New Treatments for Diabetic Neuropathy: Symptomatic Treatments

Singhan T.M. Krishnan, MRCP, and Gerry Rayman, MD, FRCP

Diagnosis
Symptoms Because painful neuropathy is common, the physician must be guarded against assuming that the diabetic patient presenting with lower limb pain has painful diabetic neuropathy. It is not unusual to occasionally see patients previously managed for painful diabetic neuropathy to be rediagnosed and effectively managed by a podiatrist for conditions such as plantar fasciitis or plantar neuromas. The history is important in helping distinguish neuropathic pain from other causes of lower limb pain. The typical symptoms are shown in Table 1. Some patients despite having pain will also describe numbness, wooden or dead feelings (the so-called painful painless foot). The pain is classically worse at night, beginning or worsening on first recumbency, but also waking the patient during the night. Getting out of bed and walking around will often give relief, although some patients find that pressure caused by standing induces pain. Relief on walking around contrasts with ischemic pain, which although improved on dependency worsens on walking. Spinal stenosis and lumbar radiculopathies produce pain on twisting and flexion, and are thus exacerbated or provoked by movements such as lifting and turning. Spinal stenosis may be associated with worsening of pain with or without numbness on walking; this is sometimes termed spinal claudication. Clinical examination In pure small-fiber neuropathy, despite classical symptoms the clinical examination may reveal very little even in the presence of severe discomfort; however, in most patients there is some loss of pinprick sensation in the toes, which extends more proximally with progression of the neuropathy. More frequently, in painful diabetic neuropathy there is a mixture of small- and large-fiber disease and thus examination also reveals distal loss of light touch and vibration sense. Loss of ankle reflexes, weakness of the small muscles of the foot leading to the clawed foot appearance, and reduced proprioception are features of more extensive largefiber involvement, and although these are found in patients with painful neuropathy they are more frequently associated with painless neuropathy. Clinical examination should also include palpation of the foot and assessment of joint mobility to exclude conditions
Address Diabetes Centre, Ipswich Hospital, Heath Road, Suffolk IP5 4PD, UK. E-mail: Gerry.Rayman@ipswichhospital.nhs.uk Current Diabetes Reports 2003, 3:459467 Current Science Inc. ISSN 1534-4827 Copyright 2003 by Current Science Inc.

Painful diabetic neuropathy is a common distressing and challenging condition. The mechanism or mechanisms involved in its pathogenesis continue to elude clinical scientists. As with other conditions of painful distal symmetrical neuropathic conditions, pain relief involves the use of a variety of analgesic and neuroleptic drugs, aimed at reducing either central responses to painful stimuli or at dampening spontaneous irritability of affected neurons. More recently, several therapies directed at putative pathologic mechanisms specific to painful diabetic neuropathy have evolved. These include vasodilators, protein kinase C inhibition, antioxidants, and novel aldose reductase inhibitors. Preliminary clinical studies of these therapies have at present involved small numbers of patients; however, the results have been encouraging. This article considers the clinical aspects of diagnosis and management of chronic painful diabetic neuropathy, focusing on existing and newer therapies.

Introduction
Diabetic neuropathy is common, with up to 60% of people with diabetes reported to be affected and with as much as half of these experiencing pain [15]. The pain of diabetic peripheral neuropathy is one of the most distressing and debilitating of all the complications of diabetes. Although diagnosis is often straightforward, controlling the pain remains a challenging and trying problem for the physician and patient. The multiple treatments available, varying from drug therapy to tactile barriers such as polyurethane films (OpSite; Smith & Nephew, Memphis, TN), testifies to the lack of any one truly effective therapy. A variety of neurologic problems can give rise to pain in patients with diabetes; these include acute painful neuropathy, acute insulin neuritis, diabetic amyotrophy, diabetic mononeuropathy including truncal radiculopathies, and entrapment neuropathies. This article deals only with chronic painful neuropathy, focusing on existing and emerging new treatments for the management of this difficult condition.

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Table 1. Typical descriptions given by patients with neuropathic pain

Burning Throbbing Prickling Like a nettle sting Freezing Shooting Shock-like Knife-like Allodynia (a non-noxious stimulus; eg, light touch being perceived as painful, such as the touch of bed clothes) Hyperalgesia (increased sensitivity; ie, a minor painful stimulus producing severe pain)

months or several years only to be followed by painless neuropathy (an insensitive foot). Simple reassurance that the pain may resolve given time is often helpful and may be all that is necessary in those with mild discomfort. Advice on footwear and the use of a cradle in the bed to reduce contact dysesthesia may be beneficial. Simple analgesics such as regular paracetamol may be helpful in those whose pain is troublesome but not severe. Patients who are smokers may be best advised to stop smoking if the hypothesis that neuropathy is related to reduced nerve blood flow is correct. If there is any suggestion of alcohol excess the patient should be advised to reduce their intake, and in these patients prescribing multivitamins to include thiamine may be prudent.

such as tarsal tunnel entrapment neuropathy, Mortons neuroma, and inflammatory conditions such as plantar fasciitis and chronic extrinsic tendonitis. Tarsal tunnel entrapment is associated with shooting pain or a shock-like sensation on pressing or percussing over the posterior tibial nerve under the flexor retinaculum and behind the medial malleolus (similar to Tinels sign in carpal tunnel syndrome). Mortons neuroma gives rise to pins and needles and shooting pains in the area of the second to fourth metatarsals and toes during weight bearing. Squeezing or massaging the foot may relieve symptoms, and pressure at the base of the toes may produce an audible click as the nerve moves within the intermetatarsal space. Examination for peripheral vascular disease is essential in all diabetic patients with painful lower limbs. This involves observation of the appearance of the foot and palpation of foot pulses, and where necessary assessment of the ankle-brachial index is important to exclude vascular disease.

Clinical investigations In patients with diabetes presenting with classical symptoms and in whom the clinical examination has excluded other conditions, further investigations may not be necessary, although excluding hypothyroidism and pernicious anemia are important. Nerve conduction studies are seldom indicated and may be normal in small-fiber neuropathy. Qualitative sensory testing, which includes measuring thermal thresholds and heat-pain sensitivity, is mainly used for clinical trial purposes. Their sensitivity and specificity are such that they cannot be recommended to exclude small-fiber neuropathy in individual patients [6]; the same is true for the sweat test [7]. More recently skin biopsy, with immunohistochemical staining for PGP 9.5, may be a more reliable diagnostic tool; however, this requires a great deal of expertise and is not practical in routine diabetes care [8].

Metabolic control There is considerable anecdotal evidence from case reports to suggest that severe painful neuropathy can be triggered by sudden improvements in metabolic control [9]. So-called insulin neuritis may be an example of this. Nevertheless, good glycemic control reduces the prevalence and progression of neuropathy as demonstrated in the Diabetes Control and Complications study and the UK Prospective Diabetes Study [1012]. This is similar to the situation of diabetic retinopathy, where sudden improvement in control leads to initial worsening but long-term good metabolic control reduces the prevalence and severity of the condition [10,13]. Thus, good metabolic control is advocated in patients with painful neuropathy. Several studies have suggested that improved glycemic control achieved by continuous subcutaneous insulin infusion is associated with a reduction in neuropathic symptoms [14,15]. Studies are currently underway to more accurately assess the effect of continuous subcutaneous insulin infusion when combined with continuous glucose monitoring on symptomatic neuropathy.

Pharmacologic Treatments
Tricyclic antidepressants Amitriptyline, imipramine, desimipramine, norimipramine, and trimipramine remain the mainstay first-line treatment of painful neuropathy [16]. The mechanism by which these drugs produce their analgesic effects is not clear but may be through inhibition of the reuptake of noradrenaline and serotonin and by the effects on sodium channels and N-methyl-Daspartate (NMDA) receptors [17]. More that 300 patients have been involved in several clinical trials of tricyclic antidepressants [1822]. The number needed to treat to receive at least a 50% reduction in pain is 2.4 (1.4 to 3.0) [23]. Side effects, which may be intolerable in some, include dry mouth, blurred vision, cardiac dysarrhythmias, sedation, postural hypotension, and urinary retention. Sedation is the most prominent side effect; thus, nocturnal administration may be helpful particularly in patients who have difficulty in sleeping, which is often the case because of nocturnal exacerbation of their pain.

Treatment of Painful Diabetic Neuropathy

Initial therapy and counseling Taking time to give patients a full explanation of their condition and allaying fears and misconceptions is important. In many patients the pain is not permanent, resolving over

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The response to tricyclic antidepressants is delayed by 2 to 3 weeks and, thus, slow titration is recommended to avoid side effects. The most commonly used of these agents is amitriptyline, which should be started at a dose of 10 mg at night and gradually increased at weekly intervals to the maximum dose of 150 mg or until the development of side effects. Amitriptyline is contraindicated in those with cardiac arrhythmias and patients with autonomic neuropathy, in which postural hypotension, urinary retention, and bowel hypermotility may be worsened. In such patients and in those who have responded to amitriptyline but have developed side effects, desimipramine, which is associated with fewer anticholinergic side effects and less sedation, may be tried.

better than other anticonvulsants, sedation, dizziness, headache, pedal edema, and weight gain are relatively common, with the first three side effects being reported in 20% to 30% of patients. Slow dose titration may reduce the incidence of side effects, and in diabetic neuropathy it appears that significantly higher doses are required (1800 mg or more daily) in comparison with its use in other painful conditions such as trigeminal neuralgia. The use of gabapentin for painful diabetic neuropathy has increased considerably since it was first licensed. In this respect, the one, albeit small, trial comparing gabapentin and amitriptyline, which demonstrates similar efficacy, bears consideration in view of the higher cost of the newer agent [22]. Lamotrigine This novel antiepileptic agent blocks voltage-sensitive sodium channels and inhibits presynaptic release of glutamate. A small open trial in 13 patients suggested benefit in spontaneous pain and cold allodynia [33]. A further placebo-controlled study by the same group of 59 patients with diabetic neuropathy demonstrated benefit in pain assessed by a numerical pain score at doses of 200 to 400 mg daily [34]. The maximum reduction in pain from baseline was 37% compared with 20% in the placebo group. Adverse events were similar in the two groups. Rash occurred in two patients treated with lamotrigine, necessitating withdrawal of the patients. Topiramate This newer anticonvulsant has been of recent interest in the field of diabetes. It appears to have weight-reducing properties and it may have analgesic effects. The precise mechanism of action is unknown; however, it appears to block sodium and calcium channels, and may be involved in GABA receptor modulation [35]. As with other anticonvulsants, side effects are common and slow dose titration has been employed in clinical trials. Unfortunately, following a single promising study further unpublished data from three clinical trials have been disappointing [36]. A recent small study has suggested benefit in normalizing skin nerve fiber pathology in diabetic peripheral neuropathy [37].

Selective serotonin reuptake inhibitors Trials of selective serotonin reuptake inhibitors in painful neuropathy have been disappointing. Fluoxetine [21] was found to be no better than placebo, and a comparison of paroxetine and imipramine found the latter to be more effective [24]. In a double-blind, placebo-controlled, crossover study, citalopram in a 40 mg/d dose was effective and was well tolerated; however, the study included only a small number of subjects who were followed for just 3 weeks [25]. Anticonvulsants Many similarities between the pathophysiologic phenomena observed in some epilepsy models and in neuropathic pain models justify the rationale for use of anticonvulsant drugs in the symptomatic management of neuropathic pain disorders [26]. Phenytoin stabilizes membranes by inhibiting sodium channels. It has been used to treat a variety of neuropathic painful conditions; however, there have been few placebocontrolled trials in patients with diabetic neuropathy and these have yielded inconsistent results [27,28]. Carbamazepine may also alleviate pain by blocking sodium channels and inhibiting ectopic discharges. Two placebo-controlled trials with carbamazepine have suggested marginal benefit, but patient numbers in both trials were small [29,30]. Furthermore, the frequency of adverse effects and difficult titration limit the use of this anticonvulsant, particularly in the elderly.
Gabapentin The precise mode of action of gabapentin is uncertain. Although structurally an analogue of -aminobutyric acid (GABA), it appears to have no direct effect on GABA uptake or metabolism. It binds to the -2- subunit of voltage-dependent calcium channels and, thus, inhibits calcium influx into secondary neurons stimulated by NMDA receptors. Two large placebo-controlled clinical trials have demonstrated significant pain relief when relatively large doses are used [31,32]. Although the side-effect profile is somewhat

Local anesthetic antiarrhythmic agents Like other local anesthetics, lignocaine results in sodium channel blockade, dampening both peripheral nociceptor sensitization, and ultimately central nervous system hyperexcitability. Intravenous lignocaine has been reported to be of benefit in two uncontrolled and one placebo-controlled study [3840]. Whether it is of benefit beyond 2 weeks is unknown because assessment of clinical symptoms in the reported studies was not extended beyond this period. The treatment regimen is complicated in that it requires intravenous administration, and because of potential cardiac effects continuous electrocardiogram monitoring is necessary. Thus, it is reserved for patients with severe intractable pain.

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Mexiletine, an oral analogue of lignocaine, has been reported to be of benefit in two studies; however, two further studies have reported negative results [4143]. As with lignocaine, electrocardiogram assessment with a rhythm strip is necessary prior to initiating treatment. Side effects include dizziness and gastrointestinal upset. In the authors experience, neither of these agents have been particularly beneficial in painful neuropathy. The use of topical lignocaine is discussed later.

OpSite (Smith & Nephew, Memphis, TN) There has been one publication reporting benefit of OpSite, a film dressing in reducing pain in an open study of diabetic patients with peripheral neuropathy [54]. This was a small open-label study comprising only 33 patients. There have been no other studies to confirm these findings; however, there is anecdotal evidence that cling film may also be effective. These presumably act as barriers to tactile stimuli and may thus be expected to be particularly valuable in patients with allodynia.

Topical treatments Capsaicin Capsaicin, the hot ingredient of red chili peppers, acts by binding to the vanilloid receptor 1depleting nociceptive C fibers in the skin of substance P [44]. Three clinical trials in painful diabetic neuropathy [4547] reported benefit, and one has not [48]. The validity of some of the measures used in the positive trials has been questioned; furthermore, difficulty in adequately blinding the studies because of pain during the initial applications needs to be considered when interpreting these results [49]. A meta-analysis of the four clinical trials reported overall favorable outcomes [50]. In a double-blind comparison with amitriptyline, capsaicin was of similar efficacy but the former was associated with more side effects [51]. Exacerbation of the pain with burning, stinging, and erythema at the application site occurs during initial applications due to substance P release. This, together with the need for three to four applications a day, is a disincentive to its use. With progressive applications and eventual depletion of substance P these side effects resolve. The maximum therapeutic effect may be delayed by 4 to 6 weeks. Concern has been expressed that long-term use may result in detrimental sensory impairment; there have been no long-term follow-up studies [52].
Lignocaine patches As previously mentioned, the lignocaine results in sodium channel blockade, dampening the peripheral nociceptor sensitization. Lignocaine (Lidocaine; A-A Spectrum Healthcare Products, Gardena, CA) patches have recently been approved by the US Food and Drug Administration for the treatment of postherpetic neuralgia, and recent studies have suggested that they may also be effective for other chronic neuropathic painful conditions including painful diabetic neuropathy. A prospective, open-labeled pilot study comprising 56 diabetic subjects with painful neuropathy reported that lidocaine 5% patches (700 mg) provided significant improvements in pain intensity and pain relief. Topical administration, even with chronic use, is associated with serum levels well below those that typically produce antiarrhythmic effects or toxicity. The most common adverse event was burning sensation and mild erythema at the application site [53]. Surprisingly, there is no loss of sensation at the application site, which may be important in those with painful neuropathy associated with a degree of sensory loss.

Vasodilators There is increasing evidence from animal and human studies to implicate microvascular dysfunction in the development of diabetic neuropathy. Neuropathologic studies of sural nerve biopsies demonstrate significant relationships between endoneurial microvascular abnormalities, nerve fiber pathology, neurophysiologic abnormalities, and clinical symptom scores [55]. Furthermore, functional and structural abnormalities including evidence of epineurial arteriovenous shunting and endoneurial hypoxia have been demonstrated in patients with acute painful neuropathy and chronic diabetic neuropathy [56]. In animal models of diabetic neuropathy where reduced endoneurial blood flow has been well documented, a variety of vasodilator therapies have been shown to be effective in correcting neurophysiologic abnormalities [57]. Based on these findings there have been a number of small studies of a variety of vasodilators in the treatment of painful diabetic neuropathy.
Angiotensin-converting enzyme inhibitors An open study of 13 patients demonstrated improvements in nerve conduction and temperature perception with lisinopril, but this study did not address pain [58]. In a small placebocontrolled study of 41 patients, the angiotensin-converting enzyme inhibitor trandolapril has been demonstrated to improve peroneal motor nerve conduction velocity and Mwave amplitude, and decrease the F-wave latency and increase sural nerve action potential amplitude in patients with chronic neuropathy, but pain was not assessed [59]. Further studies are warranted to examine angiotensin-converting enzyme inhibitors in painful neuropathy. Nitric oxide donors Recent data suggest that impaired nitric oxide (NO) synthesis plays a role in the pathogenesis of diabetic neuropathy. In rats it has been demonstrated that impaired neuronal NO generation induced hyperalgesia [60,61]. In a small, double-blind, placebo-controlled pilot study involving 22 patients, the authors examined the effect of isosorbide dinitrate (ISDN), an NO donor, when administered in the form of a spray to the feet [62]. This study was based on the authors observation that glyceryl trinitrate (GTN; also an NO donor) applied as patches to the feet appeared to be effective; thus, a placebo-controlled study was designed. Unfortunately, it was not possible to obtain placebo

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patches; therefore, ISDN spray was employed as the placebo was obtainable. The ISDN spray was found to be effective in reducing overall neuropathic pain and particularly burning sensation. Subsequently, a retrospective review of the data on 18 patients with painful neuropathy treated with GTN patches showed that eight reported benefit and seven continue to use the patches [63]. One developed a skin reaction to the adhesive; this patient has since responded equally well to the use of GTN spray. In practice, a 5-mg patch is applied to the dorsum of the foot in the early evening and replaced with a new patch the next evening. The rationale behind this is to avoid headache from prescribing too large a dose at the outset. If no headache occurs after several days, patients are recommended to use a patch on each foot. If this produces headache, they are instructed to cut the patch in half and to use half on each foot. It may be of interest that during the initial treatment period when one patch is used some patients report improvement only in the leg to which the patch is applied. This may suggest that a local mechanism is involved in the pain relief. The mechanism remains speculative and the apparent local effect if confirmed is intriguing. Further placebo-controlled studies with larger patient numbers are required to confirm the potential of NO donors in alleviating sensory symptoms associated with painful neuropathy.

Aldose reductase inhibitors Increased activity in the polyol pathway leading to accumulation of sorbitol has been implicated in the pathogenesis of diabetic neuropathy. Aldose reductase inhibitors have received considerable attention as potential treatments for neuropathic pain and also for the prevention of both painful and painless peripheral diabetic neuropathy. Unfortunately, clinical trials of these agents have been disappointing, either because of lack of efficacy or unacceptable adverse effects. Sorbinil was associated with marked hypersensitivity and rashes in up to 10% of patients [64], and zenarestat and tolrestat with renal and hepatic toxicity, respectively [65,66]. A double-blind trial in 279 patients has recently been completed with fidarestat, a novel aldose reductase inhibitor [67]. This study is of interest, as although not primarily aimed at patients with painful neuropathy, there was a reported reduction in the severity of spontaneous pain and paresthesia on walking. Further studies in painful neuropathy are warranted. Antioxidant treatment (-lipoic acid, thioctic acid) Oxidative stress resulting from increased free radical formation has been implicated in the pathogenesis of diabetic neuropathy by inducing neurovascular defects, resulting in endoneurial hypoxia and subsequent nerve dysfunction. lipoic acid (ALA), a potent lipophilic free radical scavenger antioxidant, has been shown to be effective in experimental diabetic neuropathy and has been studied in four placebocontrolled trials [68].

In the most recent, the SYDNEY trial, intravenous ALA at a dose of 600 mg for 14 treatments 5 d/wk yielded very impressive results in terms of neuropathic symptoms, including pain assessed by several independent scoring methods that included the total symptom score (TSS; lancing and burning pain, asleep numbness, and prickling) and neuropathic symptom change [68]. These findings are in keeping with the previous intravenous dose-finding study, ALLADIN (Alpha Lipoic Acid in Diabetic Neuropathy) [69]. In contrast, the ALLADIN III study, a large multicenter randomized controlled trial in which daily intravenous ALA was administered for 3 weeks followed by 6 months of oral treatment, had no effect on neuropathic symptoms (TSS) assessed at 7 months. The authors have suggested that failure to show benefit may have been due to intercenter variability in symptom scoring and may have thus challenged the use of neuropathic symptoms as primary criteria for assessing drug efficacy. This is surprising in view of the reliance of sensory symptoms in the previous short-term intravenous studies. An alternative explanation is that as far as pain is concerned ALA is only effective in the short term. However, the study did demonstrate marginal benefit in progression to clinically detectable neurologic deficits assessed by clinical examination (neuropathy impairment score) at 7 months [70]. Therefore, the acute and long-term effects may be different. A 4-year multicenter trial, NATHAN (Neurological Assessment of Thioctic Acid in Neuropathy), aimed at slowing the progression of diabetic polyneuropathy, is currently underway.

Protein kinase C inhibition Elevated protein kinase C (PKC) activity is thought to play a substantial role in the etiology of diabetic microvascular complications, the PKC isoform being identified as particularly important. Neuropathy has a microvascular component, and in animal models PKC b inhibition using the compound LY333531 completely corrected the microvascular and neurophysiologic defects seen in the nerves of diabetic animals. In these studies, reduced sciatic nerve blood flow and impaired nerve conduction velocities were returned to nondiabetic values [71]. These animal studies have been followed by a placebocontrolled dose-finding clinical trial of LY333531 in 205 patients with symptomatic diabetic peripheral neuropathy. In this study the positive symptoms of numbness, allodynia, prickling, and pain (eg, aching, burning, and lancinating) were assessed individually and also as a TSS, using the neuropathy total symptom score-6 questionnaire (NTSS-6). Significant improvements in the NTSS-6 were seen at both doses of LY333531 used, 32 and 64 mg [72]. A large phase III multicenter clinical trial is currently underway to establish the value of this compound in patients with chronic painful diabetic peripheral neuropathy. Dextromethorphan Dextromethorphan acts as an antagonist to the NMDA receptor. The stimulation of NMDA receptors can result in

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the stimulation of the second-order neurons in the spinal cord leading to an influx of calcium. Two studies have analyzed the effectiveness of dextromethorphan in diabetic painful neuropathy and postherpetic neuralgia [73,74]. Both studies showed the dextromethorphan reduced the pain intensity in diabetic painful neuropathy but not in postherpetic neuralgia. The common adverse events were sedation and ataxia. At present there are insufficient safety and efficacy data. Further clinical trials are needed.

Nonpharmacologic treatments
Acupuncture There have been no placebo-controlled studies of acupuncture. However, an uncontrolled 10-week study of traditional Chinese acupuncture in 46 patients with painful diabetic neuropathy found that 77% of patients obtained pain relief, and during follow-up of between 18 to 52 weeks 67% were able to reduce or stop their previous medications [79]. Transcutaneous electrical nerve stimulation The putative mechanism involved in pain relief with transcutaneous electrical nerve stimulation is unclear. In a comparison of transcutaneous electrical nerve stimulation (n = 18) with a sham-treated group (n = 13), symptomatic relief was experienced in 83% of the former group compared with only 38% of the sham-treated patients [80]. In another study by the same group, amitriptyline produced symptomatic relief in 15 (60%) of 26 patients by the fourth week of treatment, with an overall reduction in pain scores of 26% on a Visual Analogue Scale. When combined with sham treatment the overall reduction in pain was 55%, suggesting a procedurerelated placebo effect (n = 9). In contrast, in those receiving transcutaneous electrotherapy symptomatic improvement occurred in 85% of patients (n = 14) with a reduction in pain score of 66%. This was significantly better than the degree of pain reduction with sham treatment (P < 0.03) [81]. Electrical spinal cord stimulation Electrical spinal cord stimulation has been used to treat several chronic painful conditions, including back pain, phantom limb pain, peripheral vascular disease, and severe angina [82]. The proposed mechanism through which electrical spinal cord stimulation is thought to work is by stimulation of the dorsal columns (ie, A- fibers), thus inhibiting C-fiber transmission as in accordance with the gating theory of Melzack and Wall [83]. There has been a single uncontrolled study in only 10 patients with chronic painful diabetic neuropathy [84]. Eight patients who appeared to receive benefit during the initial trial of stimulation were converted to a more permanent implant. There was considerable benefit in both background pain and peak pain, with an improvement in exercise tolerance. This invasive treatment should be reserved for those with disabling intractable pain unresponsive to other forms of treatment.

Opioid analgesics Opioid analgesics or narcotic analgesics, such as codeine, tramadol, and oxycodone, reduce pain perception by acting in the central nervous system (eg, thalamus, midbrain, and medulla), spinal cord, and nociceptive nerve endings. The major side effects of opioid analgesics include nausea, vomiting, constipation, sedation, and physical dependency [75].
Tramadol Tramadol produces analgesia by two mechanisms: 1) opioid effect, and 2) enhancement of serotonergic and adrenergic pathways. It has fewer of the typical opioid side effects. A multicenter, outpatient, randomized, double-blind, placebo-controlled, parallel-group study involving 131 patients with diabetic painful neuropathy assessed the mean pain intensity at 42 days and quality of life based on daily activities and sleep patterns [76]. The results of this trial showed that tramadol, at an average dosage of 210 mg/d, was more effective than placebo for treating the pain of diabetic neuropathy. No important sedative effects were identified. Another study looked at the long-term effectiveness of tramadol in 117 patients for a 6-month period [77]. This study was an open extension of a 6-week randomized controlled trial and showed that the majority of the subjects continued to have lower mean pain relief scores at the end of the study period. Four patients discontinued therapy due to ineffective pain relief. The most common adverse events were constipation, nausea, and headache, and 13 patients discontinued due to adverse events. Oxycodone A recent multicenter, randomized, double-blind, placebocontrolled, parallel-group study looked at the efficacy and safety of controlled-release oxycodone in 82 subjects with moderate to severe pain due to diabetic neuropathy. The results of this 6-week trial showed that at an average dose of 37 mg/d (range 10 to 99 mg/d), controlled-release oxycodone provided more analgesia than placebo. Overall, 96% of subjects treated with oxycodone reported side effects as compared to 68% in the placebo group. The common adverse events reported were constipation, somnolence, and nausea [78]. Thus, opioid analgesics seem to be effective in alleviating moderate to severe pain due to diabetic painful neuropathy. However, more evidence is needed on long-term safety and concerns of physical dependency.

Conclusions
Chronic painful diabetic neuropathy is common and its treatment remains an enormous challenge to the physician. Until fairly recently there have been few well-designed placebo-controlled studies to help guide the physician as to the most effective therapies. Most studies have been of short duration, have included only small numbers of patients, and have not always had clearly defined outcome measures. Despite a great variety of therapies ranging from analgesics to those aimed at correcting possible pathologic mech-

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anisms, it is not possible to predict which therapy will be of benefit to an individual patient. The relatively high side-effect profiles of current pharmacologic therapies remain a major drawback to their use. Monotherapy only benefits between 30% to 50% of patients at best. Thus, combination therapy would seem a logical approach, in particular combinations aimed at the proposed pathologic mechanisms and also combinations that target different parts of the pain pathway. Unfortunately, at present there are no data on the use of combination therapy; however, such studies should be encouraged. Promise may come from some of the previously mentioned ongoing trials of newer therapies aimed specifically at the putative pathologic mechanisms, such as the trials of PKC inhibitor and antioxidants.

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