This document provides information on the approach to managing neuropathic pain in patients with diabetes. It begins by defining neuropathic pain and distinguishing it from nociceptive pain. It describes the complex nature of neuropathic pain, which can involve damage to different nerve fiber types and various excitatory and inhibitory neurotransmitters. More importantly, the pathogenesis of nerve damage is often multifactorial and can include metabolic disturbances, oxidative stress, vascular insufficiencies, and autoimmune processes. The approach to patients involves understanding the underlying cause of their pain in order to use targeted therapies. Simply prescribing general pain medications is insufficient and does not address the disease process causing the pain. The case study illustrates the need for a holistic approach employing empathy, understanding and
2. J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811 jcem.endojournals.org 4803
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-
3. 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
4. J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811 jcem.endojournals.org 4805
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 (Ͻ100 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).
5. 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.
6. J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811 jcem.endojournals.org 4807
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 ϭ 99 vs. pregabalin, Selective serotonin reuptake inhibitors (SSRIs)
n ϭ 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
7. 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).
8. J Clin Endocrinol Metab, November 2010, 95(11):4802– 4811 jcem.endojournals.org 4809
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 ϭ 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 Ͻ 0.0001), total SF-MPQ score (P Ͻ 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 Ͻ 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/kg⅐d 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
9. 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 Ͼ200 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
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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-](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)