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Home , Diabetic neuropathy

FEATURE ARTICLE

Management of Diabetic

Andrew J.M. Boulton, MD, DSc(Hon), FRCP

europathies are among the most diagnosis and management DPN two abnormalities (i.e., abnormal common of all the long-term agreed on a simple definition of diabet- symptoms and signs) is recommended.5 Ncomplications of , ic neuropathy as “the presence of affecting up to 50% of patients.1–5 symptoms and/or signs of peripheral EPIDEMIOLOGY There are many subgroups of neu- dysfunction in people with dia- DPN is by far the most common of all ropathies; readers are referred to recent betes after the exclusion of other caus- the diabetic neuropathies and may be reviews for discussion of the autonomic es.”8 This group also agreed that neu- divided into the following two main neuropathies6 and the mononeu- ropathy cannot be diagnosed without a types: acute sensory neuropathy and ropathies.7 This article will focus on the careful clinical examination and that chronic sensorimotor neuropathy. most common of all the peripheral neu- absence of symptoms must never be Acute sensory neuropathy is a distinct ropathies: the somatic neuropathies equated with absence of neuropathy. variety of the symmetrical polyneu- affecting the lower extremities. Detailed The importance of excluding nondia- ropathies with an acute or subacute discussions of all aspects of these neu- betic causes was emphasized in the onset characterized by severe sensory ropathies were recently published as a Rochester Diabetic Neuropathy Study, symptoms, usually with few if any technical review5 and will be included in which up to 10% of peripheral neu- clinical signs. It is usually precipitat- in a forthcoming American Diabetes ropathy in diabetes was deemed to be ed by an episode of glycemic instabil- Association statement. of nondiabetic causation.1 ity (such as ketoacidosis or even after In the past, a lack of awareness and For day-to-day clinical practice, the institution of ), and its nat- inappropriate management of diabetic DPN is a clinical diagnosis. It is gener- ural history is one of gradual peripheral neuropathy (DPN) has led to ally agreed that DPN should not be improvement of symptoms with much unnecessary morbidity and sub- diagnosed on the basis of one symp- establishment of stable glycemic con- stantial health care costs. At least half of tom, sign, or test alone; a minimum of trol and appropriate symptomatic all foot ulcers, the end stage of such neu- treatments. ropathy, should be preventable by appro- IN BRIEF Chronic sensorimotor neuropathy is by far the most common form of DPN. priate management and patient educa- Diabetic peripheral neuropathy It is usually of insidious onset and may tion. However, lack of time and affects up to 50% of older type 2 dia- be present at the diagnosis of type 2 inappropriate or inadequate information betic patients. Whereas some patients diabetes in up to 10% of patients. may lead to suboptimal care. may have extremely painful symp- Whereas up to 50% of patients with Diabetic somatic neuropathies do toms, others with a more marked neu- chronic DPN may be asymptomatic, represent a paradox: at one extreme there ropathic deficit may be asympto- 10–20% may experience troublesome are patients with severe neuropathic matic. Diagnosis requires careful symptoms sufficient to warrant specific who on examination may have only a examination of the lower limbs. therapy. Sensorimotor neuropathy is minimal deficit, whereas at the other Management involves establishing often accompanied by autonomic dys- extreme are patients with insensate feet that the neuropathy is caused by dia- function. Its late sequelae, which who are asymptomatic and may first betes instead of more sinister causes include foot ulceration, Charcot neuro- present with foot ulcers. and aiming for optimal glycemic con- arthropathy, and occasionally amputa- This review will provide an overview trol. , usually tricyclic tion, should in many cases be preventa- of DPN and a detailed guide to the man- drugs or agents, may ble. The prevalence of chronic DPN agement of pain in patients with signifi- be required. Patients with peripheral increases with both age and duration of cant symptomatology. neuropathy must be considered at risk diabetes, and this diagnosis is more of insensate foot ulceration and must common in those whose glycemic con- DEFINITIONS receive preventive education and trol has been suboptimal in previous Members of an International podiatric care. Consensus Meeting on the outpatient years.

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CLINICAL FEATURES OF DPN ications required may be higher, in acute Table 2. Typical Neuropathic sensory neuropathy. The natural history Symptoms Acute Sensory Neuropathy of this acute neuropathy is very different Many of the symptoms of acute sensory from the much more common chronic Painful Nonpainful and chronic sensorimotor neuropathy DPN; its onset is acute or subacute, but Burning pain Asleep are similar, although there are clear dif- the severe symptoms typically resolve in Knife-like “Dead” ferences in the mode of onset, accompa- < 12 months.10,11 Electrical sensations Numbness nying signs, and prognosis. These are Squeezing Tingling summarized in Table 1. Table 2 offers a Chronic Sensorimotor Neuropathy Constricting Prickling list of typical symptoms, both painful Painful neuropathy can be one of the Hurting and nonpainful. All painful neuropathic most distressing and debilitating of all Freezing symptoms tend to be prone to nocturnal the complications of diabetes. The rest Throbbing exacerbation. Clinical examination of of this review will discuss the approach Allodynia patients with presumed acute sensory to patients presenting with chronic DPN neuropathy may be relatively normal, and will focus on available treatments Although not mentioned in older texts, with allodynia (a painful sensation with brief comment on those that may unsteadiness is increasingly being recog- induced by nonnoxious stimulus) on soon be available. nized as a manifestation of chronic DPN sensory testing, a relatively normal As noted above, many patients are resulting from disturbed propriaception motor exam, and occasionally reduced asymptomatic, and the neurological and probably abnormal muscle sensory ankle reflexes. deficit may be discovered by chance dur- function. Many patients will have a com- In the management of this condition, ing a routine neurological exam. bination of both positive (painful) and achieving stable blood control is Because chronic DPN is a length- negative (nonpainful) symptoms. most important. Stability may well be dependent process, the sensory manifes- Clinical examination of patients with the key feature, because blood glucose tations are most pronounced in the lower chronic DPN usually reveals a symmet- flux (as assessed, for example, by the M limbs, although, in more severe cases, rical sensory loss to all modalities in a value, a measure of glycemic excursions the fingers and hands may also be stocking distribution. This may well from the mean) is associated with pain.9 involved. The symptoms, outlined in extend into the mid-calf level and may Additionally, however, most patients Table 2, tend to be peculiar to the indi- also affect the upper limbs in more will require after neuropathic vidual patient but constant during the severe cases. Ankle reflexes are usually pain, and these medications are dis- history of neuropathy in that individual. reduced or absent, and knee reflexes cussed in detail below in the section on Patients often find it very difficult to may also be reduced in some cases. management of chronic DPN. Suffice it describe the symptoms because they are In the clinical assessment of to say that the approach is similar, different from other types of pain the patients, a number of simple although the dosage and number of med- patients have previously experienced. symptom/screening questionnaires are

Table 1. Contrasts Between Acute Sensory and Chronic Sensorimotor Neuropathies

Acute Sensory Chronic Sensorimotor Mode of onset Relatively rapid Gradual, insidious Symptoms Severe burning pain, aching; Burning pain, paresthesiae numbness; weight loss usual weight loss usual Symptom severity +++ 0 to ++ Signs Mild sensory in some; motor unusual Stocking and glove sensory loss; absent ankle reflexes Other diabetic complications Unusual Increased prevalence Electrophysiological May be normal or minor Abnormalities unusual in motor and investigations abnormalities sensory Natural history Complete recovery with 12 months Symptoms may persist intermittently for years; at risk of foot ulceration

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available to record symptom quality sectional and longitudinal studies have In most cases, further investigation, and severity. Among these is the Michi- assessed the sensitivity of the 10-g such as detailed quantitative sensory gan Neuropathy Screening Instrument, monofilament and have shown it to be a testing in electrophysiology, which which is a brief 15-item question- useful tool to identify patients at risk of would require referral to a neurologist, is naire.12 It is also increasingly recog- foot ulceration.5,15 Of the simple quanti- not essential. Abnormal electrophysiolo- nized that both symptoms and deficits tative sensory testing instruments that gy simply confirms the presence of a may have an on quality are used in clinical practice, the most neuropathy but does not indicate the of life in diabetic neuropathy,13 and spe- common is the bioesthesiometer (Bio- underlying cause. cific questionnaires have been devel- medical Instruments, Newbury, Ohio). oped for the assessment of the impact This assesses in a semiquantitative man- Initial Therapy and Counseling of neuropathy on quality of life. Simi- ner the perception of vibration and has Once a diagnosis is established, giving larly, composite scores have been used similarly been shown to be a useful pre- patients a full explanation of their condi- to assess clinical signs, and one that is dictor of foot risk.16 tion, allaying their fears and misconcep- increasingly used is a modified Neu- tions, and informing them that the pain ropathy Disability Score (NDS).14 The MANAGEMENT may resolve in time can be extremely NDS, shown in Figure 1, can be easily reassuring. Simple physical treatments, performed in the clinic setting and Is It DPN? such as the use of a bed cradle to lift the takes only a minute or two to complete. The management approach to patients bed clothes off of hyperaesthetic skin, The maximum deficit score is 10, considered to have DPN is provided in can be beneficial. Advice on suitable which would indicate complete loss of Table 3. First, it must be remembered footwear may also be provided. In sensation to all sensory modalities and that there are numerous causes of patients with relatively mild pain, simple absent reflexes. In a longitudinal Euro- peripheral neuropathy, of which diabetes analgesics or anti-inflammatory agents pean community-based study, an NDS is probably the most common. However, may be sufficient to treat the discomfort. of ≥ 6 was equated with an increased exclusion of other causes, particularly risk of insensate foot ulceration.14 malignant and toxic causes, is of Metabolic Control A number of simple devices may be paramount importance. Exclusion of The most effective method of achieving used for clinical screening; the most such potentially serious conditions as stable normoglycemia is or widely used is the Semmes-Weinstein malignant disease (e.g., small-cell carci- islet cell transplantation. However, this monofilament.15 This filament assesses noma presenting as a paraneoplastic is not practical in most cases because it pressure perception when gentle pres- syndrome), toxic causes (e.g., alcohol), is mainly available to patients with end- sure is applied sufficient to buckle the and ( such as HIV) is stage who have nylon filament. A number of cross- essential. combined pancreas and renal transplants or in special cases of young people with Neuropathy Disability Score (NDS) . Right Left Although there have been no ran- Vibration Perception Threshold domized, controlled trials of intensive 128-Hz tuning fork; apex of big toe: normal = can distinguish vibrating/ insulin therapy in the management of not vibrating diabetic neuropathy, data from a number Temperature Perception on Dorsum of observational studies suggest that sta- of the Foot Normal = 0 ble glycemic control is of the greatest Use tuning fork with beaker of Abnormal = 1 import. A recent study using continuous ice/warm water glucose monitoring confirmed that Pin-Prick painful symptoms were associated with Apply pin proximal to big toe nail just erratic blood glucose control.9 Having enough to deform the skin; said this, there is no evidence that trial pair = sharp, blunt; patients whose diabetes has been well normal = can distinguish sharp/not sharp controlled on oral hypoglycemic agents Achilles Reflex Present = 0 Present with will benefit in terms of pain relief by reinforcement = 1 transferring to insulin. Absent = 2 NDS Total out of 10 Pharmacological Management A large number of therapeutic agents Figure 1. The Modified Neuropathy Disability Score have been proposed for the management

CLINICAL DIABETES • Volume 23, Number 1, 2005 11 FEATURE ARTICLE

Table 3. Initial Management of Symptomatic Neuropathy for diabetic neuropathy have been gener- ally disappointing. Such agents work by 1. Exclude nondiabetic causes: the inhibition of presynaptic reuptake of • Malignant disease (e.g., bronchogenic carcinoma) serotonin but not norepinephrine. There • Metabolic is some evidence to support the use of • Toxic (e.g., alcohol) and citalopram in dosages of • Infective (e.g., HIV ) up to 40 mg/day from small controlled • Iatrogenic (e.g., isoniazid, vinca alkaloids) studies. • Medication-related (chemotherapy, HIV treatment) . These agents have been used in the management of neuro- 2. Provide explanation, support, and information on practical measures, e.g., bed pathic pain for many years, but only lim- cradle to lift bedclothes off of hyperaesthetic skin ited evidence exists for the efficacy of 3. Assess level of blood glucose control and blood glucose profiles phenytoin and .5 is now widely used for 4. Aim for optimal, stable control neuropathic symptoms. This agent is 5. Consider pharmacological therapy structurally similar to the neurotransmit- ter -aminobutyric acid and was intro- of painful symptoms. These are shown related to anticholinergic actions, duced some years ago as an anticonvul- in Table 4 and discussed below with a include dry mouth, blurred vision, car- sant for complex partial seizures. The critique of the evidence supporting their diac , sedation, urinary efficacy of gabapentin has been con- use. Although there is only limited evi- retention, constipation, and postural firmed in two -controlled clinical dence to support the use of nonsteroidal hypotension. Although nocturnal trials.5 and anti-inflammatory drugs in DPN, administration helps reduce the sedative The side effect profile may again be some would advocate their use for the side effects, up to about one-third of all troublesome, but appears to be less so management of patients with mild patients cannot tolerate these agents. than that of the tricyclics. Reported symptoms. Such agents must be used and are most effects include sedation, dizziness, with caution in neuropathic diabetic commonly used, although headache, pedal , and weight gain. patients because many will have a renal has fewer anticholinergic side effects It should be noted that the average dose impairment, which often constitutes a and is less sedative. required for pain relief in clinical trials contraindication to the use of non- Selective serotonin reuptake was ~ 1.8 g/day. Slow dose titration may steroidal drugs. inhibitors. Trials of selective serotonin reduce the incidence of side effects, but Tricyclic agents. The use of tricyclic reuptake inhibitors (SSRIs) as treatment it has been suggested that many patients drugs in the management of is supported by several randomized, Table 4. Oral Symptomatic Therapy of Painful Neuropathy controlled studies.5,17,18 Although these drugs remain the first-line treatment for Drug Class Drug Daily Dose (mg) Side Effects symptomatic neuropathy in many cen- ters, their use is restricted because of the Tricyclics Amitriptyline 25–150 ++++ frequency and severity of side effects. Imipramine 25–150 ++++ Thus, some of the newer anticonvulsants SSRIs Paroxitene 40 +++ are increasingly being used because of Citalopram 40 +++ their superior side effect profile. Anticonvulsants Gabapentin 900–1,800 ++ The mechanism of action of the tri- 160–600 ++ cyclic agents is not clear but may occur 200–400 ++ through inhibition of reuptake of norep- Carbamazepine up to 800 +++ inephrine and serotonin but also through Antiarrhythmics* Mexilitene up to 450 +++ effects on sodium channels and the N- 50–400 +++ CR† 10–60 ++++ methyl-D-aspartate (NMDA) recep- 19 tors. Although these agents are most All medications in this table have demonstrated efficacy in randomized, controlled useful in the management of neuropath- studies. *Mexilitene should be used with caution and with regular electrocardiogram ic pain, it is, once again, their side effect monitoring; †Oxycodone controlled release (CR) may be useful as an add-on therapy in profile that limits their use. Side effects, severe symptomatic neuropathy. which are typically predictable and

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are not being treated with a sufficiently trial, and a follow-up study suggests that Other physical therapies. Many high dosage. it can be used safely for up to 6 months other physical therapies have been pro- A newer drug, pregabalin, which is a of sustained pain relief.26,27 More recent- posed. Controlled evidence has been central –active compound ly, two studies have confirmed the effica- provided for the use of percutaneous and an analog of the neurotransmitter - cy of controlled-release oxycodone.28,29 nerve stimulation,36 static magnetic field aminobutyric acid, has recently been The side effects of both drugs are therapy,37 low-intensive laser therapy,38 introduced. Preliminary evidence sug- predictable and include somnolence, and monochromatic infrared light.39 gests that this agent may be a useful addi- , and constipation; addiction is These therapies have mainly been tion to the anticonvulsants that are helpful also problematic. It may be that opioids described in small single-center studies in the management of neuropathic pain.20 such as tramadol and oxycodone may be and require confirmation in larger stud- A number of other anticonvulsant considered as add-on therapies for ies. Electrical spinal cord stimulation agents have confirmed efficacy in ran- patients failing to respond to nonopioid has been used to treat several chronic domized, controlled trials. These include medications in the first instance. painful conditions, including phantom lamotrogine21 and sodium .22 limb pain, vascular disease, and severe arrhythmic Topical and Physical Treatments neuropathy. Although anecdotal evi- agents. results in sodium . This alkaloid, which is found dence has been presented to support channel blockage, dampening both in red pepper, depletes tissue of sub- this, this treatment is invasive, expen- peripheral nociceptor sensitization and stance P and reduces chemically induced sive, and needs to be confirmed in ran- ultimately central nervous system hyper- pain. Although several controlled studies domized trials.40 excitability. Although early studies sug- combined in meta-analyses seem to pro- gested that intravenous lidocaine admin- vide some evidence of efficacy in diabet- New Potential Therapies Now in istration might be beneficial in relieving ic neuropathic pain, it may be best Clinical Trials neuropathic pain, the potential side reserved for those with localized dis- Two treatments that might be useful in effects and the need for intravenous comfort rather than those with wide- opposing some of the pathogenetic fac- administration was problematic. The oral spread generalized neuropathic pain.30 tors that are thought to lead to neuropa- analog of lidocaine, , has been Topical nitrate. Some recent data thy are now in clinical trials. reported to be of benefit in some stud- suggest that impaired nitric oxide (NO) -lipoic-acid. This free radical scav- ies,5,23 but it is not widely used because of synthesis plays a role in the pathogenesis enger antioxidant has been shown to be side effects and the need for regular elec- of diabetic neuropathy, and in experimen- efficacious in the management of painful trocardiogram monitoring with its use. tal models it has been shown that neuropathies when administered par- There are now very preliminary data impaired neuronal NO generation induces enterally.41 A large 4-year, multicenter to suggest efficacy from the use of a 5% hyperalgesia.31,32 This was followed by a study to confirm the efficacy of this lidocaine patch in diabetic polyneuropa- recent controlled study that suggested that agent in diabetic neuropathy is in thy. In an open-label study, the use of a local application to the feet of isosorbide progress and should be completed in maximum of four patches of 5% lido- dinitrate spray was effective in relieving 2005. caine per day was associated with relief overall pain and burning discomfort of kinase C inhibition. Elevat- of neuropathic symptoms without seri- DPN.33 If this is confirmed in larger ran- ed protein kinase C activity is thought to ous adverse effects.24 domized studies, this could provide a very play a substantial role in the etiology of NMDA antagonists. This is a rela- useful alternative and local treatment for diabetic microvascular complications. tively new class of drugs and includes the relief of neuropathic symptoms. A Studies have been conducted using a and memantine. Pre- subsequent retrospective review on the protein kinase C- inhibitor liminary studies of both agents suggest data from 18 patients with painful neu- (LY333531). A prelim- inary study sug- some efficacy in painful diabetic neu- ropathy treated with glyceryl trynitrate gested the possibility of this agent ropathy, although further studies are patches reported benefit from this method improving positive symptoms of allody- required.25 of applying the topical nitrate.34 nia and prickling pain. Large, phase III, analgesics. Opioids have not Acupuncture. A number of masked multicenter clinical trials are in traditionally been used in the manage- studies support the use of acupuncture. progress.42 ment of diabetic neuropathic pain, but In the most recently published report, recent trials of two agents do suggest benefits of acupuncture lasted for up to 6 FOOT CARE IN NEUROPATHIC efficacy. First, tramadol, which is an opi- months and reduced the use of other PATIENTS oid-like, centrally acting synthetic nar- analgesics.35 There is, however, a need Most of the above discussion has related cotic analgesic, has been confirmed to be for controlled studies to confirm these to the management of patients with efficacious in a randomized, controlled observations. symptomatic diabetic neuropathy.

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However, as noted at the start of this risk of foot ulceration or injury and 15Mayfield JA, Sugarman JR: The use of Semmes-Weinstein monofilament and other article, a substantial number of neuro- should receive preventive education and threshold tests for preventing foot ulceration and pathic patients may be completely referral to a podiatrist as necessary. in people with diabetes. J Fam Pract asymptomatic, and these, along with 49 (Suppl.):517–529, 2000 those who have painful neuropathy, are REFERENCES 16Abbott CA, Vileikyte L, Williamson S, Car- rington Al, Boulton AJM: Multicenter study of all at risk of insensitive foot injury. The the incidence of and predictive risk factors for 1Dyck PJ, Katz KM, Karnes JL, Litchy WJ, importance of DPN in the etiopathogen- diabetic neuropathic foot ulceration. Diabetes Klein R, Pach JM: The prevalence by staged Care 7:1071–1075, 1998 esis of foot ulceration has been con- severity of various types of diabetic neuropathy, retinopathy and nephropathy in a population- 17Watson CP: The treatment of neuropathic firmed in numerous studies and was the based cohort: the Rochester Diabetic Neuropathy pain: anti-depressants and opioids. Clin J Pain subject of a recent review.43 study. Neurology 43:817–824, 1993 16:S49–S55, 2000 It must be remembered that the neu- 2Young MJ, Boulton AJM, McLeod AF, 18Mendell JR, Sahenk Z: Painful sensory neu- ropathic does not ulcerate Williams DRR, Sonksen PH: A multicentre study ropathy. N Engl J Med 348:1243–1255, 2003 of the prevalence of diabetic peripheral neuropa- 19 spontaneously. Rather, it is the combina- thy in the UK hospital clinic population. 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Diabetic Med 15:508–514, 1998 25 once a year. Sang CN, Booher S, Gilron I, Parada S, 9 Max MB: Dextromethorphan and memantine in Oyibo S, Prasad YD, Jackson NJ, Jude EB, painful diabetic neuropathy and postherpetic neu- Until recently, in the management of Boulton AJM: The relationship between blood neuropathic pain, there have been few glucose excursions and painful diabetic peripher- ralgia: efficacy and dose-response trials. Anesthe- siology 96:1053–1061, 2002 well-designed, placebo-controlled stud- al neuropathy: a pilot study. Diabetic Med 19:870–873, 2002 26 ies. However, in recent years, a number Harati Y, Gooch C, Swenson M, Edelman S, 10Archer AG, Watkins PJ, Thomas PK, Shar- Greene D, Raskin P, Donofrio P, Cornblath D: of well-designed clinical trials have ma AK, Payan J: The natural history of acute Double-blind randomized trial of tramadol for the confirmed the efficacy of a number of painful neuropathy is diabetes. 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31Sasaki T, Yasuda H, MaedaK, Kikkawa R: for diabetic neuropathic pain. Diabetes Care ropathy with the antioxidant alpha-lipoicacid: a Hyperalgesia and decreased neuronal nitric oxide 23:365–370, 2000 meta-analysis. Diabetic Med 21:114–121, 2004 synthase in diabetic rate. Neuroreport 9:243–247, 37 42 1998 Weintraub MI, Wolfe GI, Barohn RA, Cole Litchy W, Dyck P, Tesfaye S, for the MBBQ SP, Parry GJ, Hayat G, Schwartz SL: Static mag- Study Group: Diabetic peripheral neuropathy 32Rodella L, Rezzani R, Corsetti G, Bianchi netic field therapy for symptomatic diabetic neu- (DPN) assessed by neurological examination and R: Nitric oxide involvement in the trigeminal ropathy; a randomized, double-blind, placebo- composite scores is improved with LY333531 hyperalgesia in diabetic rats. Res controlled trial. Arch Phys Med Rehabil treatment (Abstract). Diabetes 45:A197, 2002 86:736–746, 2003 865:112–115, 2000 43 38 Boulton AJM, Kirsner RS, Vileikyte L: Neu- 33Yuen KC, Baker NR, Rayman G: Treatment Zinman LH, Ngo M, Ng ET, Nwe KT, ropathic diabetic foot ulcers. N Engl J Med of chronic painful diabetic neuropathy with Gogov S, Bril V: Low-intensity laser therapy for 351:48-55, 2004 isosorbide dinitrate spray: a double-blind place- painful symptom diabetic sensorimotor polyneu- bo-controlled crossover study. Diabetes Care ropathy: a controlled trial. Diabetes Care 25:1699–1703, 2002 27:921–924, 2004 39 Andrew J.M. Boulton, MD, DSc(Hon), 34Rayman G, Baker NR, Krishnan ST: Glyc- Leonard DR, Farooqi MH, Myers S: Restoration of sensation, reduced pain, and FRCP, is a professor of medicine at the eryl trinitrate patches as an alternative to isosor- improved balance in subjects with diabetic bide dinitrate spray in the treatment of chronic peripheral neuropathy: a double-blind, random University of Manchester, U.K., and the painful diabetic neuropathy. Diabetes Care placebo-controlled study with monochromatic University of Miami in Miami, Fla. 26:2697–2698, 2003 infrared treatment. Diabetes Care 27:168–172, 35 2004 Abusaisha BB, Constanzi JB, Boulton AJM: Note of disclosure: Dr. Boulton has Acupuncture for the treatment of chronic painful 40Tesfaye S, Watt J, Benbow SJ, Pang KA, diabetic neuropathy: a long-term study. Diabetes Miles J, MacFarlane IA: Electrical spinal-cord received honoraria for speaking engage- Res Clin Pract 39:115–121, 1998 stimulation for painful diabetic peripheral neu- ments or consulting fees from Pfizer and ropathy. Lancet 348:1696–1701, 1996 36Hamza MA, White PF, Craig WF, Ghoname Eli Lilly. These companies manufacture ES, Ahmed HE, Proctor TJ: Percutaneous electri- 41Ziegler D, Nowak H, Kempler P, Vargha P, cal nerve stimulation: a novel analgesic therapy Low PA: Treatment of symptomatic diabetic neu- drugs for treatment of neuropathic pain.

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