T h e NE W E NGL A ND JOU R NA L o f M E DICINE

THE CLINICAL PROBLEM

CLINICAL PRACTICE

Caren G. Solomon, M.D., M.P.H., Editor

Diabetic Sensory and Motor Neuropathy
Aaron I. Vinik, M.D., Ph.D.

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence sup-
porting various strategies is then presented, followed by a review of formal guidelines, when they exist.
The article ends with the author’s clinical recommendations.

A 65-year-old woman with a 5-year history of type 2 diabetes (a recent hemoglobin A 1C From the Eastern Virginia Medical School,
level was 9.5%) reports the recent onset of burning, tingling, and stabbing pain in her Strelitz Diabetes Center, Norfolk. Address
reprint requests to Dr. Vinik at the Strelitz
feet that is worse at night and interferes with sleep and activities of daily living. Her Diabetes Center, Eastern Virginia Medical
medications include 500 mg of metformin and 2 mg of glimepiride, each taken twice School, 855 W. Brambleton Ave., Norfolk, VA
daily. On physical examination, the patient is alert and oriented to person, place, and 23510, or at vinikai@evms.edu.
time. Her blood pressure is 140/90 mm Hg. She has reduced sensation to pinpricks in This article was last updated on
the knees, reduced ability to detect vibration from a 128-Hz tuning fork, and a loss of Septem-ber 16, 2016, at NEJM.org.
proprioception and of sensation to a 1-g monofilament (but not to a 10-g monofilament) N Engl J Med 2016;374:1455-64.
in her toes. Strength in the lower legs is 5 out of 5 (normal) proxi-mally and 4 out of 5 DOI: 10.1056/NEJMcp1503948
distally, and there is slightly weak dorsiflexion of both big toes, with no indication of Copyright © 2016 Massachusetts Medical Society.
entrapment. Her ankle reflexes are absent. She has no foot ulcers, and her pulses are
easily palpable. How should her case be further evaluated
and managed?

N EUROPATHY IN DIABETES IS A HETEROGENEOUS CONDITION THAT MANI-fests
in different forms. It may occur in proximal or distal nerve fibers, may take the form of An audio version
mononeuritis or entrapments involving small or
1 of this article is
large fibers, and may affect the somatic or autonomic nervous system. Distal available at
symmetric polyneuropathy, the most common form of diabetic neuropathy, is a NEJM.org
chronic, nerve-length–dependent, sensorimotor polyneuropathy2,3 that affects at
least one third of persons with type 1 or type 2 diabetes and up to one quar-ter of
persons with impaired glucose tolerance.1,4 Biopsy specimens of the skin have
shown progressive reduction in the intraepidermal nerve fibers from the time of
diagnosis of diabetes; this reduction is seen even in persons with pre-diabetes. 5,6

Persons with distal symmetric polyneuropathy often have length-dependent
symptoms, which usually affect the feet first and progress proximally. The symp-
toms are predominantly sensory and can be classified as “positive” (tingling,
burning, stabbing pain, and other abnormal sensations) or “negative” (sensory loss,
weakness, and numbness) (Table 1). Motor symptoms are less common and occur
later in the disease process. Decreased sensation in the feet and legs confers a
predisposition to painless foot ulcers and subsequent amputations if the ulcers are
not promptly recognized and treated, particularly in patients with concomitant

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and anxiety. Proprioceptive impairment leads to imbalance and unsteadiness in gait and to an increased likelihood of falls and serious traumatic injury. • Laboratory testing should be used to rule out other causes of neuropathy. depression. or stabbing pain) or “negative” (manifested as sensory loss. which may occur with metformin use. • Decreased sensation confers a predisposition to painless foot ulcers and to amputations. and exercises that improve strength and balance may reduce the risk of falls. and serotonin–norepinephrine reuptake inhibitors. T h e NE W E NGL A ND JOU R NA L o f M E DICINE KEY CLINICAL POINTS DIABETIC SENSORY AND MOTOR NEUROPATHY • Symptoms of distal symmetric motor and sensory polyneuropathy may be “positive” (manifested as sensations of tingling. such as insomnia. • Lifestyle interventions (diet and exercise) may restore nerve fibers. including vitamin B 12 deficiency. . weakness. tricyclic antidepressants. or numbness). burning. These symptoms occur in one third of patients with type 1 or 2 diabetes. • Treatment choices should take into account coexisting conditions. • Medications most commonly used in pain management include anticonvulsants (particularly gabapentin and pregabalin).

increasing the likeli.and β-fibers.11. detect- . and fractures. along with a in 10 to 26% of patients with diabetes 1 and can detailed assessment of the feet.854 patients were aware of the presence of neuropathy.12 in which the Norfolk quality-of-life question- naire for diabetic neuropathy was administered. combined gnawing at the bones of the feet or as the sensation with loss of proprioception. nor had been informed of this relationship by Diagnosis is primarily clinical and involves a their health care provider. dyslipidemia.8 thorough history and physical examination with a Painful diabetic peripheral neuropathy occurs focus on vascular and neurologic tests. levels may contribute to the fre-quency and severity metric polyneuropathy may be asymptomatic.4 In disease are also associ-ated with an increased risk a recent survey of 25. smoking.peripheral artery disease. Pain and abnormal worse at night. The lifetime risk of a standing on hot coals.9 Neuropathic pain that is sensation of vibration and touch and the percep-tion the result of small-fiber dysfunction usually of position. concrete. patients persons with distal symmetric polyneuropathy is describe it as the pain they would feel if a dog were 15 to 25%. which result from damage to small. is often to large.7 greater variability in the range of blood glucose Alternatively. particularly the life. sleep. and is associated with allodynia perceptions of hot and cold tem-peratures may also — the perception of a nonpainful stimulus as be present. sensory loss.g. of painful symptoms. some persons with distal sym. contact with socks or bedclothes) thinly myelinated A-type δ-fibers and small. S TR ATEGIES AND EV IDENCE 13. including an ulcer or gangrene.8. in large-fiber dysfunction is deep-seated. 13 All sen-sory have a profound negative effect on quality of perceptions can be affected. A-type α. — and paresthesias. all of which can be affected by damage causes burning sensations. or traumatic brain injury.10 Age. The pain has been likened to unmyelinated C-type fibers (Table 1). and peripheral artery means of a detailed neurologic examination. Reduced the sensation of bees stinging through socks or of sensation of vibration. poor long-term control of blood glucose levels..000 patients with diabetes of pain. is superficial. leads to imbalance they would have if their feet were en-cased in and unsteadiness in gait.3 Pain occurs more often in patients with hood of a fall that may result in lacerations. In contrast. painful (e. whereas 6600 patients reported DIAGNOSIS AND EVALUATION symptoms of neuropathy but were neither aware Early diagnosis of distal symmetric polyneurop- that the symptoms were related to neuropathy athy is imperative to prevent irreversible damage. and mood. obesity.1 In addition. pain caused by foot lesion. and signs of disease may be detected only by hypertension.

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* Small Myelinated and Unmyelinated Large Myelinated A-Type δ-Fibers and Small Unmyelinated Approach A-Type α. allodynia. electric shocks. ataxia with poor balance. weak. deep-seated Burning pain with sensation of stabbing and gnawing or aching pain.and β-Fibers A-Type δ-Fibers and C-Type Fibers Assess symptoms Numbness. hyperalgesia. CLINICAL PRACTICE Table 1. tingling. ness. hyperesthesia falling . Approaches to the Diagnosis of Neuropathies of Large and Small Nerve Fibers.

and impaired sweating . poor blood flow. loss of propriocep- examination tion and perception of vibration. and feet. weakness in feet with dry skin. normal strength. and of pinprick. reflexes. impaired autonomic func-tion. cold feet. and wasting of small muscles of hands nerve conduction.Conduct physical Impaired sensation of warm and cold temperatures Impaired reflexes.

hu- neoplastic syndromes. ciency. toxic alcohol. Consider chronic inflammatory Consider metabolic causes such as uremia.. increased risk of amputation traumatic fractures. hypo- nosis demyelinating polyneuropathy. susceptibility to foot ulcers. Recognize clinical implica. median. and Charcot’s arthropathy Conduct diagnostic tests Nerve conduction: abnormal test Nerve conduction: normal results despite presence results (e. and industrial hydrocarbons. Vinik was a member . hereditary diseases. thyroidism. mittent porphyria. and man immunodeficiency virus. hypothyroidism. hepatitis B or C effects of chemotherapy virus. inflammation or infec- myopathies. connective-tissue diseases. B12 or folate defi tion. tions balance. and amyloidosis * This table was adapted in part from a draft version of a table developed by a committee convened by the American Diabetes Association to update guidelines for diabetic neuropathies. Lyme disease. sural. acute inter- monoclonal gammopathies. para celiac disease. paraneoplastic syndromes.g. heavy metals. B12 or folate deficiency. monoclonal gam mopathies. vasculitis.Impaired sense of pressure and Impaired nociception. of which Dr. and of symptoms peroneal nerves) Skin biopsy to detect loss of intraepidermal nerve Quantitative sensory testing to detect fibers loss of perception of vibration Corneal confocal microscopy Quantitative sensory tests to detect sensitivity to hot and cold and impairment of pain perception Sudorimetry (performed with neuropad or sudo- scan) to obtain objective measures of sweating Consider differential diag. sarcoidosis. Guillain–Barré syndrome. susceptibility to falls.

the results of which are ment of motor function than sensory function. and tests of auto- of the feet should include checking for periph. Mild muscle wasting roid dysfunction is a common coexisting condi- may be seen. greater impair. 2 In more severe folate and vitamin B12 (metformin has been as- cases. serum levels of suggests a nondiabetic cause. the hands may be involved. is an fully assessed for other conditions. and the detection of ab. Laboratory studies Deep-tendon reflexes may be absent or reduced. Patients with sociated with vitamin B12 deficiency). immunoelectrophoresis. matory demyelinating polyneuropathy. quantitative sensory testing. a complete blood count. or rapid progression should be care. measurement of dicates an increased risk of ulcers.2 changes in sensitivity. A 1-g Semmes– drug or chemical exposures and a family history Weinstein monofilament can be used to detect of inherited neuropathies should be obtained.ed with the use of a 128-Hz tuning fork. Objective testing for neuropathy (including normal sensation with a 10 -g monofilament in. and serum asymmetric symptoms or signs. should include tests for thyrotropin level (thy- especially in the lower legs. but severe weakness is rare and tion). essential for clinical care. although it is not and conducting a visual inspection for ulcers. A history of early indicator of neuropathy. Examination nerve-conduction velocities. which is . often abnormal in patients with chronic inflam- entrapment. nomic function) is required to make a defini-tive eral pulses to assess for peripheral artery disease diagnosis of neuropathy.

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T h e NE W E NGL A ND JOU R NA L o f M E DICINE .

18 In the By.was limited to vibration testing. stability may reduce the risk of falls among pa.although the assessment of somatic neuropa-thy ropathy involves nonpharmacologic and pharma. Strength and patient) and adverse effects. al-though Among patients with neuropathy associated with the neuritis generally resolves within 6 months. a diet and exercise regimen was shown to be associated with in- creased intraepidermal nerve-fiber density and PHARMACOTHERAPY reduced pain. sensation at the site of application. In randomized ment are reviewed below. the effects of glycemic control on neu. Anticonvulsants cantly (albeit modestly) lower incidence of Gabapentin and pregabalin are α2δ2 voltage-gated neuropathy at 4 years.075% cream was not pared with conventional glucose control17. In early studies. 15 However. ment in quality of life.19 In another trial based on calcium modulators that are frequently used to treat a multifactorial strategy that involved con-trol of painful diabetic neuropathy. Lifestyle interventions tion of >1% per month in hemoglobin A1C level) may prevent or possibly reverse neuropathy. no sensory deficit assigned to receive insulin-sensitizing agents as at the site of application has been reported. classes of medications commonly used for treat- including falls and foot ulcers. These agents relieve blood pressure and lipid levels.21 impaired glucose tolerance. or adding a second agent. capsaicin 0.27. The table assigned to exercise on a treadmill. Management of painful distal symmetric polyneu. every 2 to extension and foot dorsiflexion and improve gait 4 weeks) based on efficacy and side effects. switching rational glycemic control is recommended to to a new class.24 Options then include switching to a sure and blood glucose levels should be avoided.23. Patients reported improve- ment of neuropathy after 5 years.16 vide satisfactory relief at maximally tolerated Although overzealous control of blood pres. also lists reported benefits (the number needed to these trials did not include participants with treat to in order to reduce pain by 50% in one established diabetic neuropathy.25. how. effective in relieving pain and caused a burning ever.g.14 A randomized trial involving Table 2 lists agents that are commonly used for persons with diabetes mellitus who did not have pain relief in patients with distal symmetric indications of neuropathy showed a reduced risk of polyneuropathy and that have been shown to be the development of neuropathy among those effective in randomized clinical trials. trials conducted among patients with type 1 dia- betes.0% patch was applied for have been less clear. First-line monotherapy frequently does not pro- tients with large-fiber neuropathy. doses. different agent within the same class. Many treatments balance training to increase the strength of knee require careful dose adjustment (e. tight glucose control reduced the risk of Topical Capsaicin the development of neuropathy by 78% as com.a common condition in persons with diabetes tensive therapy) as compared with conventional (Table 1). and lifestyle modification (in.1.. More recent ropathy among patients with type 2 diabetes studies in which an 8. tight glycemic control resulted in modest tients had pain relief that began within a few reductions in neuropathic symptoms but no days and persisted for 3 to 6 months after a significant reduction in the risk of the develop.28 In contrast to gabapen- . improving sleep. therapy. In the Action to Control 30 to 60 minutes (after the administration of a Cardiovascular Risk in Diabetes (ACCORD) local anesthetic at the site) have shown that pa- trial.rapid lowering of blood glucose levels (a reduc- sion and relieve symptoms. single application. patients randomly fibers originating in the skin.26 compared with insulin-providing agents had improved glycemic control and had a signifi. the use of pain by means of direct mechanisms and by antioxidants.20 An overly cologic approaches to minimize disease progres. The manage symptoms and prevent further damage. may induce a neuritis with severe pain. the incidence of autonomic neuropathy but not somatic neuropathy was significantly CLINICAL MANAGEMENT lower among those receiving intensive therapy. Although researchers pass Angioplasty Revascularization Investigation worried that this agent might damage C-type 2 Diabetes (BARI 2D) trial.

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CLINICAL PRACTICE .

37. also inhibits the reuptake of norepineph- indicate that it stimulates the growth of rine and serotonin and provides effective pain intraepidermal nerve fibers. the response to treatment ergic effects than amitriptyline or imipramine with pregabalin correlates with the degree of and are generally preferred.0 fibers per In one study. AR E AS OF UNCERTAINT Y prove quality of life. tention.38 intraepidermal nerve fibers of 0. etine. although gabapentin and of QT-interval prolongation and rhythm distur. Tramadol. de- effects. including consti- Tricyclic Antidepressants pation. elec. and anxiety. and urinary re.0 fibers per millimeter per year in untreated analgesia at lower doses of each drug than the patients. particularly in elderly patients.13.23 proved to be effective in relieving neuropathic pain34. duloxetine has also been shown to im. the combined use of gabapentin and millimeter per year.27. sedation.5 to 1. addiction.may be more susceptible to the adverse effects of tors (SNRIs) venlafaxine33 and duloxetine have these therapies than younger patients. warranted regarding the use of tricyclic antide- pressants and high doses of pregabalin or gaba- Serotonin–Norepinephrine Reuptake Inhibitors pentin in elderly patients. in ad- the tricyclic antidepressants. both directly and mine. it also has a more rapid onset of action neuropathic pain caused by distal symmetric than gabapentin and a more limited dose range that polyneuropathy. head-to-head trials that compare the effects of various agents are .7. 30. constipation.35 These agents inhibit reup- take of both serotonin and norepinephrine with.28 In contrast to dulox- sion. and diversion. including sleep loss. through relief of pain. Caution is bances (Table 2). which has been pentadol has similar actions and has been ap- accompanied by improvements in lipid lev-els and proved for the treatment of diabetic neuropathic blood pressure and increases in the den-sity of pain by the Food and Drug Administration. Tricyclic antidepres. COEXISTING CONDITIONS AND CHOICE OF THERAPY nisms that are unrelated to their antidepressant Coexisting conditions.39 Pregabalin.1. dition. which can cause weight gain.29 Tricyclic antidepressants may offer substantial relief from neuropathic pain through mecha. 27-29 and only after other medications have failed to Topiramate has also been shown to reduce the be effective. which increases fragmentation of sleep.5 to 2.Most trials of drugs that are used to control pain out the muscarinic. pregabalin has linear and dose-proportional Opioid Analgesics absorption in the therapeutic dose range (150 to 600 Opioids may be effective in the treatment of mg per day). since these patients The serotonin–norepinephrine reuptake inhibi.1. improve the quality of sleep. Extended-release ta- topiramate causes weight loss. dry mouth. studies gesic.28 An SNRI or a sants should be used with caution in patients tricyclic antidepressant may be preferred in pa- with known or suspected cardiac disease.36 This drug also has a lower potential for and gabapentin. as compared with a decline of sustained-release morphine achieved better 0. abuse than other opioids. opioids gradual adjustment to the dose that is usually should generally be used only in selected cases clinically effective (1800 to 3600 mg per day). and follow the patients for only a month and do not adrenergic side effects that accompany the use of provide information on enduring effects. nortriptyline and desipra. or an SNRI may be appropriate choices for these drugs are initiated to rule out the presence patients with anxiety.3. and dry mouth. Gaba-pentin requires risks of abuse.tin. they typically compare a single agent with placebo. choosing therapy. should be considered in adverse cholinergic effects such as blurred vi.31 use of either drug alone but was accompanied by an increase in adverse effects.27. pregabalin may cause weight gain. given the attendant requires less adjustment. their use is often limited by pression. tients with depression. gabapen- trocardiography should be performed before tin. Long-term. The pregabalin and gabapentin have been shown to secondary amines. tend to have less bothersome anticholin.31 Unlike pregaba-lin relief.32 However. histamine-related. sleep loss before treatment. an atypical opiate anal- intensity of pain and to improve sleep.3. However.

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46 The guidelines generally recom- mend the use of anticonvulsant agents. 4 studies of venlafaxine.ThisdrughasbeenapprovedforthisindicationbytheFDA. 6 studies of gabapentin ER (extended release). Serious adverse events are listed alphabetically.TheFoodandDrugAdministration(FDA)alsoconsidersanimprovementof30%tobesignificant. A randomized trial involving patients with diabetes who had moderate distal Immediate release. Data suggest that oxidative and nitrosative stress are central to the pathogenesis of neu- 50 mg.40 but several types of pain were alleviated and quality of life stipation. as are trials that compare the effects of Somnolence.42. one study indicated that the threshold for the development of im-paired nerve conduction is approximately 450 pg per of 50% in One Person† NNT for Improvement milliliter41. 3 studies of topiramate. 7 studies of tramadol. More data are needed to inform the choice † Association to update guidelines for diabetic neuropathies. con. 3 studies of nortriptyline.Thisdrugisgenerallynotusedforfirst-linetherapy.44. neonatal opioid-withdrawal syn- sequent therapy when efficacy is lost or is insuf- ficient. 60 mg/ day.3–18. 2 times/day release. A randomized trial that evaluated a com- bination of methylcobalamin. dizzi- was improved.Studiesoftopiramateandnortriptylineweretoo small to provide an NNT.0 (7. the role of the other components in this regard and the overall effectiveness of this treat- ness. 25 studies of pregabalin. SNRIs §¶‖**†† * . extended day 1. and Adverse Events§ pyridoxal phosphate in patients with diabetic peripheral neuropathy showed no significant Serious drome benefit with respect to the primary outcome of threshold for vibration perception. 12 studies of tapentadol. NNT denotes number needed to treat.7) 10. of which Dr. and 7 studies of the capsaicin 8% patch andwereadaptedfromVinikandFinnerupetal. Data are also needed to inform the benefits Johnson syndrome and risks of agents other than those being used now. lipoic acid had no significant benefit with re- Effective gard to the primary outcome (a composite score calculated on the basis of neuropathic impair- Apply for 30 min ment and results of neurophysiological testing) at 4 years.6–6. Whereas neuropa- thy associated with vitamin B 12 deficiency has Common seizures typically been considered to occur at levels be- low 250 pg per milliliter. with loss of sensation reactions. Stevens– pies. Initial Dose 50–100 mg. although improvements were noted in the scores assessing neuropathic impair- OpioidsTapentadol Immediate release. 14 stud- monotherapies with those of combination thera- Damage to C-type fibers.2times/day treatment. seizures. con-Hypertension. this finding suggests that there is a 10. Numbers in parentheses represent the of initial therapy on the basis of the characteris- tics of the individual patient and to guide sub- Somnolence.5) need for more study of the role of vitamin B12 supplementation in persons with diabetic periph- eral neuropathy. symmetric polyneuropathy showed that alpha after day 1. vomiting. methylfolate.4–19) 4. hypertension. stipation. hypersensitivity ies of gabapentin. 4–6 times/day. 700 mg.2 (5. nausea.Norangeisprovidedbecausethenumberswerebasedononestudy. CLINICAL PRACTICE needed. and antioxidants have been proposed for Apply for 60 min 50 mg.0% patch(Qutenza) Tramadol (Ultram)‖ Drug Class and Agent Several guidelines from professional societies offer recommendations for the management of (Nucynta)‖†† pain resulting from distal symmetric polyneu- ropathy.ThistablewasadaptedinpartfromadraftversionofatabledevelopedbyacommitteeconvenedbytheAmericanDiabetes1322 The data reported are based on the findings of 12 studies of amitriptyline. dizziness. respiratory taking metformin who had vitamin B12 defi- ciency. Vinik was a member. ropathy. 1–2 times/day 100–200 mg/day ‡ range.Common adverse events are generally listed according to frequency.7 (3. confusion. ex- tended release. 9 studies of duloxetine.43 GU I DE L I NE S Capsaicin 8. 50 mg. headache Adverse Events‡ ment regimen are uncertain. vomiting. light headedness. nausea. ment. serotonin syndrome.Cardiac arrhythmias.40 It is possible that the methyl- Burning at site of application cobalamin component was helpful for persons depression.

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T h e NE W E NGL A ND JOU R NA L o f M E DICINE .

lipid. If there is no response after 1 month of sensorimotor neuropathy. a switch to an agent from another drug include measurement of glucose. tricyclic antidepressants. He also reports be- month) and the development of hypotension ing the inventor of a dietary supplement that includes a mixture should be avoided. and topical agents. priate first choices. It would be best to SUMM AR Y AND R ECOMMENDATIONS start with lower doses (e. Daiichi Sankyo. and ascorbic acid. randomized trials involving patients with distal although the order of preference differs among predominantly sensory neuropathy and that are the societies. neuropathy. as is seen in this patient. Alnylam. a quality-of-life instrument owned by his medical school. he. first-line agents. a com-plete is below 450 pg per milliliter. and most commonly used for treatment include pre- other antidepressants are largely considered to be gabalin or gabapentin. pregabalin or gabapentin may be appro- guidelines. Astellas. No other potential conflict of interest relevant to this article was balance and reaction times would be advisable to reported. Cline changes (diet and exercise) and adjustment of Davis Mann. Nestle Health Science–Pamlab. Since this patient has a sleep distur- article are generally consistent with these bance. his laboratory. hemo-globin class would be advisable. Vinik reports receiving fees for serving on advisory boards resolution of the neu-ropathy can be followed.g. dihomo -γ- linoleic acid. Santarus. the rights to therapy should be recommended for strength which were assigned to his medical school. reduce the risks of falls and fractures. Vinik reports that training (and focused on the weakness of dorsi. Intarcia. supplementa-tion blood count. NeuroMetrix. Dai- medications should be recommended routinely to ichi Sankyo. Tercica. lipid levels. consult-ing fees from Merck. For this patient. autonomic function should also be performed to although formal studies of its use in this regard obtain a definitive diagnosis and serve as have not been conducted. twice daily) and to adjust the dose upward if acteristic features of large-fiber and small-fiber there is no reduction in pain within the first 2 neuropathy that are consistent with diabetic weeks. Quantitative tests of sensory and (starting at a twice-daily oral dose of 300 mg). and with oral methylcobalamin (2000 μg per day) an assessment of vitamin B12 and folate levels. and Astellas. lecture fees from Merck and Nestle Health Science–Pamlab. IONIS Pharmaceuticals. and diminished glycemic control. lifestyle Medikinetics. Impeto Medical.and other antidepressants. could be initiated.org. from Merck. baselines from which the progression or Dr. anticonvulsant agents. which he codeveloped for use in clinical trials hemoglobin A1C level (by more than 1% per involving patients with diabetic neuropathy. In patients with distal predominantly sensory NeuroMetrix. although there are as yet no vitamin B12 deficiency is associated with data that show that supplementation reduces metformin use and is manifested as impaired neuropathy in the absence of frank deficiency. Janssen. and Novo Nordisk. and System Analytic. and thyrotropin levels. An overly rapid lowering of the Norfolk QOLDN tool. serum protein electrophore-sis. grant support from Pfizer. Vero- improve glycemic control. benfotiamine. fluid retention. . methylcobalamin. The recommendations in this and SNRIs. SNRIs. If the vitamin B12 level A1C. and blood Science. Dr. physical of alpha lipoic acid. ViroMed. but monitoring will be re- quired for weight gain. Disclosure forms provided by the author are available with the Agents that have proved to be effective in full text of this article at NEJM. Laboratory tests should treatment. Ipsen. and his department have not received and will flexion of the big toe). cholecalciferol.. Ipsen. and training to improve not receive any income that might derive from this product. Bayer. and royalties for the use of the pressure. perception of vibration and loss of ankle Alpha lipoic acid can be given to relieve pain reflexes. 75 mg of pregabalin The woman described in the vignette has char. Pfizer.

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