Painful Diabetic Neuropathy: Epidemiology, Natural History, Early Diagnosis, and Treatment Options

PAIN MEDICINE

Volume 9

•

Number 6

•

2008

© American Academy of Pain Medicine 1526-2375/08/$15.00/660 660–674 doi:10.1111/j.1526-4637.2007.00347.x

Blackwell Publishing IncMalden, USAPMEPain Medicine1526-2375American Academy of Pain Medicine? 200796660674RESEARCH ARTICLES

Painful Diabetic NeuropathyVeves et al.

Reprint requests to:

Aristidis Veves, MD, Microcirculation Laboratory, Palmer 317, BIDMC/West, One Deaconess Road,Boston, MA 02215, USA. Tel: 617 632 7075; Fax: 617 632 7090; E-mail: [email protected].

REVIEW ARTICLE

Painful Diabetic Neuropathy: Epidemiology, Natural History, Early Diagnosis, and Treatment Options

Aristidis Veves, MD,* Miroslav Backonja, MD,

†

and Rayaz A. Malik, MB, PhD

‡

*Microcirculation Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA;

†

Departments of Neurology, Anesthesiology, and Rehabilitation Medicine, University of Wisconsin Medical School, Madison, WI, USA;

A B S T R A C T

and

‡

Division of Cardiovascular Medicine, University of Manchester and Manchester Royal Infirmary, UK

ABSTRACT

Objective.

To facilitate the clinician’s understanding of the basis and treatment of painful diabeticneuropathy (PDN).

Background.

PDN is one of several clinical syndromes in patients with diabetic peripheral neurop-athy (DPN) and presents a major challenge for optimal management.

Methods.

A systematic review of the literature was undertaken for articles specific to PDN, usingMedline databases between 1966 and 2007.

Results.

The epidemiology of PDN has not been well established and on the basis of available datathe prevalence of pain is 10% to 20% in patients with diabetes and from 40% to 50% in those withdiabetic neuropathy. It has a significant impact on the quality of life and health care costs. Patho-physiologic mechanisms underlying PDN are similar to other neuropathic pain disorders and arebroadly characterized as peripheral and central sensitization. The natural course of PDN is variable,with many patients experiencing spontaneous improvement and resolution of pain. Hyperglycemia-induced pathways result in nerve dysfunction and damage, which lead to hyperexcitable peripheraland central pathways of pain. Glycemic control may prevent or partially reverse DPN and modulatePDN. Quantifying neuropathic pain is difficult, especially for clinical trials, although this hasimproved recently with the development of neuropathic pain-specific tools, such as the NeuropathicPain Questionnaire and the Neuropathic Pain Symptom Inventory. Current therapeutic optionsare limited to symptomatic treatment and are similar to other types of neuropathic pain.

Conclusions.

A better understanding of the peripheral and central mechanisms resulting in PDN islikely to promote the development of more targeted and effective treatment.

Key Words.

Neuropathic Pain; Diabetic Neuropathy; Symptomatic Therapy; Pain Assessment;

Mechanisms

Disclosure Information

: An earlier version of this article was written with the editorial assistance of IMPRINT Publi-cation Science, which is supported by an unrestricted grant from GlaxoSmithKline. The authors received no honorariaand GSK were not privy to any review of the material before submission.

Dr. Backonja has received honoraria, consulting fees, or grant/research support from Endo Pharmaceuticals, GlaxoSmith-Kline, Johnson & Johnson, NeurogesX, Inc., Novartis Pharmaceuticals, Pfizer Inc., Purdue Pharma LP, Wyeth, andXenoPort. Dr. Malik has received honoraria or consulting fees from AstraZeneca Pharmaceuticals, Takeda Pharmaceuti-cals, and Pharma Inc. and grant/research support from AstraZeneca. Dr. Veves is a member of the Advisory Panel ofGlaxoSmithKline.

Painful Diabetic Neuropathy

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Overview

iabetes is one of the leading causes of periph-eral neuropathy, a heterogeneous group of

disorders that can affect neuronal functionthroughout the body [1,2]. Peripheral neuropa-thies manifest with painful or painless symptomsand many patients experience both. Furthermore,diabetes may not necessarily be the cause of theneuropathy in all diabetic patients. Indeed othercauses such as hereditary, inflammatory, and othermetabolic neuropathies may coexist and shouldbe actively excluded [1]. Once diagnosed correctly,painful diabetic neuropathy (PDN) presents aunique challenge in patient management andshould be considered a syndrome clinically distinctfrom diabetic peripheral neuropathy (DPN) [3].PDN can have debilitating consequences with asignificant impact on quality of life (QOL) andcosts of management [4,5]. Current therapies thatreduce pain in PDN do not prevent progressionof DPN. This review was designed to facilitate theclinician’s understanding of PDN as one syndromeof DPN by surveying the epidemiology, patho-physiology, natural history, assessment, andmanagement of PDN. Furthermore, to provideinsights into the pathophysiology of neuropathicpain, the symptoms, signs, and pathologic abnor-malities associated with impaired glucose toler-ance (IGT) will be discussed. Assessment tools forrecognizing neuropathic pain and current thera-peutic options will be considered.

Methods

Medline database (1966–2007) searches were per-formed to provide a comprehensive, systematicreview of the literature regarding PDN. Termscombined with PDN were IGT (impaired glucosetolerance) and FGT (fasting glucose test), neuro-pathology, pathogenesis, pathophysiology, epide-miology, natural history, diagnosis, and treatmentoptions for PDN. The inclusion criteria for thisreview were primary literature of well-designedand controlled studies with results specific forPDN. References of articles identified as a resultof the database searches were reviewed.

Results

Epidemiology of PDN

The epidemiology of PDN has not been exten-sively studied. Historically, epidemiologic studiesof DPN have not differentiated between patients

D

with and without pain, but have included pain asone of several inclusion criteria. Also, most studiesdo not indicate whether patients with neuropathicpain resulting from an etiology other than diabeteshave been excluded. In the literature, the preva-lence of PDN ranges from 10% to 20% of patientswith diabetes and from 40% to 50% of those withdiabetic neuropathies [3–5]. A detailed evaluationof PDN was undertaken in a European multi-center study of 1,171 patients with type 1 and type2 diabetes and served to illustrate the complexnature of PDN [6]. Ziegler et al. reported signifi-cantly lower pain in both the lower (11.6% [75/647] vs 32.1% [168/524]) and upper (7.1% vs16.6%) extremities in patients with type 1 (meanduration, 10 years) compared with type 2 diabetes,respectively. However, there was no correction forage (the mean age of patients with type 2 diabeteswas 21 years greater than the mean age of thosewith type 1 diabetes) or comorbidities. Peripheralneuropathy was defined by the presence of at leasttwo of the following three characteristics: (1) pain,paresthesias, or numbness of

≥

10 mm on a 0- to100-mm visual analog scale (VAS); (2) absent ten-don reflexes; or (3) abnormal malleolar vibrationperception threshold assessed by a tuning fork.The study did not indicate whether an attempt wasmade to distinguish between PDN and pain ofa different origin. Of note, the percentage ofpatients with type 2 diabetes reported to havelower-limb pain was greater (32.1%) than the per-centage of patients with type 2 diabetes reportedto have neuropathy (23.9%), suggesting either thatnot all of the pain was PDN or that the criteriafor determining peripheral neuropathy did notidentify all cases.

Symptomatic neuropathies have been recog-nized in individuals with IGT and newly diag-nosed diabetes. Sumner et al. [7] performed oralglucose tolerance tests in 73 of 97 patients whowere referred to three neuromuscular clinics withneuropathy of unknown origin. Test results wereabnormal for 41 (56%) individuals, with 15 and26 meeting the criteria for diabetes and IGT,respectively [7]. The prevalence of neuropathicpain did not differ significantly between patientswith IGT (76.9%) and patients with diabetes(93.3%,

P

=

0.1). Electrophysiologic studies (suralnerve amplitude and conduction velocity anddeep peroneal amplitude) and skin biopsy todetermine intraepidermal nerve fiber (IENF)density indicated a less severe neuropathy in indi-viduals with IGT, which predominantly affectedsmall fibers.

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Pathophysiology

Although considerable data are available regard-ing the molecular processes leading to cellulardamage in the nervous system as a result of hyper-glycemia, the mechanisms specific to pain indiabetic neuropathy have not been identified.Neurophysiologic and pathologic parameters donot distinguish between patients with painful andpainless neuropathy [8]. To determine neuro-pathologic changes, studies of PDN have includedpatients with DPN without pain and a controlgroup without neuropathies. Results fromstudies comparing morphometric parametersbetween diabetic patients with and without painfulneuropathy have been inconclusive [8–10]. Inthree studies, there was no significant differencein the degree of myelinated nerve fiber loss,although there was a trend toward more activedegeneration of unmyelinated fibers in patientswith PDN. In an early study, peripheral small andlarge nerve fiber function did not differ betweenpatients with PDN and patients with painlessDPN [11]. More recently, in 191 diabetic patientswith and without painful neuropathy, patientswith pain detected a cold stimulus at a lower tem-perature (

−

3.7

°

C) compared to those without pain(

−

0.6

°

C), but there were no differences for theheat pain tests, suggestive of an effect on A-deltamyelinated fibers as opposed to C fibers [12].However, the same group have also demonstratedmore severe loss of IENF in those with neuro-pathic pain but with little or no objective sign ofneuropathy, suggesting that IENF damage mayonly partially explain pain and that differentmechanisms may underpin the genesis of pain atvarious stages of neuropathy [13].

Mechanisms of Pain

The current understanding of general mechanismsof neuropathic pain may provide insights into theabnormalities leading to pain in diabetic neuro-pathy. Damage to peripheral nerves results inhyperexcitability in primary afferent nociceptors(peripheral sensitization) that leads to hyperexcit-ability in central neurons (central sensitization)and generation of spontaneous impulses within theaxon as well as the dorsal root ganglion of theseperipheral nerves [14]. When the nerve is able torepair itself, the sensitization resolves; however,in chronic disease such as diabetes with ongoingdamage, continued sensitization and altered pro-cesses in nociceptors lead to further generation ofspontaneous symptoms. Sensitization is character-ized by a lowered activation threshold, increased

response to a given stimulus, and abnormal spon-taneous activity [14–16].

In animal studies, damaged peripheral nervesbecome hyperexcitable, mechanosensitive, andepinephrine-sensitive [15]. Several studies haveconfirmed the role of epinephrine sensitivity andsympathetically mediated pain in PDN [15,17,18].Abnormal electrical connections exist in experi-mental animal models of chronic peripheral nervedamage that may result in ephaptic transmissionor “cross-talking,” a transfer of impulses from oneaxon to another [19]. Ephaptic transmission mayoccur between sensory and sympathetic fiberscontributing to sympathetically mediated pain.Increased sympathetic activity has been shown inpatients with PDN by Tsigos et al. [17], who eval-uated circulating levels of norepinephrine andfound that patients with PDN had concentrationsequivalent to control subjects without diabetesand higher than those in diabetic patients with orwithout painless neuropathy. In a study using no-repinephrine spillover assessment and positronemission tomography, patients with PDN wereshown to have evidence of regionally selectivesympathetic denervation in their feet [20]. Fur-thermore, a recent study has shown impaired sym-pathetically mediated vasoconstriction in patientswith PDN, suggestive of inappropriate local bloodflow regulation in these patients [21].

Alteration to damaged axons causes sodiumchannels to accumulate at the injury site and alongthe length of the axon, promoting ectopic electri-cal impulses and hyperexcitability [22]. Thesephenomena contribute to the increased bursts ofelectrical impulses to the dorsal horn, altering thegating mechanism and substance P expression.The role of ectopic discharge and increasedsodium channels in PDN is consistent with theestablished efficacy of membrane stabilizers (anti-convulsants and tricyclic antidepressants) inrelieving neuropathic pain.

Changes occur in the dorsal root ganglia inmodels of chronic neuropathic pain and includecoupling of sympathetic and afferent neurons andabnormal release of substance P from A fibers[14,23]. With injury to peripheral nerves, sympa-thetic nerve fibers of local vasculature sprout bas-ket-like terminals around large primary afferentneurons [16]. Substance P, normally found only inC fibers, is released by the larger A fibers of thedorsal column and produces signals interpreted asmechanical allodynia [21].

Hyperexcitability of the peripheral nervesresults in central hyperexcitability, and persistent


663

nerve stimulation activates N-methyl-

d

-aspartate(NMDA) receptors located postsynaptically in thedorsal horn, with subsequent glutamate release[14,22]. Glutamate is an excitatory neurotransmit-ter that causes neuronal membrane depolarization,allowing stimuli to produce much larger postsyn-aptic potentials than usual—a process known assynaptic potentiation. Long-term synaptic poten-tiation has been shown in various pain states[24,25]. An important, and perhaps predominant,role of central mechanisms modulated principallyat the level of the spinal cord has thus been sug-gested recently [26]. Although a recent magneticresonance imaging study demonstrated a progres-sive reduction in cervical spine cord area at C2/C3, which correlated with neuropathic severity, itdid not find a difference between those with andwithout painful neuropathy [27].

Natural History

The pain associated with diabetic neuropathiescan be severe and sometimes intractable. Studieshave reported two possible types, an acute remit-ting [28] and a chronic PDN [29]. Archer et al.[28] studied nine patients with persistent lower-limb pain with nocturnal exacerbation and signif-icant weight loss, which resolved in all but onepatient. A follow-up study of 36 patients withPDN showed no change in pain scores, but aworsening median nerve motor conduction veloc-ity over 4.7 years [29]. Although data regardingthe natural history of PDN are limited, cliniciansshould be aware that pain symptoms can improveand completely resolve while progression of neu-ropathy continues; diminution of pain can meanworsening of sensory function [29].

Benbow et al. [30] prospectively studied thenatural history of painful symptoms, small-fiberfunction, and peripheral vascular disease (PVD) in50 patients who were followed for an average of3.6 years (3.0–4.1). Comparisons between baselineand end-of-study small-fiber function tests indi-cated significant deterioration in patients withoutPVD (thermal thresholds and weighted pinprickthresholds,

P

<

0.0001 each test). For patients withPVD at baseline, nerve function deterioration wasless, with an increase in thermal threshold reach-ing statistical significance (

P

<

0.05). In contrast,pain symptoms measured by a 10-cm VAS signif-icantly improved within each patient group, andseven patients (21%) were pain-free at the finalevaluation. For these seven patients, there was atendency toward a shorter history of pain beforestudy entry compared with the other participants,

but this difference did not reach statistical signif-icance. These findings were supported in a surveyof 105 respondents with PDN, of whom 72%,12%, and 15% reported worsening, improvement,and no change, respectively, in symptoms since theonset of PDN [4]. The mean age at diagnosis ofdiabetes was 49.6 years, and the mean age at PDNonset was 56.7 years. Pain was reported in 20 of26 patients evaluated for idiopathic neuropathywho were subsequently diagnosed with IGT, sug-gesting that PDN can be an early manifestation ofaltered glucose metabolism [7].

Early Diagnosis and Intervention

With evidence that neuropathy is associated withIGT, diabetes screening and early evaluation ofnerve function have added significance in the pre-vention of PDN [7]. While standard measuresof neuropathy such as nerve conduction studiesand vibration detection thresholds can be used todetect abnormalities in large-fiber function, sev-eral methods have been investigated for use in theclinical evaluation of small-fiber dysfunctionand damage. Measurement of nerve-axon reflex-related vasodilation is an objective measuredirectly related to function of C-nociceptive fibers[31]. IENF density measurement from skin biopsycan be used to evaluate small-fiber involvement indiabetic neuropathy and has been shown to detectchanges in patients with IGT and other neuro-pathies [32]. Although as noted previously theinterpretation of skin biopsy findings may be com-plex as the loss of IENF does not necessarilyexplain pain in all cases [13].

As neuropathies including PDN can be thepresenting symptom of IGT and diabetes, clini-cally distinguishing neuropathic pain from non-neuropathic pain could indicate individuals whoshould be evaluated for IGT or diabetes. Further-more, lifestyle intervention by improving glycemiccontrol, blood pressure, and lipid profile has beenshown to improve both painful neuropathic symp-toms and IENF density, suggesting that earlyidentification and appropriate intervention may beof significant clinical benefit [33].

Neuropathic Pain Assessment

Pain is a symptom that is difficult to classify, butfor a complete diagnosis and to judge the benefitsof treatment, the scoring of severity is necessary.Many different scores have been developed oradapted. Although the McGill Pain Questionnairehas been used frequently, it has not been rigor-ously evaluated for use in neuropathic pain disor-

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ders. Recently, scores specific for DPN have beenintroduced and include the Brief Pain Inventory(BPI) short form for DPN [34]. The BPI is apatient-completed numeric rating scale thatassesses the severity of pain and its impact on dailyfunctioning on a seven-item pain interferencescale. The Neuropathic Pain Questionnaire(NPQ) has also been developed to provide a gen-eral assessment of neuropathic pain and discrimi-nate between neuropathic and non-neuropathicpain [35]. Originally, 32 items were evaluatedusing discriminant analysis to determine the itemsthat successfully distinguished between neuro-pathic and non-neuropathic pain. The analysisindicated 12 necessary items, which were shownto differentiate neuropathic pain with 74.7% sen-sitivity and 77.6% specificity [35]. A short form ofthe NPQ has been validated (Figure 1) using step-wise discriminant analysis on three items from theoriginal NPQ, which when used clinically, dem-onstrate preserved ability to differentiate neuro-pathic from non-neuropathic pain. The threeitems are tingling pain, numbness, and increasedpain due to touch [36]. An additional diagnostictool, the pain diagnostic questionnaire (DN4), hasalso been developed recently and compares painsyndromes associated with nervous or somaticlesions [37]. Follow-up assessment of pain in PDNcan also be undertaken using either the NPQ orthe other recently developed tool, the Neuro-pathic Pain Symptom Inventory (NPSI), which isa self-questionnaire designed to evaluate differentsymptoms of neuropathic pain [38]. The NPSIincludes 10 descriptors that allow for the discrim-ination and quantification of clinically relevantaspects of neuropathic pain. It is suggested thatthis pain questionnaire may be able to (1) charac-terize subgroups of neuropathic pain patients, and(2) verify differential responses to pharmacologicor other treatment interventions. The Neuro-pathic Pain Scale has been designed specifically tomonitor effects of therapy on neuropathic pain[39].

Treatment Options

Treatment options for PDN are limited, but thefirst step for all patients is to maintain glucoseconcentrations within the normal range. Glycemiccontrol is important in individuals with diabetes toprevent progression of neuropathy, and intensiveglucose lowering therapy reduces the risk of devel-oping diabetic neuropathy [40–43]. Furthermore,a recent study has highlighted the importance offluctuations in glucose concentrations as they may

adversely affect neuropathic pain [44]. Pain scoresfrom daily diaries of 10 diabetic patients with neu-ropathic pain and 10 without neuropathic painshowed an association between pain and greatermean glucose concentrations, greater deviations ofglucose concentrations from a set point, and moreglycemic excursions [44]. The beneficial effect ofimproving glycemic control on painful symptomsis limited to small studies. In a case series of ninepatients with unrelenting acute PDN, Archer et al.reported that improved glucose control with insu-lin improved severity of symptoms [28]. In anothergroup of nine patients with PDN, Boulton et al.used continuous subcutaneous insulin infusion andreported a significant improvement in pain scoresmeasured on a 10-cm horizontal graphic ratingscale [45].

The ideal therapy should be directed at pre-venting or arresting the progressive loss of nervefunction and improving symptoms with minimalside effects. However, once pain develops, currenttreatment options are not specific for the under-lying cause of nerve damage and are aimed oftenonly at partially alleviating the symptoms due tosignificant adverse effects. Furthermore, despitethe increasing evidence base for the rational treat-ment of painful neuropathy, a recent study usingthe general practice research database demon-strated that, of 16,690 patients with diabetic neu-ropathy and postherpetic neuralgia, approximately16.6% were on tricyclic antidepressants, 11.0%were on second-generation antidepressants,12.2% on antiepileptics, and surprisingly 43.1%were taking nonsteroidal anti-inflammatory drugs[46]. Furthermore, the average daily doses wereconsiderably lower than those recommended forneuropathic pain.

Antidepressants

In recent years, drugs originally targeting verydifferent disorders have emerged as valuabletreatments of PDN. Serotonin and norepineph-rine, together with endogenous opioids and

γ

-aminobuturic acid, are neurotransmitters thatform the network of inhibitory neurons, whichmodulate actions of the nociceptive pathways.Centers in the brain and brainstem activate thebody’s natural inhibitory system for pain (descend-ing inhibitory pathways) which synapse in thedorsal horn of the spinal cord. Presynaptic re-uptake inhibition of serotonin and norepinephrineby serotonin–norepinephrine inhibitors (SNRIs)increases the levels of these amines in the synap-tic clefts and can be assumed to enhance pain


665

Figure 1

Neuropathic pain questionnaire—short form.

NEUROPATHIC PAIN QUESTIONNAIRE—Short Form

In order to assess and treat your pain problem, we need to thoroughly understand just exactly what type of pain you have, and how it may or may not change over time. You may have only one site of pain, or you may have more than one.

Please name the site of pain which is most severe or disturbing for you (arm, foot, etc):

For all the following questions, please rate your pain at the site you just listed. Please use the space below to describe your pain in your own words as well:

Please use the items below to rate your pain as it usually feels. Indicate a number that represents your pain on each scale. For example, if you have no tingling pain, you would rate the first item “0.” If you have the worst tingling pain imaginable, you would rate it “100.” If neither of those fits your pain because it is in between, choose a number that fits your pain.

1Sf. Tingling Pain

0 100 gnilgniT tsroW gnilgniT oN elbanigamI niaP niaP

Please rate your usual pain: __________

2Sf. Numbness

0 100 No Numbness Worst Numbness

elbanigamI noitasneS


We are also interested in learning what circumstances cause changes in your pain. Please write the number that indicates the amount you experience each of the following:

3Sf. Increased pain due to touch

0 100 esaercnI tsetaerG esaercnI oN elbanigamI llA tA


Canonical Discriminant Function Coefficients and Structure Coefficients

ItemCanonical Discriminant

Function CoefficientStructure

Coefficient

828. 510. niaP gnilgniT .fS1 918. 710. ssenbmuN .fS2

3Sf. Increased Pain due to Touch .011 .569 203.1– tnatsnoC

TOTAL DISCRIMINANT FUNCTION SCORE: = _______

Check one of the following boxes:

Discriminant Function Score Below 0: ________ Predicts Non-Neuropathic Pain

Discriminant Function Score at or Above 0: ________ Predicts Neuropathic Pain

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Veves et al.

suppression induced by the descending inhibitorypathways. Thus, diffuse noxious inhibitory controlby inhibition of presynaptic reuptake of serotoninand norepinephrine has been suggested as a keymechanism of how antidepressants relieve pain.Current knowledge suggests that both reuptakemechanisms play a role, as tricyclic antidepressantswith balanced reuptake inhibition tend to workbetter than noradrenergic tricyclic antidepressants[47]. In addition, SNRIs are more efficacious thanselective serotonin reuptake inhibitors (SSRIs)[47]. Thus, it can be deduced that the noradren-ergic mechanism appears to be more important.However, the mechanism of action of tricyclic an-tidepressants in neuropathic pain is probably mul-timodal with contribution of monoamine reuptakeinhibition and blockade of NMDA receptors aswell as sodium channels [48]. Unfortunately, moststudies with tricyclic antidepressant have enrolleda small number of patients with still fewer com-pleting the treatment regimens. Antidepressantscommonly prescribed for PDN include ami-triptyline [49–51], imipramine [52,53], and de-sipramine [54,55], yet for amitriptyline, the mostextensively prescribed tricyclic antidepressant,fewer than 150 patients with PDN have been stud-ied in controlled trials [49–51]. Both amitriptylineand imipramine are prescribed at a dosage between25 and 150 mg daily and the usefulness of theseagents has been confirmed in several systematicreviews [56,57]. The major problem remains thefrequency of predictable side effects, which includedrowsiness and lethargy, and the anticholinergicside effects, particularly dry mouth and posturalhypotension. Furthermore, as there were signifi-cant differences in defining patients with PDNand the outcome measures used in each of thesetrials, comparisons cannot be made between stud-ies to determine which drug may have been mostbeneficial. Other small studies have also shownefficacy in patients with PDN using the SSRIsparoxetine [58] and citalopram [59].

The only drug from this class of medication toreceive Food and Drug Administration (FDA)approval [60] for PDN is duloxetine and this isbased on several multicenter, parallel, double-blind, randomized, placebo-controlled trialsdemonstrating efficacy in patients with PDN.Duloxetine is the first relatively balanced seroto-nin and norepinephrine reuptake inhibitor forthree indications—major depressive disorder, dia-betic painful neuropathy, and female stress urinaryincontinence—and has been shown to be safe andwell tolerated with few reported side effects apart

from nausea and somnolence [61]. In 348 type 1and type 2 diabetic patients with painful neuropa-thy, duloxetine 60 mg once and twice daily over12 weeks significantly improved the weekly meanscore of 24-hour average pain evaluated on an 11-point Likert scale compared with placebo [62].Similarly, in 457 patients with PDN assignedto duloxetine 20 mg/day (20 mg QD), 60 mg/day(60 mg QD), 120 mg/day (60 mg BID), or pla-cebo, duloxetine 60 and 120 mg/day demonstratedstatistically significant greater improvement thanplacebo on the 24-hour average pain score within1 week of randomization and continued throughthe 12-week trial with less than 20% discontinuingdue to adverse events [63]. The most recent datais derived from a double-blind study of patientswith PDN but without comorbid depressionassigned to duloxetine 60 mg once and twice daily,or placebo for 12 weeks. Duloxetine 60 mg QDand 60 mg BID demonstrated an improvement inthe 24-hour average pain severity score and allsecondary measures for pain (except allodynia)within 1 week of commencing treatment. This wasassociated with an improvement in both the Clin-ical Global Impression of Severity and Patient’sGlobal Impression of Improvement [64]. All theprevious studies were of short duration, and inorder to assess both longer-term efficacy andsafety, several of these trials were converted toopen-label studies. Thus, in a follow-up open-label study, the long-term safety of duloxetine at afixed dose of 60 mg twice daily (BID) (N

=

161)was compared with 76 patients randomized to rou-tine care, which consisted primarily of treatmentwith gabapentin, amitriptyline, or venlafaxine over52 weeks [65]. There were no significant differ-ences in the 36-item Short-Form Health Surveysubscales or in the EuroQol 5-Dimension Ques-tionnaire between groups, but a higher percentageof routine care-treated patients experienced one ormore serious adverse events. In a 28-week, open-label study, 449 patients with DPN were random-ized (3:1) to receive duloxetine 60 mg twice daily(BID) (N

=

334) or duloxetine 120 mg once daily(QD) (N

=

115) with a comprehensive safety andefficacy evaluation. Patients in both groups dem-onstrated a significant improvement in the BriefPain Inventory and Clinical Global Impression ofSeverity scales with 63.8% and 62.6% of patientscompleting the 60 mg BID and 120 mg QD dos-age, respectively. Heart rate increased slightly inboth groups (

P

<

0.02) and was not associated withsignificant QTc prolongation. While systolicblood pressure was unaffected, diastolic blood


667

pressure decreased slightly in the 120 mg QDgroup (

P

=

0.04) [66].To define potential adverse metabolic effects of

duloxetine, data were pooled from three similarlydesigned clinical trials of 1,024 patients with PDNrandomized to 60 mg duloxetine QD, 60 mg BID,or placebo for 12 weeks and then in 867 patientsre-randomized to 60 mg duloxetine BID or rou-tine care for an additional 52 weeks [67]. Whilstshort-term duloxetine treatment resulted in meanweight loss (

−

1.03 kg;

P

<

0.001 vs placebo), aslight, nonsignificant weight gain was seen in bothduloxetine and routine care groups with longertreatment. Duloxetine treatment increased fastingplasma glucose in both short- (0.50 mmol/L) andlong-term (0.67 mmol/L) studies, with a greaterincrease in HbA1c relative to routine care (0.52%vs 0.19%) in long-term studies. Lipid parameterschanged slightly. Overall, these metabolic changesdid not appear to impact on the improvement inpain severity and nerve conduction. Most recently,to provide data relevant to the practicing clinicianwhen prescribing duloxetine, the impact of base-line characteristics was evaluated using data fromthree pooled placebo-controlled studies, whichshowed no effect of age, type of diabetes, durationof diabetes, duration or severity of diabetic neur-opathy, and baseline HbA1C levels [68]. Of note,duloxetine was most effective in the subgroup withthe most pain. Other SNRIs have less robust evi-dence to support their use but include venlafaxine,which has been shown to be efficacious in patientswith acute insulin neuritis [69] and chronic DPN[70].

Anticonvulsants

Although anticonvulsants have been used in themanagement of neuropathic pain for many years[71], several recent reviews, including a Cochranereview, have found limited evidence for efficacywith this class of drugs in PDN [72,73]. For car-bamazepine, “there was insufficient data for anNNT to be calculated” for its efficacy in PDN[74]. However, in a recent multicentre, placebo-controlled 16-week trial, of 146 patients withDPN randomized to oxcarbazepine (a ketoderiva-tive of carbamazepine) compared with placebo,demonstrated significantly larger decreases and agreater proportion of patients with

>

50% reduc-tion in the VAS score, together with significantimprovements in the global assessment of thera-peutic effect and sleep disturbance [75]. However,in a larger trial, with 347 patients randomized tooxcarbazepine or placebo, no significant change in

mean VAS score was observed from baseline to thelast week of the study, although the overall meanweekly VAS scores did improve significantly [76].Similarly, in 141 patients randomized to oxcarba-zepine or placebo, there was no change in meanVAS score from baseline to the last week of a16-week study [77]. Gabapentin is structurallyrelated to the neurotransmitter gamma-aminobu-tyric acid and was introduced some years ago as ananticonvulsant for complex partial seizures but isnow widely used for painful neuropathy. It actsas a ligand for the auxiliary-associated proteinalpha2delta subunit of voltage-gated calciumchannels, resulting in a reduction in neurotrans-mitter release. The first study to evaluate theefficacy of gabapentin in patients with diabeticpainful neuropathy was a double-blind, placebo-controlled, 8-week trial, which randomized 165patients to gabapentin (titrated from 900 to3600 mg/day or maximum tolerated dosage) orplacebo [78]. Gabapentin significantly improvedthe mean daily pain score and QOL (Short Form-36 Quality of Life Questionnaire and Profile ofMood States) and was associated with significantlymore dizziness (24% vs 4.9%) and somnolence(23% vs 6%). In a recent Cochrane review, sevenstudies of patients with diabetic neuropathytreated with gabapentin were analyzed and dem-onstrated a favorable number needed to treat foreffective pain relief of 2.9 (95% CI 2.2–4.3) [79].Furthermore, in a recent review of all the trials ofgabapentin for neuropathic pain, it was concludedthat dosages of 1,800–3,600 mg/day of this agentwere effective; the side-effect profile also seemssuperior to that of the tricyclic drugs [80]. Pre-gabalin is a higher-potency and higher-effectiveanalog of gabapentin and is the only other agentapart from duloxetine to receive FDA approval forthe treatment of PDN. Evidence of its efficacy isderived from three pivotal clinical trials in diabeticpainful neuropathy [81]. In 146 patients withPDN randomized to receive placebo (N

=

70)or pregabalin 300 mg/day (N

=

76), pregabalinshowed a significant improvement in the meanpain scores, mean sleep interference, mood distur-bance, and tension–anxiety during week 1, whichremained significant throughout the study, but wasassociated with dizziness and somnolence com-pared with placebo [82]. In a larger study, 338patients with PDN were randomized to receivepregabalin 300 or 600 mg or placebo three timesdaily for 5 weeks and improvements were seen inweekly pain score, sleep interference score, patientglobal impression of change, clinical global

668

Veves et al.

impression of change, Short-Form McGill PainQuestionnaire, overall pain, and sleep disturbancewithin 1 week, which were sustained for theduration of the study, but again there was a sig-nificantly higher incidence of dizziness and som-nolence [83]. In the last of these trials, 246 patientswith PDN were randomized to pregabalin 150 or600 mg/day or placebo. The most effective dosewas 600 mg/day, which significantly decreasedmean pain score; increased the proportion ofpatients who had a

>

50% decrease from baselinepain; and significantly reduced sleep interference,past week and present pain intensity, sensory andaffective pain scores, and bodily pain [84].

Lamotrigine, an antiepileptic agent with at leasttwo antinociceptive properties was assessedrecently in two replicate randomized, double-blind, placebo-controlled studies enrolling 360diabetic patients with painful neuropathy receiv-ing lamotrigine 200, 300, or 400 mg daily orplacebo over 19 weeks. Compared with placebo,lamotrigine 200 mg had no effect and the 300 and400 mg dose were inconsistently effective forreduction in pain [85].

Opioid Analgesics

The use of opioids for neuropathic pain remainscontroversial, as studies have generally beensmall, have yielded equivocal results, and havenot established the long-term risk–benefit ratio.A recent Cochrane analysis has demonstratedopioid efficacy for spontaneous neuropathic painin general with a modest but highly significantreduction in the VAS score of 13 points, on ascale from zero to 100, compared with placebo.However, the most common adverse events werenausea (33% vs 9%), constipation (33% vs 10%),drowsiness (29% vs 12%), dizziness (21% vs 6%control), and vomiting (15% vs 3%) [86]. Fur-thermore, in a recent analysis of the efficacyof mu-opioids in reducing spontaneous neuro-pathic pain, a significant attenuation of dynamicmechanical and cold-induced allodynia was dem-onstrated with no effect on static allodynia or thethreshold for mechanical or heat allodynia [87].Thus, it is not surprising that tramadol, amu-opioid agonist, demonstrated efficacy in amulticenter, double-blind, placebo-controlled,parallel-group study in 131 patients with PDNover 42 days. A significant improvementoccurred in pain and physical and social func-tioning, but with no benefit on sleep, eventhough somnolence, nausea, constipation, andheadache were significant side effects [88]. These

benefits were maintained in a 6-month openextension following the 6-week double-blind ran-domized trial [89]. Compared with morphine,oxycodone has a higher oral bioavailability and isabout twice as potent but with a lower incidenceof intolerable typical opiate side effects. In aplacebo-controlled study of 36 patients withDPN, continued release oxycodone was shownto have a significant impact on mean daily pain(both steady pain and brief pain) as well as ontotal pain and disability [90]. Recently, in 36patients with PDN, gabapentin and morphinecombined achieved a greater reduction in thetotal score on the Short-Form McGill PainQuestionnaire at lower doses of each drug thaneither as a single agent, although constipation,sedation, and dry mouth were frequent adverseeffects [91].

Antiarrhythmics

Mexilitine is a class 1B antiarrhythmic agent anda structural analog of lignocaine. Its efficacy hasbeen evaluated in several randomized, placebo-controlled trials in patients with PDN [92–94].The drug decreased mean VAS pain ratings in allstudies that used this measure, although in onlytwo studies was this effect significantly greaterthan the often substantial responses seen with pla-cebo. The dosage used in trials (up to 450 mg/day)is lower than that usually used for the treatmentof cardiac arrhythmias; however, regular ECGmonitoring is necessary and the long-term use ofmexilitine cannot be recommended.

NMDA Receptor Antagonists

These agents include ketamine and dextrometho-rphan and both have demonstrated efficacy pre-dominantly in reducing postoperative pain andanalgesic consumption [95]. In a small study of 13patients with PDN, dextromethorphan demon-strated a reduction in pain by 24% relative toplacebo [96]. In a crossover trial of 19 patientswith DPN, comparing dextromethorphan withmemantine and placebo, no statistically significantresponse for pain reduction was found, althoughin 10 patients who responded to dextromethor-phan, there was a significant dose–response effecton pain intensity [97]. Most recently, a combina-tion of dextrometorphan with quinidne in 36patients with PDN demonstrated a significantimpact on pain intensity rating scale, pain reliefrating scale, and patients’ diary assessments ofsleep and pain intensity [98].


669

Topical and Physical Treatment

Topical Nitrate

Twenty-two diabetic patients were randomized tothe local application to the feet of isosorbide dini-trate spray or placebo and showed a significantreduction in overall pain and burning discomfortover 4 weeks [99]. Similarly, glyceryl trinitratepatches were applied in 18 patients with PDN, andagain 44% reported a reduction in pain [100].

Capsaicin

Several controlled studies combined in a meta-analysis provide some evidence that the topicalapplication of capsaicin has efficacy in diabeticneuropathic pain [101]. However, of major clinicalconcern, topical capsaicin application has beenshown to produce complete or nearly completedenervation of the epidermis in both control sub-jects and people with diabetes and the presence ofneuropathy was associated with a significantreduction in regeneration [102].

Acupuncture

A number of un-masked studies support the use ofacupuncture. In the most recent published report,benefits of acupuncture lasted for up to 6 monthsand were associated with a reduction in the use ofother analgesics [103]. The conduct of potentialblinded studies of acupuncture is problematic and,although a placebo response is possible with acu-puncture, this should not detract from its use,which is generally without side effects.

Other Physical Therapies

Although many other physical therapies have beenproposed, controlled evidence has only been pro-vided for the use of percutaneous nerve stimula-tion [104] and, most recently, static magnetic fieldtherapy [105]. A case series of patients with severepainful neuropathy unresponsive to conventionaltherapy has also demonstrated efficacy when usingan implanted spinal cord stimulator [106]. Surgicaldecompression at the site of anatomic narrowinghas also been vigorously promoted recently as analternative treatment for patients with symptom-atic diabetic neuropathy [107]. However, a system-atic review of the literature has shown only ClassIV studies concerning the utility of this therapeu-tic approach and, accordingly, the Therapeuticsand Technology Assessment Subcommittee of theAmerican Academy of Neurology has reportedthat this treatment is considered unproven (LevelU) until prospective randomized controlled trialswith standard definitions and outcome measuresare undertaken [108].

Dual Action Therapy

The antioxidant alpha-lipoic acid (ALA) is theonly agent that has provided evidence of potentialefficacy for both neuropathic symptoms and mod-ifying the natural history of DPN [109–111].

In the most recent multicenter, randomized,double-blind, placebo-controlled trial, 181 dia-betic patients received once-daily oral doses of600 mg (N

=

45), 1,200 mg (N

=

47), 1,800 mg(N

=

46) ALA or placebo (N

=

43) for 5 weeks.The mean total symptom score (TSS) and propor-tion of patients achieving a

>

50% reduction inTSS, as well as the occurrence of stabbing andburning pain, were significantly lower in those onALA. Although, the neuropathy impairment scoreimproved, this was not significant and the highestdose was associated with an increased incidence ofnausea, vomiting, and vertigo [112].

Increasing data from a number of larger ran-domized trials has led to FDA approval of pre-gabalin and duloxetine and allowed formulation ofconsensus-based assessment and treatment guide-lines for PDN [2,113,114] (Table 1). Finally, drugselection should consider medical and psychiatriccomorbidities, potential adverse effects, and druginteraction in an individual patient, and manypatients may require rational multidrug therapy[115].

Table 1

Pharmacologic options with evidence from ran-domized clinical trials for efficacy in symptomatic treatment of DPNP(modified from Argoff et al. [113] with permission)

• First-tier agents (positive results from two or more randomized clinical trials)

�

duloxetine (SNRI)

�

pregabalin (alpha2delta calcium channel modulator)

�

oxycodone CR (opioid)

�

TCAs (antidepressants)Of these, duloxetine and pregabalin have FDA approval for

treatment of DPNP.• Second-tier agents (evidence of efficacy from a single trial in

patients with DPN and evidence from studies of other painful neuropathies)

�

gabapentin (alpha2delta calcium channel modulator)

�

venlafaxine (SNRI)

�

tramadol (opioid)Carbamazepine and lamotrigine may also be considered.

• Topical therapies (based on mechanism of action, may be appropriate early in treatment and for specific individuals)

�

capsaicin

�

lidocaine 5% patchSome patients may require therapy with multiple agents.

Multidrug decisions should be based on mechanism of action and adverse event profiles.

SNRI

=

serotonin–norepinephrine inhibitor; TCAs

=

tricyclic antidepressants;FDA

=

Food and Drug Administration; DPNP

=

diabetic peripheral neuropathicpain; DPN

=

diabetic peripheral neuropathy.

670

Veves et al.

Conclusions

Painful diabetic neuropathy is a common, diffi-cult-to-manage complication of diabetes. Signsand symptoms consistent with PDN have beenidentified in patients with IGT and new-onset dia-betes, indicating that early detection and interven-tion are important. Both peripheral and centralmechanisms have been proposed to play a role inthe genesis of the painful symptoms. Despite theevaluation of many pharmacologic and nonphar-macologic therapies, there are presently only twoFDA-approved treatments of PDN.

Acknowledgments

We wish to thank the staff of IMPRINT Publication Sci-ence, New York for their editorial support in the initialpreparation and styling of this article.

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Painful Diabetic Neuropathy: Epidemiology, Natural History, Early Diagnosis, and Treatment Options