Mechanisms and Management of Diabetic Painful …...radiculopathies, and entrapment neuropa-thies...

Mechanisms and Managementof Diabetic Painful Distal SymmetricalPolyneuropathySOLOMON TESFAYE, MD

1

ANDREW J.M. BOULTON, MD2

ANTHONY H. DICKENSON, PHD3

Although a number of the diabetic neuropathies may result in painful symptomatology, thisreview focuses on the most common: chronic sensorimotor distal symmetrical polyneuropathy(DSPN). It is estimated that 15–20% of diabetic patients may have painful DSPN, but not all ofthese will require therapy. In practice, the diagnosis of DSPN is a clinical one, whereas forlongitudinal studies and clinical trials, quantitative sensory testing and electrophysiological as-sessment are usually necessary. A number of simple numeric rating scales are available to assessthe frequency and severity of neuropathic pain. Although the exact pathophysiological processesthat result in diabetic neuropathic pain remain enigmatic, both peripheral and central mecha-nisms have been implicated, and extend from altered channel function in peripheral nervethrough enhanced spinal processing and changes in many higher centers. A number of pharma-cological agents have proven efficacy in painful DSPN, but all are prone to side effects, and noneimpact the underlying pathophysiological abnormalities because they are only symptomatictherapy. The two first-line therapies approved by regulatory authorities for painful neuropathyare duloxetine and pregabalin. a-Lipoic acid, an antioxidant and pathogenic therapy, has evi-dence of efficacy but is not licensed in the U.S. and several European countries. All patients withDSPN are at increased risk of foot ulceration and require foot care, education, and if possible,regular podiatry assessment.

Diabetes Care 36:2456–2465, 2013

The neuropathies are the most com-mon long-term microvascular com-plications of diabetes and affect those

with both type 1 and type 2 diabetes, withup to 50% of older type 2 diabetic patientshaving evidence of a distal neuropathy (1).These neuropathies are characterized by aprogressive loss of nerve fibers affectingboth the autonomic and somatic divisionsof the nervous system. The clinical featuresof the diabetic neuropathies vary im-mensely, and only aminority are associatedwith pain. The major portion of this reviewwill be dedicated to the most commonpainful neuropathy, chronic sensorimotordistal symmetrical polyneuropathy (DSPN).This neuropathy has major detrimental ef-fects on its sufferers, confirming an in-creased risk of foot ulceration and Charcotneuroarthropathy as well as being associ-ated with increased mortality (1).

In addition to DSPN, other rarerneuropathies may also be associatedwith painful symptoms including acutepainful neuropathy that often follows peri-ods of unstable glycemic control, mono-neuropathies (e.g., cranial nerve palsies),radiculopathies, and entrapment neuropa-thies (e.g., carpal tunnel syndrome). By farthe most common presentation of diabeticpolyneuropathy (over 90%) is typicalDSPN or chronic DSPN.

TheTorontoDiabeticNeuropathyEx-pert Group recently defined DSPN as “asymmetrical, length-dependent sensori-motor polyneuropathy attributable tometabolic and microvessel alterationsas a result of chronic hyperglycemia expo-sure and cardiovascular risk covariates” (2).An abnormality of nerve conduction (NC)tests, which is frequently subclinical, ap-pears to be the first objective quantitative

indication of the condition. The occurrenceof diabetic retinopathy and nephropathyin a given patient strengthen the case thatthe polyneuropathy is attributable to diabe-tes. DSPN results in insensitivity of the feetthat predisposes to foot ulceration (1) and/or neuropathic pain (painful DSPN), whichcan be disabling.

Clinical features of painfulDSPNdThe onset of DSPN is usuallygradual or insidious and is heralded bysensory symptoms that start in the toesand then progress proximally to involvethe feet and legs in a stocking distribution.When the disease is well established in thelower limbs in more severe cases, there isupper limb involvement, with a similarprogression proximally starting in thefingers. As the disease advances further,motor manifestations, such as wasting ofthe small muscles of the hands and limbweakness, become apparent. In somecases, there may be sensory loss that thepatient may not be aware of, and the firstpresentation may be a foot ulcer. Approx-imately 50% of patients with DSPN ex-perience neuropathic symptoms in thelower limbs including uncomfortable tin-gling (dysesthesia), pain (burning; shoot-ing or “electric-shock like”; lancinating or“knife-like”; “crawling”, or aching etc., incharacter), evoked pain (allodynia, hy-peresthesia), or unusual sensations (suchas a feeling of swelling of the feet or severecoldness of the legs when clearly thelower limbs look and feel fine, odd sen-sations on walking likened to “walkingon pebbles” or “walking on hot sand,”etc.). There may be marked pain onwalking that may limit exercise andlead to weight gain. Painful DSPN ischaracteristically more severe at nightand often interferes with normal sleep(3). It also has a major impact on theability to function normally (both men-tal and physical functioning, e.g., abilityto maintain work, mood, and quality oflife [QoL]) (3,4).

In one study from the U.S., theburden of painful DSPN was found tobe considerable, resulting in a persistentdiscomfort despite polypharmacy and

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From the 1Diabetes Research Unit, Sheffield Teaching Hospitals, Royal Hallamshire Hospital, Sheffield, U.K.;the 2Institute for Endocrinology and Diabetes, University of Manchester, Manchester, U.K.; and 3Neuro-science, Physiology and Pharmacology, University College London, London, U.K.

Corresponding author: Andrew J.M. Boulton, [email protected]: 10.2337/dc12-1964© 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly

cited, the use is educational and not for profit, and thework is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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high resource use and led to limitationsin daily activities and poor satisfactionwith treatments (4). The unremitting na-ture of the pain can be distressing, resultingin mood disorders including depressionand anxiety (4). The natural history of pain-ful DSPN has not been well studied, andthere is a need for large, population-based,prospective studies looking at the naturalhistory and potentially modifiable riskfactors, if any. However, it is generallybelieved that painful symptoms may per-sist over the years (5), occasionally be-coming less prominent as the sensoryloss worsens (6).

EpidemiologydThere have beenrelatively few epidemiological studiesthat have specifically examined the prev-alence of painful DSPN, which range from10–26% (7–9). In a recent study of alarge cohort of diabetic patients receivingcommunity-based health care in northwestEngland (n 5 15,692), painful DSPN as-sessed using neuropathy symptom and dis-ability scores was found in 21% (7). In onepopulation-based study from Liverpool,U.K., the prevalence of painful DSPN as-sessed by a structured questionnaire andexamination was estimated at 16% (8).Notably, it was found that 12.5% of thesepatients had never reported their symp-toms to their doctor and 39% had neverreceived treatment for their pain (8), in-dicating that there may be considerableunderdiagnosis and undertreatment ofpainful neuropathic symptoms comparedwith other aspects of diabetes managementsuch as statin therapy and management ofhypertension.

Risk factors for DSPN per se havebeen extensively studied, and it is clearthat apart from poor glycemic control,cardiovascular risk factors play a prom-inent role (10): risk factors for painfulDSPN are less well known. Preliminaryepidemiological studies suggest clinicalcorrelates for painful DSPN comparedwith painless DSPN to include weight(11), obesity (12), waist circumference(13), peripheral arterial disease (11,13),and triglycerides (12). However, one lim-itation of these studies was that assess-ment of both DSPN and painful DSPNwas carried out using screening methods(Michigan Neuropathy Screening Instru-ment) questionnaire (11,13) or the DouleurNeuropatique en 4 questions (12) for neu-ropathic pain, and the neurological ex-amination of Michigan NeuropathyScreening Instrument (11,13) or Neuro-pen (12) for assessment of DSPN.

Diagnosing and assessingthe severity of DSPNand painful DSPNdA broad spec-trum of presentations may occur in pa-tients with DSPN, ranging from oneextreme of the patient with very severepainful symptoms but few signs, to theother when patients may present with afoot ulcer having lost all sensation with-out ever having any painful or uncomfort-able symptoms; when pressed, suchpatients may admit to the feet feelingsomewhat “numb” or “dead.” Thus, it iswell recognized that the severity of symp-toms may not relate to the severity of thedeficit on clinical examination (1).

Diagnosing and assessing severityof DSPNThe American Diabetes Association Con-sensus Statement (14) recommended thatthe diagnosis of painful DSPN in clinicalpractice be a clinical one, relying on thepatient’s description of pain and typicalfeatures of peripheral neuropathy mani-festing in reduction of sensory modalitiesand absence/reduction of ankle/knee re-flexes. Because DSPN is a diagnosis ofexclusion, a careful clinical history and aperipheral neurological and vascular ex-amination of the lower limbs are essentialto exclude other causes of neuropathicpain and leg/foot pain such as peripheralvascular disease, arthritis, malignancy, al-cohol abuse, spinal canal stenosis, etc. NCstudies are rarely helpful in clinical prac-tice but might help in excluding othercauses of pain such as entrapment syn-dromes. Patients with asymmetricalsymptoms and/or signs (such as loss ofan ankle jerk in one leg only), rapid pro-gression of symptoms, or predominanceof motor symptoms and signs should becarefully assessed for other causes of thefindings.

For longitudinal studies and clinicaltrials in which a more accurate quantifi-cation of neuropathy is required, theToronto Diabetic Neuropathy ConsensusPanel suggested a reliable objective andquantitative measure; that is, NC abnor-mality as the minimal criteria for thediagnosis of DSPN (2). When NC valueshave not been assessed, the ConsensusPanel recommended that it is not possibleto provide a “confirmed” diagnosis ofDSPNdonly a “possible” or “probable”diagnosis.

However, subjects with pure small-fiber neuropathy may be diagnosed byquantitative sensory testing (QST) to as-sess the psychophysical thresholds for

cold and warm sensations, heat and coldpain, and pain to pin prick; or by cuta-neous vasomotor function to measureskin blood flow as a marker of c-fiberneurovascular dysfunction (15). How-ever, the gold standard for assessing smallfiber function remains quantification ofintraepidermal nerve fibers from punchskin biopsy immunostained by PGP9.5(16). Indeed, QST has also been routinelyused in some clinics to diagnose generalneuropathy (e.g., the 10-g monofilamentis widely used in diabetic clinics to screenfor DSPN), and recently, the German PainNetwork has developedQST to character-ize the somatosensory phenotype of pa-tients with neuropathic pain (17), thoughthe Toronto Consensus Panel recognizedits limitation of essentially being subjec-tive and the potential for bias by percep-tual/cognitive factors. Recent advances insmall fiber neuropathy assessment in-clude brain-evoked potentials with elec-trical and laser stimulation (laser-evokedpotentials) (18), and contact heat–evokedpotentialda measure of cerebral responsesof A-delta fiber–mediated thermonocicep-tive stimuli (19).

There are several instruments thatevaluate combinations of neuropathysymptoms, signs, and neurophysiologicaltest abnormalities giving scores for sever-ity of DSPN (20–24). However, clinicalexamination is not always reproducible,and recent studies emphasize the impor-tance of the proficiency of the clinical neu-rological assessment (24). For controlledclinical trials of DSPN, the Toronto Con-sensus Panel advocated the use of an NCtest as an early and reliable indicator of theoccurrence of this neuropathy (2). Thegroup also emphasized that to be reliablethe test must be carried out rigorously,using appropriate reference values cor-rected for applicable variables (2).

Assessing neuropathic pain severityThe frequency and severity of painfulsymptoms can be assessed by a numberof simple numeric rating scales (25). Theuse of simple scales such as the visual an-alog scale or the numerical rating scale,such as an 11-point Likert scale (0 5 nopain to 10 5 worst pain imaginable) isrecommended. These scales can then beused to monitor response to treatment inclinical practice or research context.Other validated scales and questionnairesinclude 1) the modified Brief Pain Inven-tory Short Form (BPI-MSF) (26) recentlyused as the primary end point in pharma-cological treatment trials of painful

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Tesfaye, Boulton, and Dickenson

DSPN; 2) the neuropathic pain symptominventory (27), which evaluates the differ-ent symptoms and dimensions of neuro-pathic pain; 3) the neuropathic painquestionnaire (28), which consists of 12items, including 10 related to sensationsand or sensory responses and 2 related toaffect; 4) the LANNS pain scale (29),which contains five symptom and two clin-ical examination items and is easy to scorewithin clinical settings; 5) painDETECT, ascreening tool that incorporates an easy touse, patient based (self-report) question-naire with nine items that do not require aclinical exam (30); and 6) the McGill PainQuestionnaire, whichmeasures the sensoryand affective components of pain, oftenused in its shortened format (31).

QoL might be assessed by generic in-struments thatmay allow cross comparisonwith other chronic medical conditions.However, it is also important to use vali-dated, neuropathy-specific measures ofQoL, such as the NeuroQol (32), that re-liably capture the key dimensions of pa-tients’ experience of DSPN and is a validtool for studying the impact of neuropathyand foot ulceration on QoL. Anotherneuropathy-specific measure of QoL isthe Norfolk Quality of Life Scale (33),which is a validated patient-reported out-comemeasure, sensitive to the different fea-tures of diabetic neuropathy includingsmall-fiber, large-fiber, and autonomicfunction. There are a number of scalesthat might assess pain behavior and sleepinterference and the prediction of re-sponse to therapy (34). Finally, the impactof painful symptoms on mood can be as-sessed using the Hospital Anxiety andDepression Scale (35) and Beck’s Depres-sion Inventory (36).

Mechanism of neuropathicpain in diabetesdWe will nowconsider the changes at central and pe-ripheral levels induced by DSPN thatrelate to the sensory changes experiencedby patients and the mechanisms thattreatments are thought to modulate.

The exact pathophysiological mecha-nisms of neuropathic pain in diabetesremain elusive although several mecha-nisms have been postulated (Table 1)(37). Other potential mechanisms in-clude the association of increased bloodglucose instability in the genesis of neu-ropathic pain (38), an increase in periph-eral nerve epineurial blood flow (39),altered foot skin microcirculation (40),reduced intraepidermal nerve fiber den-sity in the context of early neuropathy

(41), increased thalamic vascularity (42),and autonomic dysfunction (43).

The fact that diabetes induces neu-ropathy and that in a proportion ofpatients this is accompanied by pain de-spite the loss of input and numbness,suggests that marked changes occur in theprocesses of pain signaling in the periph-eral and central nervous system. Neuro-pathic pain is characterized by ongoingpain together with exaggerated responsesto painful and nonpainful stimuli, hyper-algesia, and allodynia. These combina-tions of loss and gain of function havebeen recently characterized by sensorytesting by Maier et al. (44), and five sub-groups of patients emerge with many ofthe signs and symptoms overlapping withthose seen in patients with postherpeticneuralgia. This suggests common mecha-nisms but importantly, the subgroupsmay turn out to have different responsesto pharmacological agents and so lead to aprediction of analgesic response. Never-theless, the changes seen suggest alteredperipheral signaling and central compen-satory changes perhaps driven by the lossof input. Indeed, the descriptors used,such as electric shock, burning, and lan-cinating indicate that diabetes induceschanges in the way peripheral signals areprocessed.

Capsaicin in chili peppers evokesburning pain due to activation of transientreceptor potential channel (TRP) V1, areceptor situated on small peripheralfibers and part of the family of 27 TRPchannels cloned in humans (45), some of

which are thought to transduce thermalsignals (46) and include TRPM8 andTRPA1, important in cold hypersensitiv-ity (47). Local application of capsaicin canbe analgesic in localized painful neurop-athies, and polymorphisms in TRPV1 canexplain some of the variation in pain seenafter neuropathy in patients (48).

There are many other less understoodor characterized peripheral sensors, in-cluding the P23 receptors for ATP, re-leased from all damaged cells suggestingfurther potential targets for therapies(49). Very clear evidence points to thekey role of changes in ion channels as aconsequence of nerve damage and theirroles in the disordered activity and trans-duction in damaged and intact fibers (50).

Sodium channels depolarize neuronsand generate an action potential. Follow-ing damage to peripheral nerves, thenormal distribution of these channelsalong a nerve is disrupted by the neuromaand “ectopic” activity results from the ac-cumulation of sodium channels at oraround the site of injury. Other changesin the distribution and levels of thesechannels are seen and impact upon thepattern of neuronal excitability in thenerve. Inherited pain disorders arisefrom mutated sodium channels, notablygain and loss of functions of the sodiumchannel Nav 1.7 (51,52), and polymor-phisms in this channel impact on the levelof pain in patients, indicating that inheriteddifferences in channel function mightexplain some of the variability in pain be-tween patients with DSPN (53). Followingperipheral nerve damage, levels of anothersodium channel, Nav 1.3, in dorsal rootganglia increase and are thought to sup-port ectopic neuronal firing. Blockers ofthese pain-related channels and also thevery important Nav1.8 have been pro-duced but have yet to reach the clinic.Thus, treatments revolve around nonse-lective sodium channel blockers includinglocal anesthetics such as lidocaine and theanticonvulsant carbamazepine in trigemi-nal neuralgia (54).

A recent study (55) proposes a mech-anism for the observed neuropathicchanges that follow diabetes. The levelsof the glycolytic metabolite methyl-glyoxal distinguished between diabeticpatients with pain and those withoutpain. Methylglyoxal activated peripheralnerves and altered the function of Nav 1.8,and Nav 1.7. In animals, the metabolite wasfound to slow NC, increase release of calci-tonin gene-related peptide from nerves, andcause thermal and mechanical hyperalgesia.

Table 1dMechanisms of neuropathic pain

Peripheral mechanismsChanges in sodium channel distributionand expression

Changes in calcium channel distributionand expression

Altered neuro-peptide expressionSympathetic sproutingLoss of spinal inhibitory controlAltered peripheral blood flowAxonal atrophy, degeneration, orregeneration

Damage to small fibersIncreased glycemic flux

Central mechanismsCentral sensitizationChanges in the balance of facilitation/inhibition within descending pathways

Increased thalamic vascularity

Adapted with permission from Tesfaye andKempler (37).


Diabetic painful DSPN

This hyperalgesia was reflected by func-tional changes in pain-related areas ofthe brain (55).

Where sodium channels act to gener-ate action potentials, potassium channelsserve as the molecular brakes of excitablecells, playing an important role in mod-ulating neuronal hyperexcitability. Thedrug retigabine, a potassiumchannel openeracting on the channel (KV7, M-current)opener, blunts behavioral hypersensitivityin neuropathic rats (56) and also inhibits Cand Ad-mediated responses in dorsal hornneurons in both naïve and neuropathic rats(57), but has yet to reach the clinic as ananalgesic although it has recently been ap-proved by the FDA as an add-on treatmentof partial seizures (58).

There are likely many other changesin potassium channels after neuropathy,and their importance is underscored bythe fact that opioids act to open thesechannels and suppress activity in painpathways by actions at both spinal andbrain sites.

The third channel set in neuronalevents is made up of voltage-gated Cachannels, which serve to release transmitter.

In the case of afferent sensory fibers, theseare glutamate and peptides such as sub-stance P. Following nerve injury, a2d sub-units of these channels are slowlyupregulated in the central terminals of pe-ripheral nerves, so favoring increased re-lease of these transmitters into the spinalcord (59). This will therefore compensatefor the loss of afferent fibers produced bythe neuropathy. Gabapentin and pregabalintarget the a2d subunit and by preventing itstrafficking into the membrane reduce theabnormal transmitter release (59).

A further permissive factor in theactions of these drugs is activity in spinal5-hydroxytryptamine 3 receptors, them-selves driven by activity in descendingpathways from the brain; this rapidlyswitching circuit may not only explainthe actions of a2d ligands after nerve in-jury but also their acute effects such asthose seen after surgery (60).

Central excitatory mechanismsAd and C fibers terminate primarily in thesuperficial laminae of the dorsal hornwhere the large majority of neurons arenociceptive specific (Fig. 1). Some of

these neurons gain low threshold inputsafter neuropathy and these cells projectpredominantly to limbic brain areas suchas the periaqueductal gray, lateral parabra-chial nucleus, thalamus, nucleus tractussolitarius, and the medullary reticular for-mation. Within deeper lamina V, neuronsare wide-dynamic range, responding toboth innocuous and noxious stimuli, andso candidates for abnormal coding of low-threshold inputs and hence allodynia, ex-hibiting wind-up and projecting to sensoryareas of the brain such as the thalamus andthence the cortex, where the sensory com-ponent of pain is represented (Fig. 2).Thus, spinal cord neurons provide paral-lel outputs to the affective and sensoryareas of the brain. Changes induced inthese neurons by repeated noxious in-puts underpin central sensitization wherethe resultant hyperexcitability of neuronsleads to greater responses to all subse-quent inputsdinnocuous and noxiousdexpanded receptive fields and enhancedoutputs to higher levels of the brain (Fig.2). These changes may then alter descend-ing controls (Fig. 2). The spinal mecha-nisms involve the actions of glutamate

Figure 1dA representation of the central spinal and peripheral changes that accompany neuropathy. The existence of a lesion or diseaseof a peripheral sensory nerve alters the conduction and transmission of sensory messages. The normal transfer of modalities (top right) ontospinal nociceptive specific (NS) and wide-dynamic range (WDR) neurons is changed by ectopic activity, sensory loss, and changes in ionchannels. Spinal cord neurons are subject to many receptor-mediated events, but increases in Ca channel function lead to increased transmitterrelease so that glutamate causes an enhanced activation of AMPA and NMDA receptors. Substance P acts on neurokinin 1 (NK1) receptors toadd to the excitation. Reduced spinal inhibition through g-aminobutyric acid (GABA) and the transporter potassium-chloride transportermember 5 (KCC2) aids enhanced pain messages. Reduced noradrenaline (NA) descending inhibition via a-2 adrenoceptors and increased5-hydroxytryptamine (5HT) descending excitation via 5HT3 receptors add to the dominance of excitatory transmission. m-Opioid receptors(MOR) are found on this circuitry.



and its coreleased transmitter substanceP permitting N-methyl-D-aspartate (NMDA)receptor activation, resulting in the wind-up of dorsal horn neurons. The analgesiceffects of ketamine result from its abilityto modulate this activity through blocksof the NMDA receptor (Fig. 1). However,similarmechanistic events underliememory,

cognitive, and related functions and so theside effects of ketamine result from a lackof selectivity for spinal-pain relatedNMDA functions (61).

As a consequence of these changes inthe sending of nociceptive informationwithin the peripheral nerve and then thespinal cord, the information sent to the

brain becomes amplified so that painratings become higher. Alongside this,the persistent input into the limbic brainareas such as the amygdala are likely to becausal in the comorbidities that patientsoften report due to ongoing painful inputsdisrupting normal function and generat-ing fear, depression, and sleep problems

Figure 2dAn overview of the ascending (left) and descending (right) pain pathways. From the spinal cord there are spinoreticular projections anddorsal column pathways to the cuneate nucleus (CN) and nucleus gracilis (NG). Other limbic projections relay in the parabrachial nucleus (PB) andthen project to the hypothalamus (Hyp) and amygdala (Am), where central autonomic function and fear/anxiety are processed. Spinothalamicpathways run to the ventrobasal medial (VPM) and lateral (VPL) areas and then run to the somatosensory part of the cerebral cortex (CC) where thelocation and the sensory components of pain are generated. Limbic brain areas (Am and Hyp) project down to the periqueductal gray (PAG) and tothe locus coereleus (LC), A5 and A7 nuclei, and the rostroventral medial medulla (RVM). Thence, descending noradrenaline (NA) inhibition viaa-2adrenoceptors and increased 5-hydroxytryptamine (5HT) descending excitation via 5HT3 receptors modulates spinal cord activity. The changesinduced by peripheral neuropathy on these brain functions are depicted together with comorbidities, and genotypic and phenotypic factors areshown.



(Fig. 2). Of course, many patients reportthat their pains are worse at night, whichmay be due to nocturnal changes in thesecentral pain processing areas. Finally, theneuropathic pain alters function and ac-tivity in the descending controls, whichrelay information from higher brain cen-ters via the midbrain and brainstem to thespinal cord. In healthy volunteers andpatients, a loss of inhibition or gain offacilitation promotes pain whereas evok-ing inhibition reduces pain (60). Preclin-ical studies suggest that the bases for thisare descending noradrenergic, mostly in-hibitory, and certain serotonergic con-trols that facilitate pain (Figs. 1 and 2).These monoamine descending controlsregulate spinal neuronal activity bidi-rectionally and underlie the efficacy ofantidepressants for the treatment ofpain (60).

The increased analgesic effect of ta-pentadol, recently shown to be effective inanimals and patients with diabetic neu-ropathy, likely resides in synergistic in-teractions between its weak opioidactions at spinal and supraspinal sitescoupling to enhancing noradrenergiccontrols and so reducing opioid load(62). Interestingly, changes in the balanceof control from the braindthe gain indescending facilitation coupled with aloss of inhibitiondoccur in the laterstages after peripheral injury suggestiveof a role in maintaining but not initiatingthe pain state. Furthermore, animal stud-ies suggest that the recruitment of de-scending inhibitions may be protectiveand so can override the pain initiated bythe neuropathic damage to the peripheralnerve (63).

So, overall, the mechanisms of pain indiabetic neuropathy extend from alteredchannel function in peripheral nervesthrough enhanced spinal processing andfinally to changes in many higher centers(Fig. 2).

Management of painfulDSPNdThe assessment and treatmentof painful DSPN should ideally involve amultidisciplinary team that may includea diabetologist, a neurologist, the painclinic team, specialist nurses, podiatrists,psychologists, physiotherapists, occupa-tional therapists, and others. However, inmost clinical settings this is not possible,and the management falls mainly to thediabetes physician, the primary care phy-sician, or the neurologist. When treat-ment is started, a realistic objective wouldbe to achieve around 50% reduction in

pain intensity. However, being “realistic”shouldn’t be interpreted as less aggressivepursuit of maximum pain relief. Second-ary objectives should include restorationor improvement in functional measures,QoL, sleep, and mood. Although it is ho-ped that improvement in pain will be fol-lowed by improvement in functionality,this may not be the case as many of thesepatients may have other comorbidities.Moreover, the multidisciplinary teamshould discuss potential interventions inaddition to pharmacotherapy to help pa-tients optimize function in the presence ofresidual pain.

Although strong evidence implicatespoor glycemic control as a pathogeneticmechanism in the etiology of DSPN, thereis no proof from randomized, controlledtrials that this is the case for neuropathicpain in diabetes. However, as increasedblood glucose flux has been reported tocontribute to pain in DSPN (38), there is ageneral consensus that good blood glu-cose control should be the first step inthe management of any form of diabeticneuropathy. Additionally, as cardiovas-cular disease is common in patientswith DSPN (10) and vascular risk factors(hypertriglyceridemia, hypertension, vis-ceral obesity etc.) appear to be implicatedin the pathogenesis of DSPN (10,64),there is a good rationale for managementof vascular risk factors beyond glycemiccontrol.

Pharmacological treatmentSeveral pharmacological treatments haveproven efficacy in the management ofpainful DSPN, although only duloxetineand pregabalin are approved for the treat-ment of neuropathic pain in diabetes byboth the Food and Drugs Administrationof the U.S. and the European MedicinesAgency.

Pharmacological treatment of pain-ful DSPN is not entirely satisfactory be-cause currently available drugs are oftenineffective and complicated by adverseevents. Tricyclic compounds (TCAs)have been used as first-line agents formany years, but their use is limited byfrequent side effects that may be centralor anticholinergic, including dry mouth,constipation, sweating, blurred vision,sedation, and orthostatic hypotension(with the risk of falls particularly inelderly patients). For this reason, low-dose amitriptyline or imipramine 10 mgtaken at night may be started. Depend-ing upon efficacy and side effects, thedose can gradually be increased to

75 mg/day and on occasions even up to150 mg/day (1). Higher doses have beenassociated with an increased risk of sud-den cardiac death, and caution shouldbe taken in any patient with a historyof cardiovascular disease (65).

The selective serotonin noradrenalinreuptake inhibitors (SNRI) duloxetineand venlafaxine have been used for themanagement of painful DSPN (65).SNRIs relieve pain by increasing synap-tic availability of 5-hydroxytryptamineand noradrenalin in the descendingpathways that inhibit pain impulses.The efficacy of duloxetine in painfulDSPN has been investigated in threeidentical trials, and pooled data fromthese shows that the 60 mg/day and120 mg/day doses are effective in reliev-ing painful symptoms, starting within 1week and lasting the full treatment pe-riod of 12 weeks (66). The main sideeffects include nausea, somnolence, diz-ziness, constipation, dry mouth, and re-duced appetite, although these tend tobe mild to moderate and are transient.It is advisable to start at 30 mg/day takenwith food for the first week and thenincrease to the standard dose of 60mg/day. Venlafaxine (150–225 mg/day)is also effective in relieving painfulDSPN, although cardiovascular adverseevents limit its use in diabetes (67).

The anticonvulsant gabapentin, whichbinds to the a2d subunit of the calciumchannel thereby reducing neurotransmitterrelease in the hyperexcited neuron, gradu-ally titrated from 100 mg t.i.d. to 3,600mg/day is also effective (68). More recently,there have been several clinical trials in-volving pregabalin in painful DSPN, andthese showed clear efficacy in managementof painful DSPN (69). Unlike gabapentin,pregabalin has linear pharmacokinetics,doesn’t require a long titration period, andis started at 75 mg b.i.d. for about a weekand increased to 150mg b.i.d.maintenancedose with a maximum dose of 600 mg/day(55). The side effects include dizziness,somnolence, peripheral edema, headache,and weight gain.

Other effective but generally consid-ered second line drugs (65) for painfulDSPN include other anticonvulsants,inparticular carbamazepine (65), althoughit has troublesome side effects includingdizziness, somnolence and gait distur-bance; tramadol, a weak opioid andweak inhibitor of noradrenaline and sero-tonin reuptake (65); the strong opioid oxy-codone controlled release (65); and topicaltreatments including the substance-P



depleter, topical capsaicin and the lido-caine patch (65). Refractory cases of pa-tients with painful DSPN may be treatedwith intravenous lignocaine (5 mg/kgover 30 min) (65). Of the pathogeneti-cally oriented treatments for painfulDSPN only the antioxidant, a-lipoic acidadministered intravenously over 3 weeks(600 mg i.v. per day) has been proven tobe efficacious (2,70).

Recent guidelines forpharmacological treatmentThe European Federation of Neurologi-cal Societies proposed that first-line treat-ments might comprise of TCAs, SNRIs,gabapentin, or pregabalin (71). The U.K.National Institute for Health and CareExcellence guidelines on the manage-ment of neuropathic pain in nonspecialistsettings proposed that duloxetine shouldbe the first-line treatment with amitripty-line as an alternative, and pregabalin as asecond-line treatment for painful DSPN(72). However, this recommendation ofduloxetine as the first-line therapy wasnot based on efficacy but rather cost-effectiveness. More recently, the AmericanAcademy of Neurology recommendedthat pregabalin is “established as effectiveand should be offered for relief of [painfulDSPN] (Level A evidence)” (73), whereasvenlafaxine, duloxetine, amitriptyline, ga-bapentin, valproate, opioids, and capsai-cin were considered to be “probablyeffective and should be considered fortreatment of painful DSPN (Level B evi-dence)” (63). However, this recommenda-tion was primarily based on achievementof greater than 80% completion rate ofclinical trials, which in turn may be influ-enced by the length of the trials. Finally,the International Consensus Panel on Di-abetic Neuropathy recommended TCAs,duloxetine, pregabalin, and gabapentinas first-line agents having carefully re-viewed all the available literature regard-ing the pharmacological treatment ofpainful DSPN (65), the final drug choicetailored to the particular patient based ondemographic profile and comorbidities.

Tailoring treatment to individualrequirementsThe initial selection of a particular first-line treatment will be influenced by theassessment of contraindications, evalua-tion of comorbidities (including sleepdisturbance, mood disorders, and otherchronic medical/diabetes complications),and cost (65). For example, in diabeticpatients with a history of heart disease,

elderly patients on other concomitantmedications such diuretics and antihy-pertensives, and patients with comorbidorthostatic hypotension TCAs have rela-tive contraindications. In patients withliver disease, duloxetine should not beprescribed, and in those with peripheraledema, pregabalin or gabapentin shouldbe avoided. Moreover, although pharma-ceutical companies may recommend aparticular starting dose for their drugsbased on their clinical trials, one has toappreciate that the clinical practice sce-nario is different from clinical trial sce-nario because many elderly patientswith multiple comorbidities would havebeen excluded from trials. Therefore,treatment has to be individualized totake patient comorbidities including oc-cupation, renal impairment, etc. into ac-count, and caution is advised to start atlower than recommended doses and ti-trate gradually.

Comparator and combination trialsA major deficiency in the area of thetreatment of neuropathic pain in diabetesis the relative lack of comparative orcombination studies. Virtually all previoustrials have been of active agents againstplacebo, whereas there is a need for morestudies that compare a given drug with anactive comparator and indeed lower-dosecombination treatments (64). These issueshave been highlighted by recent consen-sus guidelines from international institu-tions that have emphasized the need forlarge comparative and combination treat-ment trials in painful DSPN as a matter ofpriority (74,75).Comparator trials. Bansal et al. (76)compared amitriptyline with pregabalinin painful DSPN in a small, randomized,double-blind, crossover trial. This studyconfirmed that whereas there was littledifference in efficacy, pregabalin was thepreferred drug because of a superior ad-verse event profile. However, a majordrawback of this study was its smallsize, involving 51 patients only withmany patients failing to complete thestudy.

Another recent small crossoverstudy from the same group as the abovestudy has compared duloxetine withamitriptyline (77). The study foundthat both drugs were equally efficaciousalthough of the reported adverse events,dry mouth was more common with am-itriptyline than duloxetine (55 vs. 24%;P , 0.01). Numerically, more patientspreferred duloxetine although this was

not statistically significant (48 vs. 36%;P 5 0.18).

The lack of direct comparator studiesled to an indirect comparison of theefficacy and tolerability of duloxetinewith that of pregabalin and gabapentinin participants with painful DSPN, usingplacebo as a common comparator (78).Efficacy criteria were reduction in 24-hpain severity for all three treatments, andtreatment response rate ($50% pain re-duction), and overall health improve-ment (as measured on the PatientGlobal Impression of Improvement/Change questionnaire) for duloxetineand pregabalin only. Indirect compari-son between duloxetine and gabapentinfound no statistically significant differ-ences. Comparing duloxetine with pre-gabalin, the authors found significantdifferences in overall health improve-ment, favoring pregabalin, and in dizzi-ness, favoring duloxetine. There wasno significant difference in 24-h pain se-verity between duloxetine and pregaba-lin (78).Combination trials. Gilron et al. (79)studied nortriptyline and gabapentin ei-ther in combination or alone in a ran-domized trial and confirmed that whengiven together, they were more effica-cious than either drug given alone. Inanother crossover study by the samegroup, low-dose combination therapywith gabapentin and morphine was sig-nificantly more effective than higherdoses of either (80).COMBO-DN study. The COMBO-DNstudy that has just been completed (81)is the largest combination trial in painfulDSPN and assessed whether combiningstandard doses of duloxetine and prega-balin is superior to increasing each drugto its maximum recommended dose inpatients with incomplete pain relief. Pa-tients with painful DSPN with a dailypain score of at least 4 (scale 0–10)were randomly assigned in a 1:1:1:1 ra-tio to one of four groups. For the 8-weekinitial treatment period, patients ingroups 1 and 2 were treated with 60mg duloxetine/day; patients in groups3 and 4 received 300 mg pregabalin/day. Thereafter, only nonresponders(,30% improvement in pain relief) re-ceived double-blind treatment for fur-ther 8 weeks of the combination versushigh-dose monotherapy treatment pe-riod with duloxetine 120 mg/day forgroup 1, duloxetine 60 mg/day1 prega-balin 300mg/day for groups 2 and 3, andpregabalin 600 mg/day for group 4. The



primary outcome was change in the 24-haverage pain (an item from BPI-MSF) aftercombination versus high-dose monother-apy period (groups 1, 4 pooled versusgroups 2, 3 pooled).

Eight-hundred and four patientswere evaluated in the initial period and339 in the combination versus high-dosemonotherapy treatment period, respec-tively. The difference between combina-tion and monotherapy in the meanchange of BPI-MSF average pain duringcombination versus high-dose mono-therapy treatment period was not statis-tically significant (combination, 22.35;monotherapy,22.16; P5 0.37) (81). Pro-portions of patients with treatment emer-gent adverse events were however similar:36.7% (Combination) and 33.5% (Mono-therapy). As a secondary end point theCOMBO-DN study also compared the ef-ficacy of standard doses of duloxetineand pregabalin as initial treatment forpainful DSPN, and duloxetine wasfound to have superior efficacy com-pared with pregabalin, without anysafety findings of concern. At the end ofthe combination versus high-dose mono-therapy treatment period, although thegroups are no longer randomized, 50%pain relief was found in 46.9% of sub-jects on 600 mg/day pregabalin com-pared with 28.4% on 120 mg/day ofduloxetine.

Taken together, even though the pri-mary end point was not met, the COMBO-DN study demonstrated that at standarddoses duloxetine has better efficacy thanpregabalin as an initial treatment for painfulDSPN, without any safety findings of con-cern. However, pregabalin catches up withduloxetine in terms of efficacy as the dosesare increased to maximum.

ConclusiondA simple algorithm wassuggested by the Toronto InternationalNeuropathy Consensus meeting (Fig. 3)to help practitioners in the managementof patients with painful DSPN (2,65). Af-ter exclusion of other causes and optimi-zation of glycemic control, first-linetherapies would include either an antide-pressant (a tricyclic or duloxetine) or ananticonvulsant (gabapentin or pregabalin).These therapies all have level A evidence forefficacy and a clear pathway of progressionif initial therapies fail is provided. Thosepatients with the severest neuropathicpain unresponsiveness to antidepressantor anticonvulsant therapy might requireshort-term treatment with opioid oropioid-like drugs such as tramadol orcontrolled release oxycodone. Finally,it must always be emphasized that allpatients with any form of diabetic neurop-athy are at increased risk of foot ulcerationand require education in self foot care and,

if possible, regular podiatry assessment andtreatment.

AcknowledgmentsdS.T. has received hono-raria for invited lectures from Eli Lilly andPfizer. A.J.M.B. has received honoraria fromEli Lilly and Pfizer and has served on an ad-visory board for Pamlab. A.H.D. is a speakerand is on the advisory board panels for Astellas,Grunenthal, and Pfizer and Lilly. A.H.D. issupported by the Wellcome Trust London PainConsortium. No other potential conflicts of in-terest relevant to this article were reported.The authors gratefully acknowledge the

production of figures by Dr. Shafaq Sikandar.

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