009
Guidelines Her legs and feet still hurt very badly. She was very weepy,
and one could not touch her toes. She had a magnetic reso-
Figure 1 is an algorithm that we propose for the manage- nance image done bilaterally of the feet, and this was found
ment of painful neuropathy in diabetes. This starts with to be negative for impending Charcot neuropathy. Her heart
identification of neuropathic pain being focal or diffuse. 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


FIG. 1. Treatment algorithm: neuropathic pain after exclusion of Her Lantus was changed to 13 U in the morning and 26
nondiabetic etiologies and stabilization of glycemic control. U in the evening. She was also to use Novolog coverage (1

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4810 Vinik Approach to Pain Management in Diabetes J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811

U for every 12 g of carbohydrate for meals and snacks, said, “We need to go from failure to failure without losing
along with 1 U for every 50 mg/dl of blood sugar ⬎200 our enthusiasm and ultimately we will succeed….”
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. Acknowledgments
She checks her blood sugar “too much”—about 10 –15
times daily. The range is usually 70 –140 mg/dl. For the Address all correspondence and requests for reprints to: Aaron
past couple of days, the results have been higher and she Vinik, Department of Internal Medicine, Eastern Virginia Med-
is upset. For anxiety/depression, Ativan 1 mg BID was ical School, Strelitz Diabetes Center and Neuroendocrine Unit at
increased to three times daily (TID). Ambien was also in- Norfolk, Norfolk, Virginia 23510. E-mail: vinikai@evms.edu.
Disclosure Summary: A.V. is a consultant for Ansar,
creased from 10 to 12.5 mg HS.
AstraZeneca, Eli Lilly, KV Pharmaceuticals, Merck, Novartis
November 16, 2009 Pharmaceuticals, R.W. Johnson Pharmaceutical Research Insti-
She was feeling better. Her hemoglobin A1c was 5.5, tute, Sanofi-Aventis, Takeda, and Tercica; and is on the speakers
bureau for Abbott, Ansar, AstraZeneca, Bristol Meyer Squibb,
down from 8.8 in May 2009.
Eli Lilly, GlaxoSmith Kline Beecham, Merck, Novartis Pharma-
January 2010 ceuticals, Pfizer Inc., Sanofi-Aventis, and Takeda.
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 References
program including Pilates and yoga! Repeat autonomic func-
tion tests showed improvement in the autonomic function, 1. Mäntyselkä P, Ahonen R, Kumpusalo E, Takala J 2001 Variability
in prescribing for musculoskeletal pain in Finnish primary health
and the neuronal apoptosis assay had become negative. care. Pharm World Sci 23:232–236
2. Treede RD, Jensen TS, Campbell JN, Cruccu G, Dostrovsky JO,
Griffin JW, Hansson P, Hughes R, Nurmikko T, Serra J 2008 Neu-
Conclusions ropathic pain: redefinition and a grading system for clinical and
research purposes. Neurology 70:1630 –1635
Painful neuropathy is an important complication of dia- 3. Jensen MP, Chodroff MJ, Dworkin RH 2007 The impact of neu-
ropathic pain on health-related quality of life: review and implica-
betes, and our patient illustrates that pathogenesis is mul- tions. Neurology 68:1178 –1182
tifactorial and requires attention to detail of management 4. Bouhassira D, Lantéri-Minet M, Attal N, Laurent B, Touboul C
if one is to achieve success. Two drugs have been approved 2008 Prevalence of chronic pain with neuropathic characteristics in
the general population. Pain 136:380 –387
for neuropathic pain in the United States, pregabalin and
5. Vinik AI, Tuchman M, Safirstein B, Corder C, Kirby L, Wilks K,
duloxetine, but neither of these afforded relief, even when Quessy S, Blum D, Grainger J, White J, Silver M 2007 Lamotrigine
used in combination. If we had neglected the evidence for for treatment of pain associated with diabetic neuropathy: results of
an eating disorder, manipulation of insulin dosing, the two randomized, double-blind, placebo-controlled studies. Pain
128:169 –179
presence of significant autoimmunity and autonomic dys- 6. Vinik A, Ullal J, Parson HK, Casellini CM 2006 Diabetic neurop-
function, as well as the huge psychological disturbance athies: clinical manifestations and current treatment options. Nat
and not used a holistic positive approach to the patient we Clin Pract Endocrinol Metab 2:269 –281
7. Casellini CM, Vinik AI 2007 Clinical manifestations and current
might have failed. Indeed, a sobering view is that few drugs treatment options for diabetic neuropathies. Endocr Pract 13:
achieve a greater than 30% reduction in pain in more than 550 –566
50% of patients, dictating a need to use more than one 8. Pittenger GL, Liu D, Vinik AI 1993 The toxic effects of serum from
patients with type I diabetes mellitus on mouse neuroblastoma cells:
drug with different mechanisms of action. Even in the class
a new mechanism for development of autonomic neuropathy. Dia-
of AEDs, not all are created equal as shown here. There is betic Med 10:925–932
a great need to understand pathogenic mechanisms more 9. Torrance N, Smith BH, Bennett MI, Lee AJ 2006 The epidemiology
fully, particularly the differences in origin of peripheral of chronic pain of predominantly neuropathic origin. Results from
a general population survey. J Pain 7:281–289
and central pain. Our patient, when subject to traditional 10. Dieleman JP, Kerklaan J, Huygen FJ, Bouma PA, Sturkenboom MC
measures of nerve function, would have been labeled as 2008 Incidence rates and treatment of neuropathic pain conditions
hysterical because all nerve function studies are often nor- in the general population. Pain 137:681– 688
11. Cornblath DR, Vinik A, Feldman E, Freeman R, Boulton AJ 2007
mal with severe painful syndromes. A holistic approach is Surgical decompression for diabetic sensorimotor polyneuropathy.
essential, and the doctor and patient need to generate trust Diabetes Care 30:421– 422
and a positive attitude. One needs to be aware of the con- 12. Smith AG, Russell J, Feldman EL, Goldstein J, Peltier A, Smith S,
Hamwi J, Pollari D, Bixby B, Howard J, Singleton JR 2006 Lifestyle
ditions that masquerade as painful neuropathy and the
intervention for pre-diabetic neuropathy. Diabetes Care 29:1294–1299
treatment directed toward the underlying disorder as sug- 13. Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A 2008
gested in the algorithm provided. As Winston Churchill Prevalence of polyneuropathy in pre-diabetes and diabetes is asso-

Downloaded from https://academic.oup.com/jcem/article-abstract/95/11/4802/2835110


by guest
on 06 January 2018
J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811 jcem.endojournals.org 4811

ciated with abdominal obesity and macroangiopathy: the 2007 Duloxetine for the management of diabetic peripheral neuro-
MONICA/KORA Augsburg Surveys S2 and S3. Diabetes Care 31: pathic pain: evidence-based findings from post hoc analysis of three
464 – 469 multicenter, randomized, double-blind, placebo-controlled, parallel-
14. Ziegler D, Rathmann W, Meisinger C, Dickhaus T, Mielck A 2009 group studies. Clin Ther 29 Suppl:2536 –2546
Prevalence and risk factors of neuropathic pain in survivors of myo- 35. Sultan A, Gaskell H, Derry S, Moore RA 2008 Duloxetine for pain-
cardial infarction with pre-diabetes and diabetes. The KORA Myo- ful diabetic neuropathy and fibromyalgia pain: systematic review of
cardial Infarction Registry. Eur J Pain 13:582–587 randomised trials. BMC Neurol 8:29
15. Pittenger GL, Mehrabyan A, Simmons K, Rice A, Dublin C, Barlow 36. Sansone RA, Sansone LA 2008 Pain, pain, go away: antidepressants
P, Vinik AI 2005 Small fiber neuropathy is associated with the met- and pain management. Psychiatry (Edgmont) 5:16 –19
abolic syndrome. Metab Syndr Relat Disord 3:113–121 37. Simpson DA 2001 Gabapentin and venlafaxine for the treatment of
16. Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu- painful diabetic neuropathy. J Clin Neuromuscul Dis 3:53– 62
Tirgoviste C, Witte DR, Fuller JH 2005 Vascular risk factors and 38. Blom S 1962 Trigeminal neuralgia: its treatment with a new anti-
diabetic neuropathy. N Engl J Med 352:341–350 convulsant drug (g-32883). Lancet 1:839 – 840
17. Vinik EJ, Hayes RP, Oglesby A, Bastyr E, Barlow P, Ford-Molvik SL, 39. LaRoche SM, Helmers SL 2004 The new antiepileptic drugs: scien-
Vinik AI 2005 The development and validation of the Norfolk tific review. JAMA 291:605– 614
QOL-DN, a new measure of patients’ perception of the effects of 40. Eisenberg E, Lurie Y, Braker C, Daoud D, Ishay A 2001 Lamotrigine
diabetes and diabetic neuropathy. Diabetes Technol Ther 7:497– reduces painful diabetic neuropathy: a randomized, controlled
508 study. Neurology 57:505–509
18. Vinik AI, Strotmeyer ES, Nakave AA, Patel CV 2008 Diabetic neu- 41. Leach MJ, Marden CM, Miller AA 1986 Pharmacological studies on
ropathy in older adults. Clin Geriatr Med 24:407– 435, v lamotrigine, a novel potential antiepileptic drug: II. Neurochemical
19. Devigili G, Tugnoli V, Penza P, Camozzi F, Lombardi R, Melli G, studies on the mechanism of action. Epilepsia 27:490 – 497
Broglio L, Granieri E, Lauria G 2008 The diagnostic criteria for 42. Coderre TJ, Melzack R 1992 The contribution of excitatory amino
small fibre neuropathy: from symptoms to neuropathology. Brain acids to central sensitization and persistent nociception after for-
131:1912–1925 malin-induced tissue injury. J Neurosci 12:3665–3670
20. Sorensen L, Molyneaux L, Yue DK 2006 The relationship among 43. Backonja MM 2002 Use of anticonvulsants for treatment of neu-
pain, sensory loss, and small nerve fibers in diabetes. Diabetes Care ropathic pain. Neurology 59:S14 –S17
29:883– 887 44. Dworkin RH, Backonja M, Rowbotham MC, Allen RR, Argoff CR,
21. Kennedy WR 2004 Opportunities afforded by the study of unmy- Bennett GJ, Bushnell MC, Farrar JT, Galer BS, Haythornthwaite JA,
elinated nerves in skin and other organs. Muscle Nerve 29:756 –767 Hewitt DJ, Loeser JD, Max MB, Saltarelli M, Schmader KE, Stein C,
22. Said G, Bigo A, Améri A, Gayno JP, Elgrably F, Chanson P, Slama Thompson D, Turk DC, Wallace MS, Watkins LR, Weinstein SM
G 1998 Uncommon early-onset neuropathy in diabetic patients. 2003 Advances in neuropathic pain: diagnosis, mechanisms, and treat-
J Neurol 245:61– 68 ment recommendations. Arch Neurol 60:1524 –1534
23. Dogrul A, Uzbay IT 2004 Topical clonidine antinociception. Pain 45. Kalso E 2005 Sodium channel blockers in neuropathic pain. Curr
111:385–391 Pharm Des 11:3005–3011
24. Rains C, Bryson HM 1995 Topical capsaicin. A review of its pharma- 46. Dogra S, Beydoun S, Mazzola J, Hopwood M, Wan Y 2005 Ox-
cological properties and therapeutic potential in post-herpetic neural- carbazepine in painful diabetic neuropathy: a randomized, placebo-
gia, diabetic neuropathy and osteoarthritis. Drugs Aging 7:317–328 controlled study. Eur J Pain 9:543–554
25. Derry S, Lloyd R, Moore RA, McQuay HJ 2009 Topical capsaicin 47. Backonja M, Beydoun A, Edwards KR, Schwartz SL, Fonseca V,
for chronic neuropathic pain in adults. Cochrane Database Syst Rev Hes M, LaMoreaux L, Garofalo E 1998 Gabapentin for the symp-
4:CD007393 tomatic treatment of painful neuropathy in patients with diabetes
26. Baron R, Mayoral V, Leijon G, Binder A, Steigerwald I, Serpell M mellitus: a randomized controlled trial. JAMA 280:1831–1836
2009 Efficacy and safety of combination therapy with 5% lidocaine 48. DeToledo JC, Toledo C, DeCerce J, Ramsay RE 1997 Changes in
medicated plaster and pregabalin in post-herpetic neuralgia and di- body weight with chronic, high-dose gabapentin therapy. Ther Drug
abetic polyneuropathy. Curr Med Res Opin 25:1677–1687 Monit 19:394 –396
27. Jarvis B, Coukell AJ 1998 Mexiletine. A review of its therapeutic use 49. Gilron I, Bailey JM, Tu D, Holden RR, Weaver DF, Houlden RL
in painful diabetic neuropathy. Drugs 56:691–707 2005 Morphine, gabapentin, or their combination for neuropathic
28. Harati Y, Gooch C, Swenson M, Edelman S, Greene D, Raskin P, pain. N Engl J Med 352:1324 –1334
Donofrio P, Cornblath D, Sachdeo R, Siu CO, Kamin M 1998 Dou- 50. Rosenstock J, Tuchman M, LaMoreaux L, Sharma U 2004 Pre-
ble-blind randomized trial of tramadol for the treatment of the pain gabalin for the treatment of painful diabetic peripheral neuropathy:
of diabetic neuropathy. Neurology 50:1842–1846 a double-blind, placebo-controlled trial. Pain 110:628 – 638
29. Harati Y, Gooch C, Swenson M, Edelman SV, Greene D, Raskin P, 51. Vinik AI 2008 Diabetic neuropathies: endpoints in clinical research
Donofrio P, Cornblath D, Olson WH, Kamin M 2000 Maintenance studies. In: LeRoith D, Vinik AI, eds. Contemporary endocrinology:
of the long-term effectiveness of tramadol in treatment of the pain controversies in treating diabetes. Clinical and research aspects. To-
of diabetic neuropathy. J Diabetes Complications 14:65–70 towa, NJ: Humana Press; 135–156
30. Nelson KA, Park KM, Robinovitz E, Tsigos C, Max MB 1997 High- 52. Raskin P, Donofrio PD, Rosenthal NR, Hewitt DJ, Jordan DM, Xiang
dose oral dextromethorphan versus placebo in painful diabetic neu- J, Vinik AI 2004 Topiramate vs placebo in painful diabetic neuropathy:
ropathy and postherpetic neuralgia. Neurology 48:1212–1218 analgesic and metabolic effects. Neurology 63:865– 873
31. Sang CN 2000 NMDA-receptor antagonists in neuropathic pain: 53. Piovesan EJ, Teive HG, Kowacs PA, Della Coletta MV, Werneck
experimental methods to clinical trials. J Pain Symptom Manage LC, Silberstein SD 2005 An open study of botulinum-A toxin treat-
19:S21–S25 ment of trigeminal neuralgia. Neurology 65:1306 –1308
32. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH 2005 54. Tsai CP, Liu CY, Lin KP, Wang KC 2006 Efficacy of botulinum
Algorithm for neuropathic pain treatment: an evidence-based pro- toxin type A in the relief of carpal tunnel syndrome: a preliminary
posal. Pain 118:289 –305 experience. Clin Drug Investig 26:511–515
33. Max MB, Lynch SA, Muir J, Shoaf SE, Smoller B, Dubner R 1992 55. Ziegler D, Schatz H, Conrad F, Gries FA, Ulrich H, Reichel G 1997
Effects of desipramine, amitryptiline and fluoxetine on pain in di- Effects of treatment with the antioxidant ␣-lipoic acid on cardiac
abetic neuropathy. N Engl J Med 326:1250 –1256 autonomic neuropathy in NIDDM patients. A 4-month randomized
34. Kajdasz DK, Iyengar S, Desaiah D, Backonja MM, Farrar JT, Fishbain controlled multicenter trial (DEKAN Study). Deutsche Kardiale Au-
DA, Jensen TS, Rowbotham MC, Sang CN, Ziegler D, McQuay HJ tonome Neuropathie. Diabetes Care 20:369 –373

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