The Approach to the Management of thePatient with Neuropathic Pain

Aaron Vinik

Department of Internal Medicine, Eastern Virginia Medical School, Strelitz DiabetesCenter and Neuroendocrine Unit at Norfolk, Norfolk, Virginia, 23510

Neuropathic pain occurs in about 6–7% of the general population and in 15–20%of people with diabetes. It is defined as a disease or disorder of the sensorimotorsystem and must be distinguished from nociceptive pain, which is a consequenceof trauma, injury, or inflammation. A host of other conditions can masquerade asneuropathy including entrapments, fasciitis, and claudication. Pain can derivefrom damage to unmyelinated C-fibers, A� fibers in the periphery, or from mech-anisms within the spinal cord, brainstem, and cerebral cortex. A variety of exci-tatory and inhibitory neurotransmitters are involved and form the basis for tar-geted drug therapy. More important, however, is the pathogenesis of damage tothe pain mechanism, which is multifactorial and includes metabolic disturbancessuch as hyperglycemia, even impaired glucose tolerance, dyslipidemia, oxidativeand nitrosative stress, growth factor deficiencies, microvascular insufficiency, andautoimmune damage to nerve fibers. The approach to managing the patient withneuropathic pain is first to understand and recognize the cause of pain in aparticular patient and to use monotherapies or drug combinations directed at thedifferent types and sources of pain. Ultimately, therapy directed at the underlyingpathogenesis of neuropathy is needed. The case presented in this report illus-trates the complexity of resolution of pain in an individual and the need for aholistic approach to medicine, employing empathy, compassion, and understand-ing in the relationship between the doctor and the patient to succeed in allevi-ating pain. (J Clin Endocrinol Metab 95: 4802–4811, 2010)

Pain is the reason for 40% of patient visits in a primarycare setting, and about 20% of these patients have

had pain for longer than 6 months (1). Chronic pain maybe nociceptive, which occurs as a result of disease or dam-age to tissue wherein there is no abnormality in the ner-vous system or there may be no somatic abnormality. Incontrast, experts in the neurology and pain communitydefine neuropathic pain as “pain arising as a direct con-sequence of a lesion or disease affecting the somatosensorysystem” (2). Persistent neuropathic pain interferes signif-icantly with quality of life, impairing sleep and recreation,and it significantly impacts emotional well-being of suchpatients, predisposing them to depression and noncom-

ISSN Print 0021-972X ISSN Online 1945-7197Printed in U.S.A.Copyright © 2010 by The Endocrine Societydoi: 10.1210/jc.2010-0892 Received April 19, 2010. Accepted July 6, 2010.

Abbreviations: AED, Antiepileptic drug; BID, twice daily; DPN, diabetic peripheral neurop-athy; HS, at bedtime; NMDA, N-methyl-D-aspartate; QD, daily; SNRI, serotonin norepi-nephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclicantidepressants; TID, three times daily.

Accreditation and Credit Designation StatementsThe Endocrine Society is accredited by the AccreditationCouncil for Continuing Medical Education to provide con-tinuing medical education for physicians. The Endocrine So-ciety has achieved Accreditation with Commendation.The Endocrine Society designates this educational activityfor a maximum of 1 AMA PRA Category 1 Credit(s)™.Physicians should only claim credit commensurate with theextent of their participation in the activity.Learning ObjectivesUpon completion of this educational activity, participantsshould be able to• Perform differential diagnosis of painful diabetic

neuropathy.• Make informed decisions based on the numbers needed to

treat vs. the numbers needed to harm as well as the like-lihood of success or failure of treatment.

• Understand pathogenesis-based management.Target AudienceThis continuing medical education activity should be of sub-stantial interest to endocrinologists.Disclosure PolicyAuthors, editors, and Endocrine Society staff involved inplanning this CME activity are required to disclose to learn-ers any relevant financial relationship(s) that have occurredwithin the last 12 months with any commercial interest(s)whose products or services are discussed in the CME con-tent. The Endocrine Society has reviewed all disclosures andresolved or managed all identified conflicts of interest, asapplicable.The following individual reported relevant financialrelationships:Aaron Vinik, M.D., has served as a consultant for Ansar,AstraZeneca, Eli Lilly, KV Pharmaceuticals, Merck, Novar-tis Pharmaceuticals, R.W. Johnson Pharmaceutical Re-search Institute, sanofi-aventis, Takeda, and Tercica; andhas served on speaker’s bureaus for Abbott, Ansar, Astra-Zeneca, Bristol Meyer Squibb, Eli Lilly, GlaxoSmith KlineBeecham, Merck, Novartis Pharmaceuticals, Pfizer, Inc.,sanofi-aventis, and Takeda. He has received grant fundingfrom Takeda Pharmaceuticals, Abbot, GlaxoSmithKline,sanofi-aventis, Arcion Therapeutics, Inc., Eli Lilly & Company,and Merck Research Labs.Disclosures for JCEM Editors are found at http://www.endo-society.org/journals/Other/faculty_jcem.cfm.The following individual reported NO relevant financialrelationships:Leonard Wartofsky, M.D., reported no relevant financialrelationships.Endocrine Society staff associated with the development ofcontent for this activity reported no relevant financialrelationships.Acknowledgement of Commercial SupportThis activity is not supported by grants, other funds, or in-kind contributions from commercial supporters.Privacy and Confidentiality StatementThe Endocrine Society will record learner’s personal infor-mation as provided on CME evaluations to allow for issu-ance and tracking of CME certificates. No individual per-formance data or any other personal information collectedfrom evaluations will be shared with third parties.Method of ParticipationThis Journal CME activity is available in print and online asfull text HTML and as a PDF that can be viewed and/orprinted using Adobe Acrobat Reader. To receive CMEcredit, participants should review the learning objectivesand disclosure information; read the article and reflect on itscontent; then go to http://jcem.endojournals.org and findthe article, click on CME for Readers, and follow the in-structions to access and complete the post-activity test ques-tions and evaluation. The estimated time to complete thisactivity, including review of material, is 1 hour. If you havequestions about this CME activity, please direct them toeducation@endo-society.org.Activity release date: November 2010Activity expiration date: November 2011

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

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

pliance with treatment resulting in a general worsening ofthe condition. Patients with chronic neuropathic pain re-port poor physical health and mental conditions com-pared with those with other causes of chronic pain evenadjusting for pain intensity (3). Diabetic neuropathy painis a difficult-to-manage clinical problem. It is often asso-ciated with mood and sleep disturbances, and patientswith diabetic neuropathy pain are more apt to seek med-ical attention than those with other types of diabetic neu-ropathy. Two population-based studies showed that neu-ropathic pain is associated with a greater psychologicalburden than nociceptive pain (4) and is considered to bemore severe than other pain types. Early recognition ofpsychological problems is critical to the management ofpain, and physicians need to go beyond the managementof pain per se if they are to achieve success. Patients mayalso complain of decreased physical activity and mobility,increased fatigue, and negative effects on their social lives.Providing significant pain relief markedly improves qual-ity-of-life measures, including sleep and vitality (5). Be-cause of its complexity, the presentation of pain poses adiagnostic dilemma for the clinician who needs to distin-guish between neuropathic pain arising as a direct conse-quence of a lesion or disease of the somatosensory systemand nociceptive pain that is due to trauma, inflammation,or injury. It is imperative to try to establish the nature ofany predisposing factor, including the pathogenesis of thepain, if one is to be successful in its management. Man-agement of neuropathic pain requires a sound relationshipbetween patient and physician, with an emphasis on apositive outlook and encouragement that there is a solu-tion, using patience and targeted pain-centered strategiesthat deal with the underlying disorder rather than theusual “Band-aid” prescription of drugs approved for gen-eral pain, which do not address the disease process. Theinciting injury may be focal or diffuse and may involvesingle, or more likely, multiple mechanisms such as meta-bolic disturbances encompassing hyperglycemia, dyslipide-mia, glucose fluctuations, or intensification of therapy withinsulin. On the other hand, the injury might embrace auto-immune mechanisms, neurovascular insufficiency, deficientneurotrophism, oxidative and nitrosative stress, and inflam-mation (6). Because pain syndromes in diabetes may be focalor diffuse, proximal or distal, acute or chronic, each has itsown pathogenesis, and the treatment must be tailored to theunderlying disorder if the outcome is to be successful.

The Case

We first saw the patient—a 24-yr-old female with poorlycontrolled type 1 diabetes for the past 6 yr and an eatingdisorder with anorexia/bulimia syndrome—on May 19,

2009. She had been admitted to an eating disorder clinicfrom February 2009 through April 10, 2009. She had beenon an insulin pump that she had manipulated to controlher weight and was subsequently placed on an injectablecombination of short- and long-acting insulin, Lantus (40U in the morning) and NovoLog (1 U for every 15 g ofcarbohydrate for meals and snacks and 1 U for every 50mg/dl of her blood glucose greater than 100 mg/dl). Onthis regimen, her blood glucose levels averaged 100 to 220mg/dl without hypoglycemic episodes. Within 2–3 monthsof this therapy, she developed intractable pain and wasreferred for consultation. The pain was burning and ach-ing with tenderness bilaterally in the feet and the legs, aswell as in the hips. A rheumatologist had diagnosed fibro-myalgia and prescribed Gabapentin [100 mg twice daily(BID), 200 mg at bedtime (HS) for 2 wk, increased to 200 mgthree times a day for 1 week, and then increased to 300 mgBID and 600 mg at bedtime]. This had no real impact on thepain. She was very distressed and tearful, was confined tobed,andwasunable tosleep.Advil twotothree timesperdayeased the pain slightly. Her last hemoglobin A1c was 9.0.

She had exercised regularly, including Pilates, beforethe pain occurred, but she stopped because of pain. Shehad an eye exam in the fall of 2008, and there was noevidence of retinopathy. Her urine specimen contained noprotein and was negative for ketones. She had developedgrand mal seizures controlled with lamotrigine 150 mgdaily (QD). She denied stress or phobia, although she hadsome difficulty with heights. She attended college andlived at home with her parents. Her family history revealedan older sister who suffered from some degree of anxiety;her mother had Hashimoto thyroiditis and also had rheu-matoid arthritis, for which she was treated with Enbrel andmethotrexate in small doses. Her father is disease free. Hermaternal grandmother had Hashimoto thyroiditis with di-abetes, and her grandfather had a myocardial infarction. Onthe paternal side, there was a history of lung cancer. Thepatient smoked a pack of cigarettes a day for 5 yr, but quit inNovember 2008. She did not consume alcohol or use illegaldrugs. She had not been exposed to heavy metals, organo-toxins, or other toxins. She was not intolerant to cold orconstipated and had no voice change or hair loss.

Physical examinationPhysical exam revealed an alert and oriented individual

who, although tearful, communicated well. She had no pig-mentation change and no dry or brittle hair. She had a fewpsoriatic lesions at the back of her head, but not elsewhere.

Head, eyes, ears, nose, and throat were within normallimits. She had no lymphadenopathy. Her chest and lungswere clear. There were no breast masses. Her heart wasnormal without murmurs. Her abdomen was soft, non-

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tender, and without masses. Her musculoskeletal systemwas intact. She had good dorsalis pedis and posterior tibialpulses. Application of pressure to her feet caused her toscream in agony. She weighed 120.4 pounds and was 5 feet11 inches tall. Her body mass index was 16.7 kg/m2. Herwaist was 26 inches and hip measurement was 34 in, with awaist-hip ratio of 0.766. Supine blood pressure was 119/78mm Hg with a pulse of 94 bpm, sitting blood pressure was125/82 mm Hg with a pulse of 107 bpm, and standing bloodpressure was 109/78 mm Hg with a pulse of 81 bpm.

Neurological examinationCranial nerves were intact. Her pupils were large, re-

acted to light, and accommodated poorly suggesting au-tonomic dysfunction. She had no evidence of muscleweakness. Handgrip dynamometry was at the 10th per-centile bilaterally. All her reflexes were present, and upperlimb sensation was entirely intact. In the lower limb, shehad a reduction of prickling pain perception to 15 cm onthe right and 22 cm on the left, but she had marked hy-peralgesic and hyperesthetic soles of her feet. Vibrationperception was intact, there was some slight loss of jointposition, but perception of 1- and 10-g monofilament wasintact. Her total neuropathy scores were 5 on the right and6 on the left, which indicated a mild degree of peripheralneuropathy (7). The use of simple clinical tools is illus-trated in Table 1.

Laboratory studiesA quantitative sensory test done on May 12, 2009,

showed normal vibration perception, touch/pressure,warm and cold thermal perception, indicating that hersomatic nervous system was intact.

A cardiac autonomic function test revealed an expira-tion/inspiration ratio of 1.14, a Valsalva ratio of 1.05, anda 30:15 ratio of 1.05. This very abnormal result indicatedautonomic nerve dysfunction. The QTc interval was425 msec on electrocardiogram, which was normal. Shehad a sinus tachycardia syndrome of 100 bpm and ap-peared to have slight left atrial enlargement, but noother abnormalities.

Vitamin D level was 10.7 ng/ml, which is inordinatelylow. The remainder of the biochemistries were: urine pro-

tein microalbumin, 12.8 �g/ml; TSH, 1.329 �U/ml; glu-cose, 253 mg/dl (elevated); blood urea nitrogen, 18 mg/dl;creatinine, 0.5 mg/dl; electrolytes, within normal limits;serum glutamic oxaloacetic transaminase, 19; serum glu-tamic pyruvic transaminase, 25; alkaline phosphatase, 64;calcium and magnesium, within normal limits; estimatedglomerular filtration rate, 59 ml/min; antinuclear factorantibodies, negative; C-reactive protein, 0.1; sedimenta-tion rate, 12; glutamic acid decarboxylase antibody, 4.7(elevated); and gastric parietal cell antibodies, 1.6. Serumprotein electrophoresis revealed no gammopathy, and nomotor or sensory nerve antibodies were detected; acetyl-choline receptor antibodies in serum and antinuclear fac-tor were negative. Serum folate and B12 were normal.Urine porphyrins and urine heavy metals were negative.Serum angiotensin-converting enzyme was normal. Lyme,HIV, and hepatitis screening tests were all negative.

Neuronal cells were incubated in culture with her se-rum. With control pooled human serum, 100,000 cellsincreased to 871,250 by the fourth day; with her serum,100,000 cells fell to 11,250 by the second day and fellfurther to zero by the third and fourth days. There was norecovery of these cells, indicating that her serum washighly toxic to neuronal cells in culture and indicative ofan autoimmune response (8).

Clinical Considerations

My impressions were that this young woman had type 1diabetes for 6 yr, a seizure disorder, and anxiety, withclaustrophobic panic disorder. She was an anorexic bu-limic and was using an insulin pump to allow her to adjustthe insulin doses down so that she could lose weight. Whenplaced on a regular insulin regimen, monitored in an in-stitution, she could no longer do this and within a fewweeks of the intensification of insulin developed a severe,highly sensory form of neuropathy with autonomic man-ifestations, classic of the insulin neuritis syndrome. Shehad a long family history of autoimmune disease, and herserum was highly toxic to neurons in culture, suggestingthe possibility of autoimmune disease. Neuropathic painis not uncommon. A population-based survey of 6000patients treated in family practice in the United Kingdom

TABLE 1. Examination: bedside sensory tests

Sensory modality Nerve fiber Instrument Associated sensory receptorsVibration A� (large) 128-Hz tuning fork Ruffini corpuscle mechanoreceptorsPain (pin prick) C (small) Neuro-tips Nociceptors for pain and warmthPressure A�, A� (large) 1 and 10 g monofilament Pacinian corpuscleLight touch A�, A� (large) Wisp of cotton Meissner’s corpuscleCold A� (small) Cold tuning fork Cold thermoreceptors

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

reported 6% prevalence of pain predominantly of neuro-pathic origin (9). Similarly, a large population-based studyin France showed that 6.9% of the population had neu-ropathic pain (4). Interestingly, in a Dutch population sur-vey of more than 362,000 people, younger people withpain tended to be mostly women, but with advancing agethe gender differences disappeared. Perhaps a little recog-nized fact is that mononeuritis and entrapments were threetimes as common as diabetic peripheral neuropathy(DPN), and fully one third of the diabetic population hassome form of entrapment (10), which when recognized isreadily amenable to intervention (11). Even more salutaryis the mounting evidence that even with impaired glucosetolerance, patients may experience pain (12–14). As a cor-ollary, patients presenting with painful neuropathy haveimpaired fasting glucose or impaired glucose tolerance,and about 50% of the time, they are overweight and haveautonomic dysfunction (12). Even in the absence of ele-vated fasting blood glucose (�100 mg/dl), pain may be thepresenting feature of the metabolic syndrome and coseg-regates with elevated triglycerides and a low high-densitylipoprotein-cholesterol (15). Indeed, a risk factor for neu-ropathic pain in diabetic and nondiabetic populations isan impairment of peripheral vascular function (14, 16).

The Clinical History

History taking is becoming an obsolete art. Without it, ar-riving at the correct diagnosis can be hazardous. Pain asso-ciated with a peripheral nerve injury has several distinct clin-ical characteristics. Neuropathic pain derived from smallnerve fibers isoftenburning, lancinating,or shooting inqual-ity with unusual, tingling, or crawling sensations referred toas formication. Some describe bees stinging through thesocks, whereas others talk of walking on hot coals. The pain,worseatnight,keepsthepatientawakeandisassociatedwithsleep deprivation (17). Patients volunteer that they have al-lodynia or pain from normal stimuli, such as the touch ofbedclothes, and may have hyperesthesias, increased sensitiv-ity to touch, or hyperalgesia with increased sensitivity topainful stimuli or even altered sensation to cold or heat.These may be paradoxical with differences in sensation toone or other modality of stimulation. Unlike animal modelsof DPN, the pain is spontaneous and does not need provo-cation such as a hot plate or laser heat. It is a glove andstocking distribution. Small fiber neuropathies usuallypresent with pain in the feet or hands, do not have abnor-malities in sensation, lack weakness or loss of reflexes, areelectrophysiologically silent, and often lead to the erroneousdiagnosis of hysteria or conversion reactions.

Large fiber neuropathy presents with characteristicweakness, ataxia, loss of reflexes, and impaired nerve con-

duction. Pain is deep seated and gnawing in quality, “likea toothache” in the foot, or “a dog gnawing at the bonesof the feet,” or “feet feel as if they are encased in concrete.”

In contrast, the nociceptive pain of arthritis does nothave these qualities. It is localized to the joints; fasciitis islocalized to the fascia; entrapment produces pain in a der-matome, and claudication is made worse by walking. Ar-thritic pain starts with morning stiffness and improves asthe day wears on (18).

It is noteworthy that one third of patients with diabeteshave some form of entrapment. In contrast with themononeuropathies, the condition begins gradually and ismade worse with repeated minor trauma or history ofoccupational exposure. The sensory disturbance oftendoes not reflect the nerve distribution, and the pain canexceed the area of sensory innervation leading to incorrectdiagnosis. Nerve conduction velocity is required to showimpairment of conduction across the site of entrapment.

Evaluation of pain intensity is essential for monitoringresponse to therapy. There are a number of symptom-based screening tools, such as: Nerve Total SymptomScore-6, Brief Pain Inventory, Quality of Life DiabeticNeuropathy, Short Form-36, Visual Analog Scale for PainIntensity, Neuro-QOL, and Norfolk Neuropathy Symp-toms Score (7). With the visual analog scale, the patientmarks the intensity of their pain on a scale from 0–10, al-lowing an assessment of the response to intervention. Simul-taneously, the patient should complete a quality of life toolsuch as the Norfolk QOL-DN (17), which permits evalua-tion of the impact of the pain on quality of life, anxiety, anddepression, known to be accompanying features of DPN.

The Clinical Examination

A careful evaluation of the nature of pain and its exactlocation and a detailed examination of the lower limbs aremandatory to ascertain alternate causes of pain (Table 1).

Laboratory Tests

These tests usually done for research: laser-evoked poten-tials; contact heat-evoked potentials, whereby brain sig-nals evoked by peripheral heat stimulation can be quan-tified and amplitudes and conduction velocities of the slowconducting fibers measured; and quantitative sensory teststhat measure the thresholds for various sensory modali-ties, such as vibration and heat and cold perception, andcan be adapted to identifying hypoalgesia and hypoes-thesia. Also included are 3-mm skin biopsies to quan-titatively assess the number of nerve fibers present in theepidermis. Paradoxically, these are reduced in numberin DPN (19 –21).

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Conditions Mimicking Diabetic Neuropathy

There are a number of conditions that can be mistaken forpainful diabetic neuropathy: intermittent claudication, inwhich the pain is exacerbated by walking; Morton’s neu-roma, in which the pain and tenderness are localized to theintertarsal space, elicited by applying pressure with thethumb in the appropriate intertarsal space; osteoarthritis,in which the pain is confined to the joints and made worsewith joint movement or exercise and is associated withmorning stiffness that improves with ambulation; radic-ulopathy, in which the pain originates in the shoulder,arm, thorax, and back and radiates into the legs and feet;Charcot neuropathy, in which the pain is localized to thesite of the collapse of the bones of the foot and the foot ishot rather than cold, as occurs in neuropathy; plantar fas-ciitis, in which there is shooting or burning in the heel witheach step and there is exquisite tenderness in the sole ofthe foot; and tarsal tunnel syndrome, in which the painand numbness radiate from beneath the medial malle-olus to the sole and are localized to the inner side of thefoot. These contrast with the pain of DPN, which isbilateral, symmetrical, covering the whole foot and par-ticularly the dorsum, and worse at night, interferingwith sleep.

Therapeutic Modalities forNeuropathic Pain

The growing knowledge about the neural and pharmaco-logical basis of neuropathic pain is likely to have impor-tant treatment implications, including development andrefinement of a symptom/mechanism-based approach toneuropathic pain and implementation of novel treatment

strategies using the newer antiepileptic agents, which mayaddress the underlying neurophysiological aberrations inneuropathic pain, allowing the clinician to increase thelikelihood of effective management (Table 2). The neuro-pharmacology of pain is also becoming better understood.For example, recent data suggest that �-aminobutyricacid, voltage-gated sodium channels, and glutamate re-ceptors may be involved in the pathophysiology of neu-ropathic pain. Many of the newer agents have significanteffects on these neurophysiological mechanisms. Hyper-glycemia may be a factor in lowering the pain threshold.Pain is often worse with wide glycemic excursions. Para-doxically, acute onset of pain may appear soon after ini-tiation of therapy with insulin or oral agents (22). In con-trast, it has been reported that a striking amelioration ofsymptoms can occur with continuous sc insulin adminis-tration, which may reduce the amplitudes of excursion ofblood glucose (22). This dichotomy is not well explained.There is a sequence in diabetic neuropathy, beginningwhen A, �, and C nerve fiber function is intact and thereis no pain. With damage to C-fibers, there is sympatheticsensitization, and peripheral autonomic symptoms are in-terpreted as painful. Topical application of clonidinecauses antinociception by blocking emerging pain signalsat the peripheral terminals via �-2 adrenoreceptors (23), incontrast with the central actions of clonidine on bloodpressure control. With the death of C-fibers, there is no-ciceptor sensitization. A� fibers conduct all varieties ofperipheral stimuli such as touch and these are interpretedas painful, e.g. allodynia. With time there is reorganizationat the cord level and the patient experiences cold hyper-algesia and ultimately, even with the death of all fibers,pain is registered in the cerebral cortex, whereupon thesyndrome becomes chronic without the need for periph-

TABLE 2. Treatments for symptomatic diabetic polyneuropathy: dosing and side effects

Drug class Drug Dose (mg) Side effectsTricyclics Amitryptyline 50–150 HS Somnolence, dizziness, dry mouth, tachycardia

Nortriptyline 50–150 HS Constipation, urinary retention, blurred visionImipramine 25–150 HS ConfusionDesipramine 25–150 HS

SSRIs Paroxetine 40 QD Somnolence, dizziness, sweating, nausea, anorexiaCitalopram 40 QD Diarrhea, impotence, tremor

SNRIs Duloxetine 60 QD Nausea, somnolence, dizziness, anorexiaAnticonvulsants Gabapentin 300–1200 TID Somnolence, dizziness, confusion, ataxia

Pregabalin 50–150 TID Somnolence, confusion, edema, weight gainCarbamazepine/oxcarbezepine Up to 200 QID Dizziness, somnolence, nausea, leukopeniaTopiramate Up to 400 QD Somnolence, dizziness, ataxia, tremor

Opiods Tramadol 50–100 BID Nausea, constipation, HA somnolenceOxycodone CR 10–30 BID Somnolence, nausea, constipation, HA

Topical Capsaicin 0.075% QID Local irritationLidocaine 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-sarily reflect nerve recovery but rather nerve death. Whenpatients volunteer the loss of pain, progression of the neu-ropathy must be excluded by careful examination.

Adrenergic blockersInitially, when there is ongoing damage to the nerves,

the patient experiences pain of the burning, lancinating,dysesthetic type often accompanied by hyperalgesia andallodynia. Because the peripheral sympathetic nerve fibersare also small unmyelinated C-fibers, sympathetic block-ing agents (clonidine) may improve the pain.

Topical capsaicinC-fibers use the neuropeptide substance P as their neu-

rotransmitter, and depletion of axonal substance P(through the use of capsaicin) will often lead to amelio-ration of the pain. Prolonged application of capsaicin de-pletes stores of substance P, and possibly other neuro-transmitters, from sensory nerve endings. This reduces orabolishes the transmission of painful stimuli from the pe-ripheral nerve fibers to the higher centers (24). Recentanalysis of randomized and controlled studies revealedthat either a repeated application of low doses of capsaicinor single application of high doses affords pain relief (25).

LidocaineA multicenter randomized, open-label, parallel-group

study of lidocaine vs. pregabalin with a drug washoutphase of up to 2 wk and a comparative phase of 4-wktreatment periods of 5% lidocaine (n � 99 vs. pregabalin,n � 94) showed that lidocaine was as effective as pregaba-lin in reducing pain and was free of side effects (26). Thisform of therapy may be of most use in self-limited formsof neuropathy. If successful, therapy can be continuedwith oral mexiletine. This class of compounds targets thepain caused by hyperexcitability of superficial, free nerveendings (27).

Tramadol and N-methyl-D-aspartate (NMDA)receptor antagonists

There are two possible targeted therapies. Tramadol isa centrally acting weak opioid analgesic for use in treatingmoderate to severe pain. Tramadol was shown to be betterthan placebo in a randomized controlled trial (28) of only6-wk duration, but a subsequent follow-up study sug-gested that symptomatic relief could be maintained for atleast 6 months (29). Side effects are, however, relativelycommon and are similar to other opioid-like drugs. An-other spinal cord target for pain relief is the excitatoryglutaminergic NMDA receptor. Blockade of NMDA re-ceptors is believed to be one mechanism by which dextro-

methorphan exerts analgesic efficacy (30). The NMDAreceptors play an important role in central sensitization ofneuropathic pain. Their use, however, has not been wide-spread due in part to dose-limiting side effects (31).

AntidepressantsAntidepressants are now emerging as the first line of

agents in the treatment of chronic neuropathic pain (32).Clinical trials have focused on interrupting pain trans-mission using antidepressant drugs that inhibit the re-uptake of norepinephrine or serotonin. This central ac-tion accentuates the effects of these neurotransmittersin activation of endogenous pain-inhibitory systems inthe brain that modulate pain-transmission cells in thespinal cord (33).

Tricyclic antidepressants (TCA)With the development of newer agents, this class is now

being used less frequently due to cholinergic side effects ofdysautonomia, dry mouth, and fatigue that can be trou-blesome. Caution needs to be exercised in patients withischemic heart disease and arrhythmias. Amitriptylineand imipramine should be avoided in elderly patientsbecause they can exacerbate cognitive impairment andgait disturbances, predisposing them to falls. Switchingto nortriptyline or desipramine may lessen some of theanticholinergic effects of amitriptyline. The advantagesof TCA are that they can be administered once daily andare inexpensive.

Selective serotonin reuptake inhibitors (SSRIs)SSRIs inhibit presynaptic reuptake of serotonin but not

norepinephrine, but are not effective.

Selective serotonin norepinephrine reuptakeinhibitors (SNRIs)

There has been much focus on this group of drugs latelyin treatment of diabetic neuropathic pain. Duloxetine hasbeen studied in two doses of 60 and 120 mg for its effectsof reducing diabetic neuropathic pain and for pain in fi-bromyalgia. To achieve an outcome of 50% pain reliefover 12–13 wk, the number needed to treat was 6 (Table3). Adverse effects include nausea, constipation, somno-lence, decreased appetite, some increase in fasting bloodsugar, and dry mouth (34, 35). There do not appear to beany significant cardiovascular risks. Venlafaxine is an-other SNRI that has mixed action on catecholamine up-take. At lower doses, it inhibits serotonin uptake, and athigher doses it inhibits norepinephrine uptake (36). Theextended-release version of venlafaxine was found to besuperior to placebo in diabetic neuropathic pain in non-depressed patients at doses of 150–225 mg/d, and when

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added to gabapentin there was improved pain, mood, andquality of life (37).

Antiepileptic Drugs (AEDs)Antiepileptic drugs (AEDs) have a long history of effec-tiveness in the treatment of neuropathic pain, dating backto case studies of the treatment of trigeminal neuralgiawith phenytoin in 1942 and carbamazepine in 1962 (38).Principal mechanisms of action include sodium channelblockade (felbamate, lamotrigine, oxcarbazepine, topira-mate, zonisamide), potentiation of �-aminobutyric acidactivity (tiagabine, topiramate), calcium channel blockade(felbamate, lamotrigine, topiramate, zonisamide), an-tagonism of glutamate at NMDA receptors (felbamate)or �-amino-3-hydroxy-5-methyl-4-isoxazole propionicacid (felbamate, topiramate), and mechanisms of actionas yet to be fully determined (gabapentin, pregabalin,levetiracetam) (39). An understanding of the mecha-nisms of action of the various drugs leads to the conceptof “rational polytherapy,” where drugs with comple-mentary mechanisms of action can be combined for syn-ergistic effect. For example, one might choose a sodiumchannel blocker such as lamotrigine to be used with aglutamate antagonist such as felbamate. Furthermore, asingle drug may possess multiple mechanisms of action,perhaps increasing its likelihood of success (e.g. topi-ramate). If pain is divided according to its derivationfrom different nerve fiber types (e.g. A� vs. C-fiber),spinal cord or cortical, then different types of painshould respond to different therapies.

In addition to providing efficacy against epilepsy, thesenew AEDs may also be effective in neuropathic pain. Forexample, spontaneous activity in regenerating small-cal-iber primary afferent nerve fibers may be quelled by so-dium channel blockade, and hyperexcitability in dorsalhorn spinal neurons may be decreased by the inhibition ofglutamate release—two mechanisms of action possessedby the AED lamotrigine (40, 41). Clinical trials, how-ever, have not been salutary (5). This was evident in ourpatient who was being treated with lamotrigine for sei-zures, and lamotrigine was ineffective in relieving pain.In addition, the “wind-up” phenomenon caused bynerve injury and the kindling that occurs in hippocam-

pal neurons in patients with mesial temporal sclerosisboth enlist activation of NMDA receptors (42, 43),which can be affected by felbamate (39). The evidencesupporting the use of AEDs for the treatment of DPNcontinues to evolve (36). Patients who have failed torespond to one AED may respond to another or to twoor more drugs in combination (44).

Sodium Channel BlockersVoltage-gated sodium channels are crucial determinantsof neuronal excitability and signaling. After nerve injury,hyperexcitability and spontaneous firing develop at thesite of injury and also in the dorsal root ganglion cell bod-ies. This hyperexcitability results at least partly from ac-cumulation of sodium channels at the site of injury (45).Carbamazepine and oxcarbazepine are most effectiveagainst “lightning” pain (46).

Calcium Channel ModulatorsFive types of voltage-gated calcium channels have been iden-tified, and the L- and N-types of channels have a role to playin the neuromodulation in the sensory neurons of the spinalcord. Gabapentin and pregabalin are medications that bindat the � 2 � subunits of the channels. Unlike traditional cal-cium channel antagonists, they do not block calcium chan-nels but modulate their activity and sites of expression. Theexact mechanism of action of this group of agents on neu-romodulation has yet to be clearly defined.

GabapentinGabapentin was significantly superior to placebo in paincontrol,beginningatwk2andcontinuing throughwk8,andit significantly reduced sleep interference beginning at wk 1and continuing through wk 8. The most common adverseevents with gabapentin were dizziness and somnolence (47).

Gabapentin has the additional benefit of improvingsleep (47), which is often compromised in patients withchronic pain (44). Over the long term, it is known to pro-duce weight gain, which may complicate diabetes man-agement (48). Combination therapy has been examinedusing gabapentin and morphine, indicating slight superi-ority of the combination (49).

TABLE 3. Odds ratios for efficacy and withdrawal, numbers needed to treat (NNT) and numbers needed to harm (NNH)

Drug class

Odds ratio

NNT NNHEfficacy Withdrawal due to adverse effectTricyclics 22.2 (5.8–84.7) 2.3 (0.6–9.7) 1.5–3.5 2.7–17.0Duloxetine 2.6 (1.6–4.8) 2.4 (1.1–5.4) 5.7–5.8 15.0Traditional anticonvulsants 5.3 (1.8–16.0) 1.5 (0.3–7.0) 2.1–3.2 2.7–3.0Newer generation anticonvulsants 3.3 (2.3–4.7) 3.0 (1.75–5.1) 2.9–4.3 26.1Opioids 4.3 (2.3–7.8) 4.1 (1.2–14.2) 2.6–3.9 9.0

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

PregabalinSeveral randomized, double-blind, placebo-controlled, mul-ticenter studieshaveevaluatedtheeffectivenessofpregabalinin a fixed dose with an open-label extension in alleviatingpainassociatedwithDPN.Fortypercentofpatientsreceivingpregabalin reported at least a 50% reduction in pain, com-pared with 14.5% of the placebo group (P � 0.001) (50).

Secondary measures that improved included a reduc-tion in mean sleep interference scores on the SF-36 BodilyPain subscale (P � 0.0001), total SF-MPQ score (P �0.05), and total mood disturbance and tension-anxietycomponents of the Profile of Mood States (P � 0.03) (50).In this respect, the data appear to be not unlike the earlyreports on gabapentin.

TopiramateAlthough topiramate failed in three clinical trials, due tothe use of the wrong endpoint (51), it has been shown tosuccessfully reduce pain and induce nerve regeneration(52), and has the added advantage of causing weight lossand improving the lipoprotein profile particularly usefulin overweight type 2 diabetic patients.

Botulinum ToxinBotulinum toxin has been tried for trigeminal neuralgia(53) and has been shown to have long-lasting antinoci-ceptive effects in carpal tunnel syndrome with no electro-physiological restoration (54).

Guidelines

Figure 1 is an algorithm that we propose for the manage-ment of painful neuropathy in diabetes. This starts withidentification of neuropathic pain being focal or diffuse.

Focal neuropathic pain is best treated with diuretics toreduce edema in the canal, splinting, and surgery to releaseentrapment. Diffuse neuropathies are treated with medi-cal therapy and in a majority of cases, need multidrugtherapy. Immune-mediated neuropathies are treated withiv Ig, steroid, or other immunomodulators.

Back to the Patient

Having reviewed the treatment options we return to thepatient.

If this was insulin neuritis syndrome, it would simply bea matter of time and would recover spontaneously. How-ever, the patient clearly had an eating disorder, anxiety/depression, evidence of autoimmunity, and autonomicnerve dysfunction. She was started on topiramate 15 mgQD for 1 month, increased to 25 mg, and then to 50 mg/d.Topiramate has been shown to induce nerve regenerationand also reduces body weight in contrast with gabapentin,which causes weight gain. We added NutriNerve (an over-the-counter combination of antioxidants) at a dose oftwo tablets BID because this contains �-lipoic acid,which has been shown to improve autonomic dysfunc-tion (55). Thirdly, she was placed on topical lidodermto reduce the allodynia and hyperalgesia. Because of theseizure disorder, we endorsed the use of gabapentin andlamotrigine.

June 16, 2009Her legsand feet still hurt verybadly. Shewasveryweepy,

and one could not touch her toes. She had a magnetic reso-nance image done bilaterally of the feet, and this was foundto be negative for impending Charcot neuropathy. Her heartrate 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 wasthat the pain has lessened some, but was still bad at night. Inlight of the very intense autoimmune response with the ap-optosis of neuronal cells in culture, we resolved to do thefollowing: 1) give her a course of iv Ig at 1.0 g/kg�d on con-secutive days (two per week) for 3 wk; 2) increase the dose oftopiramate to 50 mg/d and possibly to 100 mg/d; and 3)replace the vitamin D with 50,000 U ergocalciferol everymonth.

July to November 2009We were making slow progress and decided to give her a

courseofbotulinumtoxin intoher feet.Thepainsoonstartedto improve, and a second course was given in December.

October 19, 2009Her Lantus was changed to 13 U in the morning and 26

U in the evening. She was also to use Novolog coverage (1FIG. 1. Treatment algorithm: neuropathic pain after exclusion ofnondiabetic etiologies and stabilization of glycemic control.

J Clin Endocrinol Metab, November 2010, 95(11):4802–4811 jcem.endojournals.org 4809

U for every 12 g of carbohydrate for meals and snacks,along with 1 U for every 50 mg/dl of blood sugar �200mg/dl). She is currently covering with 1 U for 10 g ofcarbohydrate and 1 U for every 50 mg/dl blood sugargreater than 150 mg/dl.

She checks her blood sugar “too much”—about 10–15times daily. The range is usually 70–140 mg/dl. For thepast couple of days, the results have been higher and sheis upset. For anxiety/depression, Ativan 1 mg BID wasincreased to three times daily (TID). Ambien was also in-creased from 10 to 12.5 mg HS.

November 16, 2009She was feeling better. Her hemoglobin A1c was 5.5,

down from 8.8 in May 2009.

January 2010Pain had resolved completely. Diabetes control remained

superb. The patient had started to reduce the dosages of themedications, and she had returned to doing a full exerciseprogramincludingPilatesandyoga!Repeatautonomicfunc-tion tests showed improvement in the autonomic function,and the neuronal apoptosis assay had become negative.

Conclusions

Painful neuropathy is an important complication of dia-betes, and our patient illustrates that pathogenesis is mul-tifactorial and requires attention to detail of managementif one is to achieve success. Two drugs have been approvedfor neuropathic pain in the United States, pregabalin andduloxetine, but neither of these afforded relief, even whenused in combination. If we had neglected the evidence foran eating disorder, manipulation of insulin dosing, thepresence of significant autoimmunity and autonomic dys-function, as well as the huge psychological disturbanceand not used a holistic positive approach to the patient wemight have failed. Indeed, a sobering view is that few drugsachieve a greater than 30% reduction in pain in more than50% of patients, dictating a need to use more than onedrug with different mechanisms of action. Even in the classof AEDs, not all are created equal as shown here. There isa great need to understand pathogenic mechanisms morefully, particularly the differences in origin of peripheraland central pain. Our patient, when subject to traditionalmeasures of nerve function, would have been labeled ashysterical because all nerve function studies are often nor-mal with severe painful syndromes. A holistic approach isessential, and the doctor and patient need to generate trustand a positive attitude. One needs to be aware of the con-ditions that masquerade as painful neuropathy and thetreatment directed toward the underlying disorder as sug-gested in the algorithm provided. As Winston Churchill

said, “We need to go from failure to failure without losingour enthusiasm and ultimately we will succeed….”

Acknowledgments

Address all correspondence and requests for reprints to: AaronVinik, Department of Internal Medicine, Eastern Virginia Med-ical School, Strelitz Diabetes Center and Neuroendocrine Unit atNorfolk, Norfolk, Virginia 23510. E-mail: vinikai@evms.edu.

Disclosure Summary: A.V. is a consultant for Ansar,AstraZeneca, Eli Lilly, KV Pharmaceuticals, Merck, NovartisPharmaceuticals, R.W. Johnson Pharmaceutical Research Insti-tute, Sanofi-Aventis, Takeda, and Tercica; and is on the speakersbureau for Abbott, Ansar, AstraZeneca, Bristol Meyer Squibb,Eli Lilly, GlaxoSmith Kline Beecham, Merck, Novartis Pharma-ceuticals, Pfizer Inc., Sanofi-Aventis, and Takeda.

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