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Diabetes Care 31:S255-S261, 2008
DOI: 10.2337/dc08-s263
© 2008 by the American Diabetes Association
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Section II: Diabetes Complications and Hypertension-Novel Insights into Pathophysiology and Management
Original Article

Treatment of Diabetic Neuropathy and Neuropathic Pain

How far have we come?

Dan Ziegler, MD, FRCPE

From the Institute for Clinical Diabetes Research, German Diabetes Center, Leibniz Institute at the Heinrich Heine University, Düsseldorf, Germany

Address correspondence and reprint requests to Prof. Dan Ziegler, FRCPE, Institut für Klinische Diabetologie, Deutsches Diabetes-Zentrum, Leibniz-Zentrum an der Heinrich-Heine-Universität Düsseldorf, Auf’m Hennekamp 65, 40225 Düsseldorf, Germany. E-mail: dan.ziegler{at}ddz.uni-duesseldorf.de


   ABSTRACT
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CLINICAL IMPACT AND EPIDEMIOLOGY...
 DISTAL SYMMETRIC POLYNEUROPATHY-...
 PATHOGENETIC MECHANISMS--
 TREATMENT--
 CONCLUSIONS--
 References
 
At least one of four diabetic patients is affected by distal symmetric polyneuropathy, which represents a major health problem, since it may present with partly excruciating neuropathic pain and is responsible for substantial morbidity, increased mortality, and impaired quality of life. Treatment is based on four cornerstones: 1) causal treatment aimed at (near)-normoglycemia, 2) treatment based on pathogenetic mechanisms, 3) symptomatic treatment, and 4) avoidance of risk factors and complications. Recent experimental studies suggest a multifactorial pathogenesis of diabetic neuropathy. From the clinical point of view, it is important to note that, based on these pathogenetic mechanisms, therapeutic approaches could be derived, some of which are currently being evaluated in clinical trials. Among these agents, only {alpha}-lipoic acid is available for treatment in several countries and epalrestat in Japan. Although several novel analgesic drugs such as duloxetine and pregabalin have recently been introduced into clinical practice, the pharmacologic treatment of chronic painful diabetic neuropathy remains a challenge for the physician. Individual tolerability remains a major aspect in any treatment decision. Epidemiological data indicate that not only increased alcohol consumption but also the traditional cardiovascular risk factors such as hypertension, smoking, and cholesterol play a role in development and progression of diabetic neuropathy and hence need to be prevented or treated.

Abbreviations: DSP, distal sensorimotor polyneuropathy • NNT, number needed to treat


   CLINICAL IMPACT AND EPIDEMIOLOGY—
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Diabetic neuropathy has been defined as a demonstrable disorder, either clinically evident or subclinical, that occurs in the setting of diabetes without other causes for peripheral neuropathy. It includes manifestations in the somatic and/or autonomic parts of the peripheral nervous system (1), which are being classified along clinical criteria. However, because of the variety of the clinical syndromes with possible overlaps, there is no universally accepted classification. The most widely used classification differentiates between rapidly reversible persistent symmetric polyneuropathies and focal or multifocal neuropathies (2). The distal symmetric sensory or distal sensorimotor polyneuropathy (DSP) represents the most relevant clinical manifestation, affecting ~30% of the hospital-based population and ~25% of community-based samples of diabetic patients (3). The incidence of DSP is ~2% per year. The most important etiological factors that have been associated with DSP are poor glycemic control, diabetes duration, visceral obesity and height, with possible roles for hypertension, age, smoking, hypoinsulinemia, and dyslipidemia (3). There is accumulating evidence suggesting that not only surrogate markers of microangiopathy, such as albuminuria, but also those used for polyneuropathy, such as nerve conduction velocity and vibration perception threshold, may predict mortality in diabetic patients (4,5). Elevated vibration perception threshold also predicts the development of neuropathic foot ulceration, one of the most common causes for hospital admission and lower-limb amputations among diabetic patients (6). Pain is a subjective symptom of major clinical importance, since it is often this complaint that motivates patients to seek health care. Chronic neuropathic pain is present in 16–26% of diabetic patients (7). Pain associated with diabetic neuropathy exerts a substantial impact on the quality of life, particularly by causing considerable interference in sleep and enjoyment of life (8). Despite this significant impact, 25 and 39% of the diabetic patients, respectively, had no treatment for their pain in two surveys (7,9).


   DISTAL SYMMETRIC POLYNEUROPATHY—
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The term "hyperglycemic neuropathy" has been used to describe sensory symptoms in poorly controlled diabetic patients that are rapidly reversible after institution of near-normoglycemia (2). The most frequent form is the distal symmetric sensory, or DSP, commonly associated with autonomic involvement. The onset is insidious, and, in the absence of intervention, the course is chronic and progressive. It seems that the longer axons to the lower limbs are more vulnerable toward the nerve lesions induced by diabetes (length-related distribution). This notion is supported by the correlation found between the presence of DSP and height. DSP typically develops as a dying-back neuropathy, affecting the most distal extremities (toes) first. The neuropathic process then extends proximally up the limbs, and later it may also affect the anterior abdominal wall and then spread laterally around the trunk. Occasionally, the upper limbs are involved, with the fingertips being affected first (glove-and-stocking distribution). Variants including painful small-fiber or pseudosyringomyelic syndromes and an atactic syndrome (diabetic pseudotabes) have been described. Small-fiber unmyelinated (C) fibers and thinly myelinated (A{delta}) fibers as well as large-fiber myelinated (A{alpha}, Aβ) neurons are typically involved. However, it is as yet uncertain whether the various fiber type damage develops after a regular sequence, with small fibers being affected first, followed by larger fibers, or whether the small-fiber or large-fiber involvement reflects either side of a continuous spectrum of fiber damage. However, there is evidence suggesting that small fiber neuropathy may occur early, often presenting with pain and hyperalgesia before sensory deficits or nerve conduction slowing can be detected (2). The reduction or loss of small fiber–mediated sensation results in loss of pain sensation (heat pain, pin-prick) and temperature perception to cold (A{delta}) and warm (C) stimuli. Large fiber involvement leads to nerve conduction slowing and reduction or loss of touch, pressure, two-point discrimination, and vibration sensation, which may lead to sensory ataxia (atactic gait) in severe cases. Sensory fiber involvement causes "positive" sensory symptoms such as paresthesia, dysesthesia, and pain as well as "negative" symptoms such as reduced sensation.

Persistent or episodic pain that typically may worsen at night and improve during walking is localized predominantly in the feet. The pain is often described as a deep-seated aching, but there may be superimposed lancinating stabs or it may have a burning thermal quality. Evoked pain such as allodynia (pain due to a stimulus that does not normally cause pain, e.g., stroking) and hyperalgesia (severe pain due to a stimulus that normally causes slight pain, e.g., pin-prick) may be present. The symptoms may be accompanied by sensory loss, but patients with severe pain may have few clinical signs. Pain may persist over several years, causing considerable disability and impaired quality of life in some patients, whereas it remits partially or completely in others, despite further deterioration in small fiber function. Pain remission tends to be associated with sudden metabolic change, short duration of pain or diabetes, preceding weight loss, and less severe sensory loss (10).

Compared with the sensory deficits, motor involvement is usually less prominent and restricted to the distal lower limbs, resulting in muscle atrophy and weakness at the toes and foot. Ankle reflexes are frequently reduced or absent. At the foot level, the loss of the protective sensation (painless feet), motor dysfunction, and reduced sweat production resulting in dry and chapped skin due to autonomic involvement increase the risk of callus and foot ulcers. Thus, the neuropathic patient is a high-risk patient to develop severe and potentially life-threatening foot complications such as ulceration, osteoarthropathy (Charcot foot), and osteomyelitis as well as medial arterial calcification and neuropathic edema. Because DSP is the major contributory factor for diabetic foot ulcers and the lower-limb amputation rates in diabetic subjects are 15 times higher than in the nondiabetic population, an early detection of DSP by screening is of paramount importance (11). This is even more imperative because many patients with DSP are asymptomatic or have only mild symptoms. In view of these causation pathways, the majority of amputations should be potentially preventable if appropriate screening and preventative measures were adopted.


   PATHOGENETIC MECHANISMS—
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Recently performed experimental studies suggest a multifactorial pathogenesis of diabetic neuropathy. Most data have been generated in the diabetic rat model. Two approaches have contributed to elucidate the pathogenesis of diabetic neuropathy. The first is a better characterization of the pathophysiological, pathobiochemical, and structural abnormalities that result in experimental diabetic neuropathy. The second approach is the performance of specific therapeutic interventions aimed to prevent the development of these alterations, to halt their progression, or to induce their regression despite concomitant hyperglycemia. At present, several mechanisms are thought to contribute to the pathogenesis. In contrast to previous years, however, they are no longer regarded as being separate, but as resulting in a complex interplay giving rise to multiple interactions, e.g., between metabolic and vascular factors (12):

  • Increased flux through the polyol pathway that leads to accumulation of sorbitol and fructose, myo-inositol depletion, and reduction in Na+-K+-ATPase activity.
  • Disturbances in n-6 essential fatty acid and prostaglandin metabolism that results in alterations of nerve membrane structure and microvascular and hemorrheologic abnormalities.
  • Endoneurial microvascular deficits with subsequent ischemia and hypoxia induced by generation of reactive oxygen species (oxidative stress), activation of the redox-sensitive transcription factor nuclear factor-{kappa}B, and increased activity of the diacylglycerol (DAG)-protein kinase C β (PKCβ) signal transduction pathway.
  • Deficits in neurotrophism leading to reduced expression and depletion of neurotrophic factors such as nerve growth factor, neurotrophin-3, and insulin-like growth factor as well as alterations in axonal transport.
  • Accumulation of nonenzymatic advanced glycation end products on nerve and/or vessel proteins.
  • Immunological processes with autoantibodies to vagal nerve, sympathetic ganglia, and adrenal medulla as well as inflammatory changes.


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Role of intensive diabetes therapy in treatment and prevention of diabetic neuropathy
Seven long-term prospective studies that assess the effects intensive diabetes therapy have on the prevention and progression of chronic diabetic complications have been published (13). In type 1 diabetic patients, these studies show that intensive diabetes therapy retards but not completely prevents the development of polyneuropathy and autonomic neuropathy. In the Epidemiology of Diabetes Interventions and Complications study, the benefits of 6.5 years of intensive therapy on neuropathy status extended for at least 8 years beyond the end of the Diabetes Control and Complications Trial despite equal A1C levels, similar to the findings described for diabetic retinopathy and nephropathy (14). In contrast, in type 2 diabetic patients, who represent the vast majority of people with diabetes, the results were variable. Intensive diabetes therapy either had no effect or only partially slowed the progression of polyneuropathy. Although observational studies suggested a glycemic threshold for the development and progression of the long-term complications in type 1 diabetes, the Diabetes Control and Complications Trial data do not support such an assumption. Thus, attempts to achieve optimal glycemic control should not aim at a certain A1C threshold within the diabetic range but follow "the goal of achieving normal glycemia as early as possible in as many type 1 diabetic patients as is safely possible" (15). In general, intensive diabetes therapy is associated with a moderately increased risk of weight gain and hypoglycemia.

Treatment based on pathogenetic concepts
Recent experimental studies suggest a multifactorial pathogenesis of diabetic neuropathy. From the clinical point of view, it is important to note that, based on the various pathogenetic mechanisms, therapeutic approaches could be derived, some of which have been evaluated in randomized clinical trials (Table 1). These drugs have been designed to favorably influence the underlying neuropathic process rather than for symptomatic pain treatment. For clinical use, {alpha}-lipoic acid is licensed and used for treatment of symptomatic DSP in several countries worldwide, whereas epalrestat is marketed in Japan. According to a recent meta-analysis comprising 1,258 patients, infusions of {alpha}-lipoic acid (600 mg i.v./day) ameliorated neuropathic symptoms and deficits after 3 weeks, whereas the Alpha-Lipoic Acid in Diabetic Nephropathy (ALADIN) III Study showed oral treatment with 600 mg t.i.d. resulted in a favorable effect on neuropathic deficits after 6 months (16,17). Moreover, the SYDNEY 2 Trial suggests that treatment for 5 weeks using 600 mg {alpha}-lipoic acid orally q.d. reduces the chief symptoms of diabetic polyneuropathy, including pain, paresthesias, and numbness to a clinically meaningful degree (18). Clinical and postmarketing surveillance studies have revealed a highly favorable safety profile of this drug. A phase III trial of the protein kinase C β inhibitor ruboxistaurin has disappointed after encouraging data from phase II studies were reported (19). The aldose reductase inhibitor ranirestat (20), C-peptide (21), and other compounds seem promising (22). Because in the foreseeable future normoglycemia will not be achievable in the majority of diabetic patients, the advantage of the aforementioned treatment approaches is that they may exert their effects despite prevailing hyperglycemia. Experimental studies of low-dose combined drug treatment suggest enhanced drug efficacy mediated by facilitatory interactions between drugs. In the future, combinations of drugs that produce synergistic effects could be a therapeutic option.


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  		Table 1— Treatment of diabetic neuropathy based on the putative pathogenetic mechanisms

 
Symptomatic treatment of painful neuropathy
Pain associated with diabetic neuropathy exerts a substantial impact on the quality of life, particularly by causing considerable interference in sleep and enjoyment of life. Pain is a subjective symptom of major clinical importance, since it is often this complaint that motivates patients to seek health care. Painful symptoms in diabetic polyneuropathy may constitute a considerable management problem. The efficacy of a single therapeutic agent is not the rule, and simple analgesics are usually inadequate to control the pain. Therefore, various therapeutic schemes have been previously proposed, but none of them has been validated. Nonetheless, there is agreement that patients should be offered the available therapies in a stepwise fashion. Effective pain treatment considers a favorable balance between pain relief and side effects without implying a maximum effect. The possible treatments are summarized in Table 2. Before any decision regarding the appropriate treatment option, the diagnosis of the underlying neuropathic manifestation allowing estimating its natural history should be established. In contrast to the agents that have been derived from the pathogenetic mechanisms of diabetic neuropathy, those used for symptomatic therapy were designed to modulate the pain, without favorably influencing the underlying neuropathy (23).


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  		Table 2— Treatment options for painful diabetic neuropathy

 
The relative benefit of an active treatment over a control in clinical trials is usually expressed as the relative risk, the relative risk reduction, or the odds ratio. However, to estimate the extent of a therapeutic effect (i.e., pain relief) that can be translated into clinical practice, it is useful to apply a simple measure that serves the physician to select the appropriate treatment for the individual patient. Such a practical measure is the number needed to treat (NNT), i.e., the number of patients that need to be treated with a particular therapy to observe a clinically relevant effect or adverse event in one patient. This measure is expressed as the reciprocal of the absolute risk reduction, i.e., the difference between the proportion of events in the control group (Pc) and the proportion of events in the intervention group (Pi): NNT = 1/(Pc – Pi). The 95% CI of NNT can be obtained from the reciprocal value of the 95% CI for the absolute risk reduction. The NNT and NNH (number needed to harm) for the individual agents used in the treatment of painful diabetic neuropathy are given in Table 2. The pros and cons for the different drugs currently being used are summarized in Table 3.


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  		Table 3— Differential treatment of painful diabetic neuropathy

 
Antidepressants.
Recently, the rate of publications of controlled clinical trials demonstrating significant pain relief with several drugs has accelerated. Nevertheless, the symptomatic pharmacological treatment of chronic painful diabetic neuropathy remains a challenge. A survey of physicians experienced in treating neuropathic pain demonstrated that only a minority would rate results of analgesic treatment as excellent or good using antidepressants (40%), anticonvulsants (35%), opioids (30%), or simple analgesics (18%) (24). For >30 years, psychotropic agents, among which antidepressants have been evaluated most extensively, have constituted an important component in the treatment of chronic pain syndromes. Several authors consider the tricyclic antidepressants to be the drug treatment of choice for neuropathic pain (25–27). However, their use is limited by relative high rates of adverse events and several contraindications. Thus, there is a need for agents that exert efficacy equal to or better than that achieved with tricyclic antidepressants but have a more favorable side effect profile. Because selective serotonin reuptake inhibitors have been found to be less effective than tricyclic antidepressants (25), recent interest has focused on antidepressants with dual selective inhibition of serotonin and norepinephrine such as duloxetine and venlafaxine. The efficacy and safety of duloxetine was evaluated in three controlled studies using a dose of 60 and 120 mg/day over 12 weeks (28–30). In all three studies, the average 24-h pain intensity was significantly reduced with both doses compared with placebo treatment, with the difference between active and placebo being achieving statistical significance after 1 week. The response rates defined as ≥50% pain reduction were 48.2% (120 mg/day), 47.2% (60 mg/day), and 27.9% (placebo), giving an NNT of 4.9 (95% CI 3.6–7.6) for 120 mg/day and 5.3 (3.8–8.3) for 60 mg/day. Initial pain intensity but not metabolic variables such as glycemic control or duration of diabetes were predictors of response (31). The most frequent side effects of duloxetine (60/120 mg/day) include nausea (16.7/27.4%), somnolence (20.2/28.3%), dizziness (9.6/23%), constipation 14.9/10.6%), dry mouth (7.1/15%), and reduced appetite (2.6/12.4%). These adverse events are usually mild to moderate and transient. To minimize them, the starting dose should be 30 mg/day for 4–5 days. In contrast to tricyclic antidepressants and some anticonvulsants, duloxetine does not cause weight gain.

Calcium-channel modulators
Gabapentin is an anticonvulsant structurally related to {gamma}-aminobutyric acid, a neurotransmitter that plays a role in pain transmission and modulation. The exact mechanisms of action of this drug in neuropathic pain are not fully elucidated. Among others, they involve an interaction with the system L-amino acid transporter and high affinity binding to the {alpha}2-{delta} subunit of voltage-activated calcium channels. In an 8-week multicenter dose-escalation trial including 165 diabetic patients with painful neuropathy, 60% of the patients on gabapentin (3,600 mg/day achieved in 67%) had at least moderate pain relief compared with 33% on placebo. Dizziness and somnolence were the most frequent adverse events in ~23% of the patients (32). Pregabalin is a more specific {alpha}2-{delta} ligand with a sixfold higher binding affinity than gabapentin. The efficacy and safety of pregabalin was reported in a pooled analysis of seven studies over 5–11 weeks in 1,510 diabetic patients with painful neuropathy. The response rates defined as ≥50% pain reduction were 47% (600 mg/day), 39% (300 mg/day), 27% (150 mg/day), and 22% (placebo), giving an NNT of 4.2, 5.9, and 20 (33). The most frequent side effects for 150–600 mg/day are dizziness (22.7%), somnolence (12.1%), peripheral edema (12.4%), headache (6.6%), and weight gain (6.6%). The evidence supporting a favorable effect in painful diabetic neuropathy is more solid, and dose titration is considerably easier for pregabalin than gabapentin.

Sodium-channel blockers
Sodium-channel blockers such as carbamazepine cannot be recommended because of inadequate evidence in painful diabetic neuropathy. The successor drug oxcarbazepine has been withdrawn from clinical trials (34). Other anticonvulsants such as topiramate (35) and lamotrigine (36) have also disappointed, while lacosamide is being evaluated in phase III trials.

Opioids.
The weak opioid tramadol is effective in painful DSP, but most severe pain requires administration of strong opioids such as oxycodone. Although there is little data available on combination treatment, combinations of different substance classes have to be used in patients with pain resistant to monotherapy. Two trials over 4 and 6 weeks have demonstrated significant pain relief and improvement in quality of life after treatment with controlled-release oxycodone, a pure µ-agonist, in a dose range of 10–100 mg (mean 40 mg/day) in patients with painful diabetic neuropathy whose pain was not adequately controlled on standard treatment with antidepressants and anticonvulsants, which were not discontinued throughout the trial (37,38). As expected, adverse events were frequent and typical of opioid-related side effects. A recent study examined the maximum tolerable dose of a combination treatment of gabapentin and morphine compared with monotherapy of each drug. The maximum tolerable dose was significantly lower and efficacy was better during combination therapy than with monotherapy, suggesting an additive interaction between the two drugs (39). The results of these studies suggest that opioids should be included among the therapeutic options for painful diabetic neuropathy, provided that careful selection of patients unresponsive to standard treatments, regular monitoring, appropriate dose titration, and management of side effects are ensured. Combination therapy using antidepressants and anticonvulsants may also be useful, particularly if monotherapy is not tolerated because of side effects.

Nonpharmacological treatment.
Because there is no entirely satisfactory pharmacotherapy of painful diabetic neuropathy, nonpharmacological treatment options such as psychological support, transcutaneous electrical nerve stimulation, or physical measures (e.g., cold water immersion) have been tried. As for the pharmacological treatment, considerable efforts must also be made to develop effective nonpharmacological approaches. We recently showed a better effect of high-frequency muscle stimulation than transcutaneous electrical nerve stimulation on neuropathic symptoms after 3 days (40). A frequency-modulated electromagnetic nerve stimulation applied during 10 sessions over 3 weeks resulted in a significant pain reduction compared with placebo stimulation (41). Monochromatic infrared energy has been shown to reduce neuropathic symptoms and signs in diabetic patients in uncontrolled studies (42). However, 30 min of active monochromatic infrared energy applied 3 days per week for 4 weeks was no more effective than placebo in increasing sensation in subjects with diabetic peripheral neuropathy (43), emphasizing the need for controlled studies in this area to allow an evidence-based treatment decision.


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Although considerable improvement in the quality of controlled trials has recently been achieved, no major breakthrough in slowing the progression of diabetic neuropathy in the long run has been achieved with drugs used on the basis of present pathogenetic concepts. Some of the newer drugs have shown promising results in phase II trials that require confirmation from large phase III trials. It is conceivable that drugs interfering with the pathogenesis of diabetic neuropathy may be most effective in terms of prevention rather than intervention. Although several novel analgesic drugs have recently been introduced into clinical practice, the pharmacologic treatment of chronic painful diabetic neuropathy remains a challenge for the physician. Individual tolerability remains a major aspect in any treatment decision. Almost no information is available from controlled trials on long-term analgesic efficacy, and only a few studies have used drug combinations. Combination drug use or the addition of a new drug to a therapeutic regimen may lead to increased efficacy. In the future, drug combinations may also include those aimed at symptomatic pain relief and quality of life on the one hand and improvement or slowing of the progression of the underlying neuropathic process on the other hand.


   Footnotes
 
D.Z. has received honoraria, consulting fees, and research grants from Meda Pharma, Eli Lilly, Pfizer, Schwarz-Pharma, and Eisai.

This article is based on a presentation at the 1st World Congress of Controversies in Diabetes, Obesity and Hypertension (CODHy). The Congress and the publication of this article were made possible by unrestricted educational grants from MSD, Roche, sanofi-aventis, Novo Nordisk, Medtronic, LifeScan, World Wide, Eli Lilly, Keryx, Abbott, Novartis, Pfizer, Generx Biotechnology, Schering, and Johnson & Johnson.


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