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FEATURE ARTICLE
Management of Diabetic Peripheral Neuropathy
Andrew J.M. Boulton,MD,DSc(Hon),FRCP
N
europathies are among the mostcommon of all the long-termcomplications of diabetes,affecting up to 50% of patients.
1–5
There are many subgroups of neu-ropathies; readers are referred to recentreviews for discussion of the autonomicneuropathies
6
and the mononeu-ropathies.
7
This article will focus on themost common of all the peripheral neu-ropathies:the somatic neuropathiesaffecting the lower extremities. Detaileddiscussions of all aspects of these neu-ropathies were recently published as atechnical review
5
and will be includedin a forthcoming American DiabetesAssociation statement.In the past,a lack of awareness andinappropriate management of diabeticperipheral neuropathy (DPN) has led tomuch unnecessary morbidity and sub-stantial health care costs. At least half of all foot ulcers,the end stage of such neu-ropathy,should be preventable by appro-priate management and patient educa-tion. However,lack of time andinappropriate or inadequate informationmay lead to suboptimal care.Diabetic somatic neuropathies dorepresent a paradox:at one extreme thereare patients with severe neuropathic painwho on examination may have only aminimal deficit,whereas at the otherextreme are patients with insensate feetwho are asymptomatic and may firstpresent with foot ulcers.This review will provide an overviewof DPN and a detailed guide to the man-agement of pain in patients with signifi-cant symptomatology.
DEFINITIONS
Members of an InternationalConsensus Meeting on the outpatient
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CLINICAL DIABETES
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 Volume 23, Number 1, 2005
diagnosis and management DPNagreed on a simple definition of diabet-ic neuropathy as “the presence of symptoms and/or signs of peripheralnerve dysfunction in people with dia-betes after the exclusion of other caus-es.”
8
This group also agreed that neu-ropathy cannot be diagnosed without acareful clinical examination and thatabsence of symptoms must never beequated with absence of neuropathy.The importance of excluding nondia-betic causes was emphasized in theRochester Diabetic Neuropathy Study,in which up to 10% of peripheral neu-ropathy in diabetes was deemed to beof nondiabetic causation.
1
For day-to-day clinical practice,DPN is a clinical diagnosis. It is gener-ally agreed that DPN should not bediagnosed on the basis of one symp-tom,sign,or test alone; a minimum of two abnormalities (i.e.,abnormalsymptoms and signs) is recommended.
5
EPIDEMIOLOGY
DPN is by far the most common of allthe diabetic neuropathies and may bedivided into the following two maintypes:acute sensory neuropathy andchronic sensorimotor neuropathy.Acute sensory neuropathy is a distinctvariety of the symmetrical polyneu-ropathies with an acute or subacuteonset characterized by severe sensorysymptoms,usually with few if anyclinical signs. It is usually precipitat-ed by an episode of glycemic instabil-ity (such as ketoacidosis or even afterthe institution of insulin),and its nat-ural history is one of gradualimprovement of symptoms withestablishment of stable glycemic con-trol and appropriate symptomatictreatments.Chronic sensorimotor neuropathy isby far the most common form of DPN.It is usually of insidious onset and maybe present at the diagnosis of type 2diabetes in up to 10% of patients.Whereas up to 50% of patients withchronic DPN may be asymptomatic,10–20% may experience troublesomesymptoms sufficient to warrant specifictherapy. Sensorimotor neuropathy isoften accompanied by autonomic dys-function. Its late sequelae,whichinclude foot ulceration,Charcot neuro-arthropathy,and occasionally amputa-tion,should in many cases be preventa-ble. The prevalence of chronic DPNincreases with both age and duration of diabetes,and this diagnosis is morecommon in those whose glycemic con-trol has been suboptimal in previousyears.Diabetic peripheral neuropathyaffects up to 50% of older type 2 dia-betic patients. Whereas some patientsmay have extremely painful symp-toms,others with a more marked neu-ropathic deficit may be asympto-matic. Diagnosis requires carefulexamination of the lower limbs.Management involves establishingthat the neuropathy is caused by dia-betes instead of more sinister causesand aiming for optimal glycemic con-trol. Medications,usually tricyclicdrugs or anticonvulsant agents,maybe required. Patients with peripheralneuropathy must be considered at risk of insensate foot ulceration and mustreceive preventive education andpodiatric care.
IN BRIEF
 
ications required may be higher,in acutesensory neuropathy. The natural historyof this acute neuropathy is very differentfrom the much more common chronicDPN; its onset is acute or subacute,butthe severe symptoms typically resolve in< 12 months.
10,11
Chronic Sensorimotor Neuropathy
Painful neuropathy can be one of themost distressing and debilitating of allthe complications of diabetes. The restof this review will discuss the approachto patients presenting with chronic DPNand will focus on available treatmentswith brief comment on those that maysoon be available.As noted above,many patients areasymptomatic,and the neurologicaldeficit may be discovered by chance dur-ing a routine neurological exam.Because chronic DPN is a length-dependent process,the sensory manifes-tations are most pronounced in the lowerlimbs,although,in more severe cases,the fingers and hands may also beinvolved. The symptoms,outlined inTable 2,tend to be peculiar to the indi-vidual patient but constant during thehistory of neuropathy in that individual.Patients often find it very difficult todescribe the symptoms because they aredifferent from other types of pain thepatients have previously experienced.
FEATURE ARTICLE
CLINICAL FEATURES OF DPNAcute Sensory Neuropathy
Many of the symptoms of acute sensoryand chronic sensorimotor neuropathyare similar,although there are clear dif-ferences in the mode of onset,accompa-nying signs,and prognosis. These aresummarized in Table 1. Table 2 offers alist of typical symptoms,both painfuland nonpainful. All painful neuropathicsymptoms tend to be prone to nocturnalexacerbation. Clinical examination of patients with presumed acute sensoryneuropathy may be relatively normal,with allodynia (a painful sensationinduced by nonnoxious stimulus) onsensory testing,a relatively normalmotor exam,and occasionally reducedankle reflexes.In the management of this condition,achieving stable blood glucose control ismost important. Stability may well bethe key feature,because blood glucoseflux (as assessed,for example,by the
 M 
value,a measure of glycemic excursionsfrom the mean) is associated with pain.
9
Additionally,however,most patientswill require medication after neuropathicpain,and these medications are dis-cussed in detail below in the section onmanagement of chronic DPN. Suffice itto say that the approach is similar,although the dosage and number of med-
 Volume 23, Number 1, 2005
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CLINICAL DIABETES
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Although not mentioned in older texts,unsteadiness is increasingly being recog-nized as a manifestation of chronic DPNresulting from disturbed propriaceptionand probably abnormal muscle sensoryfunction. Many patients will have a com-bination of both positive (painful) andnegative (nonpainful) symptoms.Clinical examination of patients withchronic DPN usually reveals a symmet-rical sensory loss to all modalities in astocking distribution. This may wellextend into the mid-calf level and mayalso affect the upper limbs in moresevere cases. Ankle reflexes are usuallyreduced or absent,and knee reflexesmay also be reduced in some cases.In the clinical assessment of patients,a number of simplesymptom/screening questionnaires are
Table 1. Contrasts Between Acute Sensory and Chronic Sensorimotor NeuropathiesAcute SensoryChronic SensorimotorMode of onset
Relatively rapidGradual,insidious
Symptoms
Severe burning pain,aching;Burning pain,paresthesiae numbness;weight loss usualweight loss usual
Symptom severity
+++0 to ++
Signs
Mild sensory in some; motor unusualStocking and glove sensory loss; absent anklereflexes
Other diabetic complications
UnusualIncreased prevalence
Electrophysiological
May be normal or minorAbnormalities unusual in motor and
investigations
abnormalitiessensory nerves
Natural history
Complete recovery with 12 monthsSymptoms may persist intermittently foryears; at risk of foot ulceration
Table 2. Typical NeuropathicSymptomsPainfulNonpainful
Burning painAsleepKnife-like“Dead”Electrical sensationsNumbnessSqueezingTinglingConstrictingPricklingHurtingFreezingThrobbingAllodynia
 
sectional and longitudinal studies haveassessed the sensitivity of the 10-gmonofilament and have shown it to be auseful tool to identify patients at risk of foot ulceration.
5,15
Of the simple quanti-tative sensory testing instruments thatare used in clinical practice,the mostcommon is the bioesthesiometer (Bio-medical Instruments,Newbury,Ohio).This assesses in a semiquantitative man-ner the perception of vibration and hassimilarly been shown to be a useful pre-dictor of foot ulcer risk.
16
MANAGEMENTIs It DPN?
The management approach to patientsconsidered to have DPN is provided inTable 3. First,it must be rememberedthat there are numerous causes of peripheral neuropathy,of which diabetesis probably the most common. However,exclusion of other causes,particularlymalignant disease and toxic causes,is of paramount importance. Exclusion of such potentially serious conditions asmalignant disease (e.g.,small-cell carci-noma presenting as a paraneoplasticsyndrome),toxic causes (e.g.,alcohol),and infections (diseases such as HIV) isessential.
FEATURE ARTICLE
available to record symptom qualityand severity. Among these is the Michi-gan Neuropathy Screening Instrument,which is a brief 15-item question-naire.
12
It is also increasingly recog-nized that both symptoms and deficitsmay have an adverse effect on qualityof life in diabetic neuropathy,
13
and spe-cific questionnaires have been devel-oped for the assessment of the impactof neuropathy on quality of life. Simi-larly,composite scores have been usedto assess clinical signs,and one that isincreasingly used is a modified Neu-ropathy Disability Score (NDS).
14
TheNDS,shown in Figure 1,can be easilyperformed in the clinic setting andtakes only a minute or two to complete.The maximum deficit score is 10,which would indicate complete loss of sensation to all sensory modalities andabsent reflexes. In a longitudinal Euro-pean community-based study,an NDSof 
≥
6 was equated with an increasedrisk of insensate foot ulceration.
14
A number of simple devices may beused for clinical screening; the mostwidely used is the Semmes-Weinsteinmonofilament.
15
This filament assessespressure perception when gentle pres-sure is applied sufficient to buckle thenylon filament. A number of cross-
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 Volume 23, Number 1, 2005
In most cases,further investigation,such as detailed quantitative sensorytesting in electrophysiology,whichwould require referral to a neurologist,isnot essential. Abnormal electrophysiolo-gy simply confirms the presence of aneuropathy but does not indicate theunderlying cause.
Initial Therapy and Counseling
Once a diagnosis is established,givingpatients a full explanation of their condi-tion,allaying their fears and misconcep-tions,and informing them that the painmay resolve in time can be extremelyreassuring. Simple physical treatments,such as the use of a bed cradle to lift thebed clothes off of hyperaesthetic skin,can be beneficial. Advice on suitablefootwear may also be provided. Inpatients with relatively mild pain,simpleanalgesics or anti-inflammatory agentsmay be sufficient to treat the discomfort.
Metabolic Control
The most effective method of achievingstable normoglycemia is pancreas orislet cell transplantation. However,thisis not practical in most cases because itis mainly available to patients with end-stage diabetic nephropathy who havecombined pancreas and renal transplantsor in special cases of young people withtype 1 diabetes.Although there have been no ran-domized,controlled trials of intensiveinsulin therapy in the management of diabetic neuropathy,data from a numberof observational studies suggest that sta-ble glycemic control is of the greatestimport. A recent study using continuousglucose monitoring confirmed thatpainful symptoms were associated witherratic blood glucose control.
9
Havingsaid this,there is no evidence thatpatients whose diabetes has been wellcontrolled on oral hypoglycemic agentswill benefit in terms of pain relief bytransferring to insulin.
Pharmacological Management
A large number of therapeutic agentshave been proposed for the management
 Figure 1. The Modified Neuropathy Disability Score
Neuropathy Disability Score (NDS)Right LeftVibration Perception Threshold
128-Hz tuning fork; apex of big toe:normal = can distinguish vibrating/ not vibrating
Temperature Perception on Dorsumof the Foot
Normal = 0Use tuning fork with beaker of Abnormal = 1ice/warm water
Pin-Prick
Apply pin proximal to big toe nail justenough to deform the skin;trial pair = sharp,blunt;normal = can distinguish sharp/not sharp
Achilles Reflex
Present = 0Present withreinforcement = 1Absent = 2NDS Total out of 10
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