Management of Diabetic Peripheral Neuropathy
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《临床糖尿病学》
Abstract
IN BRIEF
Diabetic peripheral neuropathy affects up to 50% of older type 2 diabetic patients. Whereas some patients may have extremely painful symptoms, others with a more marked neuropathic deficit may be asymptomatic. Diagnosis requires careful examination of the lower limbs. Management involves establishing that the neuropathy is caused by diabetes instead of more sinister causes and aiming for optimal glycemic control. Medications, usually tricyclic drugs or anticonvulsant agents, may be required. Patients with peripheral neuropathy must be considered at risk of insensate foot ulceration and must receive preventive education and podiatric care.
Introduction
Neuropathies are among the most common of all the long-term complications of diabetes, affecting up to 50% of patients.1-5 There are many subgroups of neuropathies; readers are referred to recent reviews for discussion of the autonomic neuropathies6 and the mononeuropathies.7 This article will focus on the most common of all the peripheral neuropathies: the somatic neuropathies affecting the lower extremities. Detailed discussions of all aspects of these neuropathies were recently published as a technical review5 and will be included in a forthcoming American Diabetes Association statement.
In the past, a lack of awareness and inappropriate management of diabetic peripheral neuropathy (DPN) has led to much unnecessary morbidity and substantial health care costs. At least half of all foot ulcers, the end stage of such neuropathy, should be preventable by appropriate management and patient education. However, lack of time and inappropriate or inadequate information may lead to suboptimal care.
Diabetic somatic neuropathies do represent a paradox: at one extreme there are patients with severe neuropathic pain who on examination may have only a minimal deficit, whereas at the other extreme are patients with insensate feet who are asymptomatic and may first present with foot ulcers.
This review will provide an overview of DPN and a detailed guide to the management of pain in patients with significant symptomatology.
DEFINITIONS
Members of an International Consensus Meeting on the outpatient diagnosis and management DPN agreed on a simple definition of diabetic neuropathy as "the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes."8 This group also agreed that neuropathy cannot be diagnosed without a careful clinical examination and that absence of symptoms must never be equated with absence of neuropathy. The importance of excluding nondiabetic causes was emphasized in the Rochester Diabetic Neuropathy Study, in which up to 10% of peripheral neuropathy in diabetes was deemed to be of nondiabetic causation.1
For day-to-day clinical practice, DPN is a clinical diagnosis. It is generally agreed that DPN should not be diagnosed on the basis of one symptom, sign, or test alone; a minimum of two abnormalities (i.e., abnormal symptoms and signs) is recommended.5
EPIDEMIOLOGY
DPN is by far the most common of all the diabetic neuropathies and may be divided into the following two main types: acute sensory neuropathy and chronic sensorimotor neuropathy. Acute sensory neuropathy is a distinct variety of the symmetrical polyneuropathies with an acute or subacute onset characterized by severe sensory symptoms, usually with few if any clinical signs. It is usually precipitated by an episode of glycemic instability (such as ketoacidosis or even after the institution of insulin), and its natural history is one of gradual improvement of symptoms with establishment of stable glycemic control and appropriate symptomatic treatments.
Chronic sensorimotor neuropathy is by far the most common form of DPN. It is usually of insidious onset and may be present at the diagnosis of type 2 diabetes in up to 10% of patients. Whereas up to 50% of patients with chronic DPN may be asymptomatic, 10-20% may experience troublesome symptoms sufficient to warrant specific therapy. Sensorimotor neuropathy is often accompanied by autonomic dysfunction. Its late sequelae, which include foot ulceration, Charcot neuroarthropathy, and occasionally amputation, should in many cases be preventable. The prevalence of chronic DPN increases with both age and duration of diabetes, and this diagnosis is more common in those whose glycemic control has been suboptimal in previous years.
CLINICAL FEATURES OF DPN
Acute Sensory Neuropathy
Many of the symptoms of acute sensory and chronic sensorimotor neuropathy are similar, although there are clear differences in the mode of onset, accompanying signs, and prognosis. These are summarized in Table 1. Table 2 offers a list of typical symptoms, both painful and nonpainful. All painful neuropathic symptoms tend to be prone to nocturnal exacerbation. Clinical examination of patients with presumed acute sensory neuropathy may be relatively normal, with allodynia (a painful sensation induced by nonnoxious stimulus) on sensory testing, a relatively normal motor exam, and occasionally reduced ankle reflexes.
In the management of this condition, achieving stable blood glucose control is most important. Stability may well be the key feature, because blood glucose flux (as assessed, for example, by the M value, a measure of glycemic excursions from the mean) is associated with pain.9
Additionally, however, most patients will require medication after neuropathic pain, and these medications are discussed in detail below in the section on management of chronic DPN. Suffice it to say that the approach is similar, although the dosage and number of medications required may be higher, in acute sensory neuropathy. The natural history of this acute neuropathy is very different from the much more common chronic DPN; its onset is acute or subacute, but the severe symptoms typically resolve in < 12 months.10,11
Chronic Sensorimotor Neuropathy
Painful neuropathy can be one of the most distressing and debilitating of all the complications of diabetes. The rest of this review will discuss the approach to patients presenting with chronic DPN and will focus on available treatments with brief comment on those that may soon be available.
As noted above, many patients are asymptomatic, and the neurological deficit may be discovered by chance during a routine neurological exam. Because chronic DPN is a length-dependent process, the sensory manifestations are most pronounced in the lower limbs, although, in more severe cases, the fingers and hands may also be involved. The symptoms, outlined in Table 2, tend to be peculiar to the individual patient but constant during the history of neuropathy in that individual. Patients often find it very difficult to describe the symptoms because they are different from other types of pain the patients have previously experienced. Although not mentioned in older texts, unsteadiness is increasingly being recognized as a manifestation of chronic DPN resulting from disturbed propriaception and probably abnormal muscle sensory function. Many patients will have a combination of both positive (painful) and negative (nonpainful) symptoms.
Clinical examination of patients with chronic DPN usually reveals a symmetrical sensory loss to all modalities in a stocking distribution. This may well extend into the mid-calf level and may also affect the upper limbs in more severe cases. Ankle reflexes are usually reduced or absent, and knee reflexes may also be reduced in some cases.
In the clinical assessment of patients, a number of simple symptom/screening questionnaires are available to record symptom quality and severity. Among these is the Michigan Neuropathy Screening Instrument, which is a brief 15-item questionnaire.12 It is also increasingly recognized that both symptoms and deficits may have an adverse effect on quality of life in diabetic neuropathy,13 and specific questionnaires have been developed for the assessment of the impact of neuropathy on quality of life. Similarly, composite scores have been used to assess clinical signs, and one that is increasingly used is a modified Neuropathy Disability Score (NDS).14 The NDS, shown in Figure 1, can be easily performed in the clinic setting and takes only a minute or two to complete. The maximum deficit score is 10, which would indicate complete loss of sensation to all sensory modalities and absent reflexes. In a longitudinal European community-based study, an NDS of 6 was equated with an increased risk of insensate foot ulceration.14
A number of simple devices may be used for clinical screening; the most widely used is the Semmes-Weinstein monofilament.15 This filament assesses pressure perception when gentle pressure is applied sufficient to buckle the nylon filament. A number of cross-sectional and longitudinal studies have assessed the sensitivity of the 10-g monofilament and have shown it to be a useful tool to identify patients at risk of foot ulceration.5,15 Of the simple quantitative sensory testing instruments that are used in clinical practice, the most common is the bioesthesiometer (Biomedical Instruments, Newbury, Ohio). This assesses in a semiquantitative manner the perception of vibration and has similarly been shown to be a useful predictor of foot ulcer risk.16
MANAGEMENT
Is It DPN
The management approach to patients considered to have DPN is provided in Table 3. First, it must be remembered that there are numerous causes of peripheral neuropathy, of which diabetes is probably the most common. However, exclusion of other causes, particularly malignant disease and toxic causes, is of paramount importance. Exclusion of such potentially serious conditions as malignant disease (e.g., small-cell carcinoma presenting as a paraneoplastic syndrome), toxic causes (e.g., alcohol), and infections (diseases such as HIV) is essential.
In most cases, further investigation, such as detailed quantitative sensory testing in electrophysiology, which would require referral to a neurologist, is not essential. Abnormal electrophysiology simply confirms the presence of a neuropathy but does not indicate the underlying cause.
Initial Therapy and Counseling
Once a diagnosis is established, giving patients a full explanation of their condition, allaying their fears and misconceptions, and informing them that the pain may resolve in time can be extremely reassuring. Simple physical treatments, such as the use of a bed cradle to lift the bed clothes off of hyperaesthetic skin, can be beneficial. Advice on suitable footwear may also be provided. In patients with relatively mild pain, simple analgesics or anti-inflammatory agents may be sufficient to treat the discomfort.
Metabolic Control
The most effective method of achieving stable normoglycemia is pancreas or islet cell transplantation. However, this is not practical in most cases because it is mainly available to patients with end-stage diabetic nephropathy who have combined pancreas and renal transplants or in special cases of young people with type 1 diabetes.
Although there have been no randomized, controlled trials of intensive insulin therapy in the management of diabetic neuropathy, data from a number of observational studies suggest that stable glycemic control is of the greatest import. A recent study using continuous glucose monitoring confirmed that painful symptoms were associated with erratic blood glucose control.9 Having said this, there is no evidence that patients whose diabetes has been well controlled on oral hypoglycemic agents will benefit in terms of pain relief by transferring to insulin.
Pharmacological Management
A large number of therapeutic agents have been proposed for the management of painful symptoms. These are shown in Table 4 and discussed below with a critique of the evidence supporting their use. Although there is only limited evidence to support the use of nonsteroidal and anti-inflammatory drugs in DPN, some would advocate their use for the management of patients with mild symptoms. Such agents must be used with caution in neuropathic diabetic patients because many will have a renal impairment, which often constitutes a contraindication to the use of nonsteroidal drugs.
Tricyclic agents. The use of tricyclic drugs in the management of neuropathic pain is supported by several randomized, controlled studies.5,17,18 Although these drugs remain the first-line treatment for symptomatic neuropathy in many centers, their use is restricted because of the frequency and severity of side effects. Thus, some of the newer anticonvulsants are increasingly being used because of their superior side effect profile.
The mechanism of action of the tricyclic agents is not clear but may occur through inhibition of reuptake of norepinephrine and serotonin but also through effects on sodium channels and the Nmethyl-D-aspartate (NMDA) receptors.19 Although these agents are most useful in the management of neuropathic pain, it is, once again, their side effect profile that limits their use. Side effects, which are typically predictable and related to anticholinergic actions, include dry mouth, blurred vision, cardiac arrhythmias, sedation, urinary retention, constipation, and postural hypotension. Although nocturnal administration helps reduce the sedative side effects, up to about one-third of all patients cannot tolerate these agents. Amitriptyline and imipramine are most commonly used, although desipramine has fewer anticholinergic side effects and is less sedative.
Selective serotonin reuptake inhibitors. Trials of selective serotonin reuptake inhibitors (SSRIs) as treatment for diabetic neuropathy have been generally disappointing. Such agents work by the inhibition of presynaptic reuptake of serotonin but not norepinephrine. There is some evidence to support the use of paroxetine and citalopram in dosages of up to 40 mg/day from small controlled studies.
Anticonvulsants. These agents have been used in the management of neuropathic pain for many years, but only limited evidence exists for the efficacy of phenytoin and carbamazepine.5
Gabapentin is now widely used for neuropathic symptoms. This agent is structurally similar to the neurotransmitter -aminobutyric acid and was introduced some years ago as an anticonvulsant for complex partial seizures. The efficacy of gabapentin has been confirmed in two placebo-controlled clinical trials.5
The side effect profile may again be troublesome, but appears to be less so than that of the tricyclics. Reported effects include sedation, dizziness, headache, pedal edema, and weight gain. It should be noted that the average dose required for pain relief in clinical trials was 1.8 g/day. Slow dose titration may reduce the incidence of side effects, but it has been suggested that many patients are not being treated with a sufficiently high dosage.
A newer drug, pregabalin, which is a central nervous system-active compound and an analog of the neurotransmitter -aminobutyric acid, has recently been introduced. Preliminary evidence suggests that this agent may be a useful addition to the anticonvulsants that are helpful in the management of neuropathic pain.20
A number of other anticonvulsant agents have confirmed efficacy in randomized, controlled trials. These include lamotrogine21 and sodium valproate.22
Local anesthetic arrhythmic agents. Lidocaine results in sodium channel blockage, dampening both peripheral nociceptor sensitization and ultimately central nervous system hyperexcitability. Although early studies suggested that intravenous lidocaine administration might be beneficial in relieving neuropathic pain, the potential side effects and the need for intravenous administration was problematic. The oral analog of lidocaine, mexiletine, has been reported to be of benefit in some studies,5,23 but it is not widely used because of side effects and the need for regular electrocardiogram monitoring with its use.
There are now very preliminary data to suggest efficacy from the use of a 5% lidocaine patch in diabetic polyneuropathy. In an open-label study, the use of a maximum of four patches of 5% lidocaine per day was associated with relief of neuropathic symptoms without serious adverse effects.24
NMDA antagonists. This is a relatively new class of drugs and includes dextromethorphan and memantine. Preliminary studies of both agents suggest some efficacy in painful diabetic neuropathy, although further studies are required.25
Opioid analgesics. Opioids have not traditionally been used in the management of diabetic neuropathic pain, but recent trials of two agents do suggest efficacy. First, tramadol, which is an opioid-like, centrally acting synthetic narcotic analgesic, has been confirmed to be efficacious in a randomized, controlled trial, and a follow-up study suggests that it can be used safely for up to 6 months of sustained pain relief.26,27 More recently, two studies have confirmed the efficacy of controlled-release oxycodone.28,29
The side effects of both drugs are predictable and include somnolence, nausea, and constipation; addiction is also problematic. It may be that opioids such as tramadol and oxycodone may be considered as add-on therapies for patients failing to respond to nonopioid medications in the first instance.
Topical and Physical Treatments Capsaicin. This alkaloid, which is found in red pepper, depletes tissue of substance P and reduces chemically induced pain. Although several controlled studies combined in meta-analyses seem to provide some evidence of efficacy in diabetic neuropathic pain, it may be best reserved for those with localized discomfort rather than those with widespread generalized neuropathic pain.30
Topical nitrate. Some recent data suggest that impaired nitric oxide (NO) synthesis plays a role in the pathogenesis of diabetic neuropathy, and in experimental models it has been shown that impaired neuronal NO generation induces hyperalgesia.31,32 This was followed by a recent controlled study that suggested that local application to the feet of isosorbide dinitrate spray was effective in relieving overall pain and burning discomfort of DPN.33 If this is confirmed in larger randomized studies, this could provide a very useful alternative and local treatment for the relief of neuropathic symptoms. A subsequent retrospective review on the data from 18 patients with painful neuropathy treated with glyceryl trynitrate patches reported benefit from this method of applying the topical nitrate.34
Acupuncture. A number of masked studies support the use of acupuncture. In the most recently published report, benefits of acupuncture lasted for up to 6 months and reduced the use of other analgesics.35 There is, however, a need for controlled studies to confirm these observations.
Other physical therapies. Many other physical therapies have been proposed. Controlled evidence has been provided for the use of percutaneous nerve stimulation,36 static magnetic field therapy,37 low-intensive laser therapy,38 and monochromatic infrared light.39 These therapies have mainly been described in small single-center studies and require confirmation in larger studies. Electrical spinal cord stimulation has been used to treat several chronic painful conditions, including phantom limb pain, vascular disease, and severe neuropathy. Although anecdotal evidence has been presented to support this, this treatment is invasive, expensive, and needs to be confirmed in randomized trials.40
New Potential Therapies Now in Clinical Trials
Two treatments that might be useful in opposing some of the pathogenetic factors that are thought to lead to neuropathy are now in clinical trials.
-lipoic-acid. This free radical scavenger antioxidant has been shown to be efficacious in the management of painful neuropathies when administered parenterally.41 A large 4-year, multicenter study to confirm the efficacy of this agent in diabetic neuropathy is in progress and should be completed in 2005.
Protein kinase C inhibition. Elevated protein kinase C activity is thought to play a substantial role in the etiology of diabetic microvascular complications. Studies have been conducted using a protein kinase C- inhibitor (LY333531). A preliminary study suggested the possibility of this agent improving positive symptoms of allodynia and prickling pain. Large, phase III, multicenter clinical trials are in progress.42
FOOT CARE IN NEUROPATHIC PATIENTS
Most of the above discussion has related to the management of patients with symptomatic diabetic neuropathy. However, as noted at the start of this article, a substantial number of neuropathic patients may be completely asymptomatic, and these, along with those who have painful neuropathy, are all at risk of insensitive foot injury. The importance of DPN in the etiopathogenesis of foot ulceration has been confirmed in numerous studies and was the subject of a recent review.43
It must be remembered that the neuropathic diabetic foot does not ulcerate spontaneously. Rather, it is the combination of neuropathy with other extrinsic factors (e.g., ill-fitting footwear or a foreign body in shoe) or intrinsic factors (e.g., high foot pressures or a plantar callus that results in ulceration). Thus, all patients with neuropathic deficit must be considered as being at risk of foot ulceration and require more frequent review, education in routine foot care, and regular podiatric assessments.
CONCLUSIONS
DPN, which may be asymptomatic in up to 50% of cases, is one of the most important complications of diabetes. All diabetic patients, regardless of their type of diabetes, duration of diabetes, or age, require careful clinical examination of the lower extremities and feet at least once a year.
Until recently, in the management of neuropathic pain, there have been few well-designed, placebo-controlled studies. However, in recent years, a number of well-designed clinical trials have confirmed the efficacy of a number of therapies that are outlined above. Unfortunately, it is not possible to predict which therapy might be of greatest benefit to a particular patient. The tricyclic and anticonvulsant agents remain firstline drugs for the management of painful symptoms, although some new classes of drugs are showing promise. Patients who fail to respond to the medications listed in this review might be considered for referral to a pain clinic or a neurologist.
Any patient with diabetic neuropathy should be considered to be at potential risk of foot ulceration or injury and should receive preventive education and referral to a podiatrist as necessary.
Andrew J.M. Boulton, MD, DSc(Hon), FRCP, is a professor of medicine at the University of Manchester, U.K., and the University of Miami in Miami, Fla.
Note of disclosure: Dr. Boulton has received honoraria for speaking engagements or consulting fees from Pfizer and Eli Lilly. These companies manufacture drugs for treatment of neuropathic pain.
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6 Vinik AI, Maser RE, Mitchell B, Freeman R: Diabetic autonomic neuropathy: a technical review. Diabetes Care 26:1553 -1579, 2003
7 Vinik AI, Mehrabyan A, Cohen L, Boulton AJM: Focal entrapment neuropathies in diabetes. Diabetes Care 27:1783 -1788, 2004
8 Boulton AJM, Gries FA, Jervell JA: Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathy. Diabetic Med15 : 508-514,1998
9 Oyibo S, Prasad YD, Jackson NJ, Jude EB, Boulton AJM: The relationship between blood glucose excursions and painful diabetic peripheral neuropathy: a pilot study. Diabetic Med 19:870 -873, 2002
10 Archer AG, Watkins PJ, Thomas PK, Sharma AK, Payan J: The natural history of acute painful neuropathy is diabetes. J Neurol Neurosurg Psychiatry48 : 491-499,1983
11 Watkins PJ: Pain and diabetic neuropathy. BMJ288 : 168-169,1984
12 Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA: A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care17 : 1281-1289,1996
13 Vileikyte L: Psychological aspects of diabetic peripheral neuropathy. Diabetes Rev 7: 387-394,1999
14 Abbott CA, Carrington AL, Ashe H, Every L, Whalley A, Van Ross ERE, Boulton AJM: The North-West Diabetes Foot Care Study: incidence of, and risk factors for new diabetic foot ulceration in a community-based patient cohort. Diabetic Med 19:377 -384, 2002
15 Mayfield JA, Sugarman JR: The use of Semmes-Weinstein monofilament and other threshold tests for preventing foot ulceration and amputation in people with diabetes. J Fam Pract 49 (Suppl.):517 -529, 2000
16 Abbott CA, Vileikyte L, Williamson S, Carrington Al, Boulton AJM: Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration. Diabetes Care 7:1071 -1075, 1998
17 Watson CP: The treatment of neuropathic pain: anti-depressants and opioids. Clin J Pain 16: S49-S55,2000
18 Mendell JR, Sahenk Z: Painful sensory neuropathy. N Engl J Med348 : 1243-1255,2003
19 Ulugol A, Karadag HC, Tamer M: Involvement of adenosine in the anti-allodynic effect of amitriptyline in streptozotocin-induced diabetic rats. Neurosci Lett 328:129 -132, 2002
20 Rosenstock J, Tuckman M, La Moreaux L, Sharma U: Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain 110:628 -638, 2004
21 Eisenberg E, Luri Y, Braker C, Daoud D, Ishay A: Lamotrigine reduces painfuldiabetic neuropathy: a randomized, controlled study. Neurology57 : 505-509,2001
22 Kochar DK, Rawat N, Agrawal RP, Vyas A, Kochar SK, Garg P: Sodium valproate for painful diabetic neuropathy: a randomized double-blind placebo-controlled study. Q J Med 97:33 -38, 2004
23 Krishnan STM, Rayman G: Symptomatic diabetic neuropathy: an update. Curr Diabetes Rep 16: 2-9,2004
24 Barbano RL, Herrman DN, Hart-Gouleau S, Dworkin RH: Effectiveness to tolerability and inpact on qualify of life of the 5% lidocaine patch in diabetic polyneuropathy. Arch Neurol 61:914 -918, 2004
25 Sang CN, Booher S, Gilron I, Parada S, Max MB: Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials. Anesthesiology 96:1053 -1061, 2002
26 Harati Y, Gooch C, Swenson M, Edelman S, Greene D, Raskin P, Donofrio P, Cornblath D: Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology50 : 1841-1846,1998
27 Harati Y, Gooch C, Swenson M, Edelman S, Greene D, Raskin P, Donofrio P, Cornblath D: Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy. J Diabetes Compl14 : 65-70,2000
28 Gimbel JS, Richards P, Portenoy RK: Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Neurology60 : 927-934,2003
29 Watson CPN, Moulin D, Watt-Watson J, Gordon A, Eisenhoffer J: Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain 105:71 -78, 2003
30 Zhang WY, Wan Po AL: The effectiveness of topically applied capsaicin: a meta-analysis. Eur J Clin Pharmacol 45:517 -522, 1994
31 Sasaki T, Yasuda H, MaedaK, Kikkawa R: Hyperalgesia and decreased neuronal nitric oxide synthase in diabetic rate. Neuroreport9 : 243-247,1998
32 Rodella L, Rezzani R, Corsetti G, Bianchi R: Nitric oxide involvement in the trigeminal hyperalgesia in diabetic rats. Brain Res865 : 112-115,2000
33 Yuen KC, Baker NR, Rayman G: Treatment of chronic painful diabetic neuropathy with isosorbide dinitrate spray: a double-blind placebo-controlled crossover study. Diabetes Care 25:1699 -1703, 2002
34 Rayman G, Baker NR, Krishnan ST: Glyceryl trinitrate patches as an alternative to isosorbide dinitrate spray in the treatment of chronic painful diabetic neuropathy. Diabetes Care 26:2697 -2698, 2003
35 Abusaisha BB, Constanzi JB, Boulton AJM: Acupuncture for the treatment of chronic painful diabetic neuropathy: a long-term study. Diabetes Res Clin Pract 39:115 -121, 1998
36 Hamza MA, White PF, Craig WF, Ghoname ES, Ahmed HE, Proctor TJ: Percutaneous electrical nerve stimulation: a novel analgesic therapy for diabetic neuropathic pain. Diabetes Care 23:365 -370, 2000
37 Weintraub MI, Wolfe GI, Barohn RA, Cole SP, Parry GJ, Hayat G, Schwartz SL: Static magnetic field therapy for symptomatic diabetic neuropathy; a randomized, double-blind, placebo-controlled trial. Arch Phys Med Rehabil86 : 736-746,2003
38 Zinman LH, Ngo M, Ng ET, Nwe KT, Gogov S, Bril V: Low-intensity laser therapy for painful symptom diabetic sensorimotor polyneuropathy: a controlled trial. Diabetes Care 27:921 -924, 2004
39 Leonard DR, Farooqi MH, Myers S: Restoration of sensation, reduced pain, and improved balance in subjects with diabetic peripheral neuropathy: a double-blind, random placebo-controlled study with monochromatic infrared treatment. Diabetes Care 27:168 -172, 2004
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IN BRIEF
Diabetic peripheral neuropathy affects up to 50% of older type 2 diabetic patients. Whereas some patients may have extremely painful symptoms, others with a more marked neuropathic deficit may be asymptomatic. Diagnosis requires careful examination of the lower limbs. Management involves establishing that the neuropathy is caused by diabetes instead of more sinister causes and aiming for optimal glycemic control. Medications, usually tricyclic drugs or anticonvulsant agents, may be required. Patients with peripheral neuropathy must be considered at risk of insensate foot ulceration and must receive preventive education and podiatric care.
Introduction
Neuropathies are among the most common of all the long-term complications of diabetes, affecting up to 50% of patients.1-5 There are many subgroups of neuropathies; readers are referred to recent reviews for discussion of the autonomic neuropathies6 and the mononeuropathies.7 This article will focus on the most common of all the peripheral neuropathies: the somatic neuropathies affecting the lower extremities. Detailed discussions of all aspects of these neuropathies were recently published as a technical review5 and will be included in a forthcoming American Diabetes Association statement.
In the past, a lack of awareness and inappropriate management of diabetic peripheral neuropathy (DPN) has led to much unnecessary morbidity and substantial health care costs. At least half of all foot ulcers, the end stage of such neuropathy, should be preventable by appropriate management and patient education. However, lack of time and inappropriate or inadequate information may lead to suboptimal care.
Diabetic somatic neuropathies do represent a paradox: at one extreme there are patients with severe neuropathic pain who on examination may have only a minimal deficit, whereas at the other extreme are patients with insensate feet who are asymptomatic and may first present with foot ulcers.
This review will provide an overview of DPN and a detailed guide to the management of pain in patients with significant symptomatology.
DEFINITIONS
Members of an International Consensus Meeting on the outpatient diagnosis and management DPN agreed on a simple definition of diabetic neuropathy as "the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes."8 This group also agreed that neuropathy cannot be diagnosed without a careful clinical examination and that absence of symptoms must never be equated with absence of neuropathy. The importance of excluding nondiabetic causes was emphasized in the Rochester Diabetic Neuropathy Study, in which up to 10% of peripheral neuropathy in diabetes was deemed to be of nondiabetic causation.1
For day-to-day clinical practice, DPN is a clinical diagnosis. It is generally agreed that DPN should not be diagnosed on the basis of one symptom, sign, or test alone; a minimum of two abnormalities (i.e., abnormal symptoms and signs) is recommended.5
EPIDEMIOLOGY
DPN is by far the most common of all the diabetic neuropathies and may be divided into the following two main types: acute sensory neuropathy and chronic sensorimotor neuropathy. Acute sensory neuropathy is a distinct variety of the symmetrical polyneuropathies with an acute or subacute onset characterized by severe sensory symptoms, usually with few if any clinical signs. It is usually precipitated by an episode of glycemic instability (such as ketoacidosis or even after the institution of insulin), and its natural history is one of gradual improvement of symptoms with establishment of stable glycemic control and appropriate symptomatic treatments.
Chronic sensorimotor neuropathy is by far the most common form of DPN. It is usually of insidious onset and may be present at the diagnosis of type 2 diabetes in up to 10% of patients. Whereas up to 50% of patients with chronic DPN may be asymptomatic, 10-20% may experience troublesome symptoms sufficient to warrant specific therapy. Sensorimotor neuropathy is often accompanied by autonomic dysfunction. Its late sequelae, which include foot ulceration, Charcot neuroarthropathy, and occasionally amputation, should in many cases be preventable. The prevalence of chronic DPN increases with both age and duration of diabetes, and this diagnosis is more common in those whose glycemic control has been suboptimal in previous years.
CLINICAL FEATURES OF DPN
Acute Sensory Neuropathy
Many of the symptoms of acute sensory and chronic sensorimotor neuropathy are similar, although there are clear differences in the mode of onset, accompanying signs, and prognosis. These are summarized in Table 1. Table 2 offers a list of typical symptoms, both painful and nonpainful. All painful neuropathic symptoms tend to be prone to nocturnal exacerbation. Clinical examination of patients with presumed acute sensory neuropathy may be relatively normal, with allodynia (a painful sensation induced by nonnoxious stimulus) on sensory testing, a relatively normal motor exam, and occasionally reduced ankle reflexes.
In the management of this condition, achieving stable blood glucose control is most important. Stability may well be the key feature, because blood glucose flux (as assessed, for example, by the M value, a measure of glycemic excursions from the mean) is associated with pain.9
Additionally, however, most patients will require medication after neuropathic pain, and these medications are discussed in detail below in the section on management of chronic DPN. Suffice it to say that the approach is similar, although the dosage and number of medications required may be higher, in acute sensory neuropathy. The natural history of this acute neuropathy is very different from the much more common chronic DPN; its onset is acute or subacute, but the severe symptoms typically resolve in < 12 months.10,11
Chronic Sensorimotor Neuropathy
Painful neuropathy can be one of the most distressing and debilitating of all the complications of diabetes. The rest of this review will discuss the approach to patients presenting with chronic DPN and will focus on available treatments with brief comment on those that may soon be available.
As noted above, many patients are asymptomatic, and the neurological deficit may be discovered by chance during a routine neurological exam. Because chronic DPN is a length-dependent process, the sensory manifestations are most pronounced in the lower limbs, although, in more severe cases, the fingers and hands may also be involved. The symptoms, outlined in Table 2, tend to be peculiar to the individual patient but constant during the history of neuropathy in that individual. Patients often find it very difficult to describe the symptoms because they are different from other types of pain the patients have previously experienced. Although not mentioned in older texts, unsteadiness is increasingly being recognized as a manifestation of chronic DPN resulting from disturbed propriaception and probably abnormal muscle sensory function. Many patients will have a combination of both positive (painful) and negative (nonpainful) symptoms.
Clinical examination of patients with chronic DPN usually reveals a symmetrical sensory loss to all modalities in a stocking distribution. This may well extend into the mid-calf level and may also affect the upper limbs in more severe cases. Ankle reflexes are usually reduced or absent, and knee reflexes may also be reduced in some cases.
In the clinical assessment of patients, a number of simple symptom/screening questionnaires are available to record symptom quality and severity. Among these is the Michigan Neuropathy Screening Instrument, which is a brief 15-item questionnaire.12 It is also increasingly recognized that both symptoms and deficits may have an adverse effect on quality of life in diabetic neuropathy,13 and specific questionnaires have been developed for the assessment of the impact of neuropathy on quality of life. Similarly, composite scores have been used to assess clinical signs, and one that is increasingly used is a modified Neuropathy Disability Score (NDS).14 The NDS, shown in Figure 1, can be easily performed in the clinic setting and takes only a minute or two to complete. The maximum deficit score is 10, which would indicate complete loss of sensation to all sensory modalities and absent reflexes. In a longitudinal European community-based study, an NDS of 6 was equated with an increased risk of insensate foot ulceration.14
A number of simple devices may be used for clinical screening; the most widely used is the Semmes-Weinstein monofilament.15 This filament assesses pressure perception when gentle pressure is applied sufficient to buckle the nylon filament. A number of cross-sectional and longitudinal studies have assessed the sensitivity of the 10-g monofilament and have shown it to be a useful tool to identify patients at risk of foot ulceration.5,15 Of the simple quantitative sensory testing instruments that are used in clinical practice, the most common is the bioesthesiometer (Biomedical Instruments, Newbury, Ohio). This assesses in a semiquantitative manner the perception of vibration and has similarly been shown to be a useful predictor of foot ulcer risk.16
MANAGEMENT
Is It DPN
The management approach to patients considered to have DPN is provided in Table 3. First, it must be remembered that there are numerous causes of peripheral neuropathy, of which diabetes is probably the most common. However, exclusion of other causes, particularly malignant disease and toxic causes, is of paramount importance. Exclusion of such potentially serious conditions as malignant disease (e.g., small-cell carcinoma presenting as a paraneoplastic syndrome), toxic causes (e.g., alcohol), and infections (diseases such as HIV) is essential.
In most cases, further investigation, such as detailed quantitative sensory testing in electrophysiology, which would require referral to a neurologist, is not essential. Abnormal electrophysiology simply confirms the presence of a neuropathy but does not indicate the underlying cause.
Initial Therapy and Counseling
Once a diagnosis is established, giving patients a full explanation of their condition, allaying their fears and misconceptions, and informing them that the pain may resolve in time can be extremely reassuring. Simple physical treatments, such as the use of a bed cradle to lift the bed clothes off of hyperaesthetic skin, can be beneficial. Advice on suitable footwear may also be provided. In patients with relatively mild pain, simple analgesics or anti-inflammatory agents may be sufficient to treat the discomfort.
Metabolic Control
The most effective method of achieving stable normoglycemia is pancreas or islet cell transplantation. However, this is not practical in most cases because it is mainly available to patients with end-stage diabetic nephropathy who have combined pancreas and renal transplants or in special cases of young people with type 1 diabetes.
Although there have been no randomized, controlled trials of intensive insulin therapy in the management of diabetic neuropathy, data from a number of observational studies suggest that stable glycemic control is of the greatest import. A recent study using continuous glucose monitoring confirmed that painful symptoms were associated with erratic blood glucose control.9 Having said this, there is no evidence that patients whose diabetes has been well controlled on oral hypoglycemic agents will benefit in terms of pain relief by transferring to insulin.
Pharmacological Management
A large number of therapeutic agents have been proposed for the management of painful symptoms. These are shown in Table 4 and discussed below with a critique of the evidence supporting their use. Although there is only limited evidence to support the use of nonsteroidal and anti-inflammatory drugs in DPN, some would advocate their use for the management of patients with mild symptoms. Such agents must be used with caution in neuropathic diabetic patients because many will have a renal impairment, which often constitutes a contraindication to the use of nonsteroidal drugs.
Tricyclic agents. The use of tricyclic drugs in the management of neuropathic pain is supported by several randomized, controlled studies.5,17,18 Although these drugs remain the first-line treatment for symptomatic neuropathy in many centers, their use is restricted because of the frequency and severity of side effects. Thus, some of the newer anticonvulsants are increasingly being used because of their superior side effect profile.
The mechanism of action of the tricyclic agents is not clear but may occur through inhibition of reuptake of norepinephrine and serotonin but also through effects on sodium channels and the Nmethyl-D-aspartate (NMDA) receptors.19 Although these agents are most useful in the management of neuropathic pain, it is, once again, their side effect profile that limits their use. Side effects, which are typically predictable and related to anticholinergic actions, include dry mouth, blurred vision, cardiac arrhythmias, sedation, urinary retention, constipation, and postural hypotension. Although nocturnal administration helps reduce the sedative side effects, up to about one-third of all patients cannot tolerate these agents. Amitriptyline and imipramine are most commonly used, although desipramine has fewer anticholinergic side effects and is less sedative.
Selective serotonin reuptake inhibitors. Trials of selective serotonin reuptake inhibitors (SSRIs) as treatment for diabetic neuropathy have been generally disappointing. Such agents work by the inhibition of presynaptic reuptake of serotonin but not norepinephrine. There is some evidence to support the use of paroxetine and citalopram in dosages of up to 40 mg/day from small controlled studies.
Anticonvulsants. These agents have been used in the management of neuropathic pain for many years, but only limited evidence exists for the efficacy of phenytoin and carbamazepine.5
Gabapentin is now widely used for neuropathic symptoms. This agent is structurally similar to the neurotransmitter -aminobutyric acid and was introduced some years ago as an anticonvulsant for complex partial seizures. The efficacy of gabapentin has been confirmed in two placebo-controlled clinical trials.5
The side effect profile may again be troublesome, but appears to be less so than that of the tricyclics. Reported effects include sedation, dizziness, headache, pedal edema, and weight gain. It should be noted that the average dose required for pain relief in clinical trials was 1.8 g/day. Slow dose titration may reduce the incidence of side effects, but it has been suggested that many patients are not being treated with a sufficiently high dosage.
A newer drug, pregabalin, which is a central nervous system-active compound and an analog of the neurotransmitter -aminobutyric acid, has recently been introduced. Preliminary evidence suggests that this agent may be a useful addition to the anticonvulsants that are helpful in the management of neuropathic pain.20
A number of other anticonvulsant agents have confirmed efficacy in randomized, controlled trials. These include lamotrogine21 and sodium valproate.22
Local anesthetic arrhythmic agents. Lidocaine results in sodium channel blockage, dampening both peripheral nociceptor sensitization and ultimately central nervous system hyperexcitability. Although early studies suggested that intravenous lidocaine administration might be beneficial in relieving neuropathic pain, the potential side effects and the need for intravenous administration was problematic. The oral analog of lidocaine, mexiletine, has been reported to be of benefit in some studies,5,23 but it is not widely used because of side effects and the need for regular electrocardiogram monitoring with its use.
There are now very preliminary data to suggest efficacy from the use of a 5% lidocaine patch in diabetic polyneuropathy. In an open-label study, the use of a maximum of four patches of 5% lidocaine per day was associated with relief of neuropathic symptoms without serious adverse effects.24
NMDA antagonists. This is a relatively new class of drugs and includes dextromethorphan and memantine. Preliminary studies of both agents suggest some efficacy in painful diabetic neuropathy, although further studies are required.25
Opioid analgesics. Opioids have not traditionally been used in the management of diabetic neuropathic pain, but recent trials of two agents do suggest efficacy. First, tramadol, which is an opioid-like, centrally acting synthetic narcotic analgesic, has been confirmed to be efficacious in a randomized, controlled trial, and a follow-up study suggests that it can be used safely for up to 6 months of sustained pain relief.26,27 More recently, two studies have confirmed the efficacy of controlled-release oxycodone.28,29
The side effects of both drugs are predictable and include somnolence, nausea, and constipation; addiction is also problematic. It may be that opioids such as tramadol and oxycodone may be considered as add-on therapies for patients failing to respond to nonopioid medications in the first instance.
Topical and Physical Treatments Capsaicin. This alkaloid, which is found in red pepper, depletes tissue of substance P and reduces chemically induced pain. Although several controlled studies combined in meta-analyses seem to provide some evidence of efficacy in diabetic neuropathic pain, it may be best reserved for those with localized discomfort rather than those with widespread generalized neuropathic pain.30
Topical nitrate. Some recent data suggest that impaired nitric oxide (NO) synthesis plays a role in the pathogenesis of diabetic neuropathy, and in experimental models it has been shown that impaired neuronal NO generation induces hyperalgesia.31,32 This was followed by a recent controlled study that suggested that local application to the feet of isosorbide dinitrate spray was effective in relieving overall pain and burning discomfort of DPN.33 If this is confirmed in larger randomized studies, this could provide a very useful alternative and local treatment for the relief of neuropathic symptoms. A subsequent retrospective review on the data from 18 patients with painful neuropathy treated with glyceryl trynitrate patches reported benefit from this method of applying the topical nitrate.34
Acupuncture. A number of masked studies support the use of acupuncture. In the most recently published report, benefits of acupuncture lasted for up to 6 months and reduced the use of other analgesics.35 There is, however, a need for controlled studies to confirm these observations.
Other physical therapies. Many other physical therapies have been proposed. Controlled evidence has been provided for the use of percutaneous nerve stimulation,36 static magnetic field therapy,37 low-intensive laser therapy,38 and monochromatic infrared light.39 These therapies have mainly been described in small single-center studies and require confirmation in larger studies. Electrical spinal cord stimulation has been used to treat several chronic painful conditions, including phantom limb pain, vascular disease, and severe neuropathy. Although anecdotal evidence has been presented to support this, this treatment is invasive, expensive, and needs to be confirmed in randomized trials.40
New Potential Therapies Now in Clinical Trials
Two treatments that might be useful in opposing some of the pathogenetic factors that are thought to lead to neuropathy are now in clinical trials.
-lipoic-acid. This free radical scavenger antioxidant has been shown to be efficacious in the management of painful neuropathies when administered parenterally.41 A large 4-year, multicenter study to confirm the efficacy of this agent in diabetic neuropathy is in progress and should be completed in 2005.
Protein kinase C inhibition. Elevated protein kinase C activity is thought to play a substantial role in the etiology of diabetic microvascular complications. Studies have been conducted using a protein kinase C- inhibitor (LY333531). A preliminary study suggested the possibility of this agent improving positive symptoms of allodynia and prickling pain. Large, phase III, multicenter clinical trials are in progress.42
FOOT CARE IN NEUROPATHIC PATIENTS
Most of the above discussion has related to the management of patients with symptomatic diabetic neuropathy. However, as noted at the start of this article, a substantial number of neuropathic patients may be completely asymptomatic, and these, along with those who have painful neuropathy, are all at risk of insensitive foot injury. The importance of DPN in the etiopathogenesis of foot ulceration has been confirmed in numerous studies and was the subject of a recent review.43
It must be remembered that the neuropathic diabetic foot does not ulcerate spontaneously. Rather, it is the combination of neuropathy with other extrinsic factors (e.g., ill-fitting footwear or a foreign body in shoe) or intrinsic factors (e.g., high foot pressures or a plantar callus that results in ulceration). Thus, all patients with neuropathic deficit must be considered as being at risk of foot ulceration and require more frequent review, education in routine foot care, and regular podiatric assessments.
CONCLUSIONS
DPN, which may be asymptomatic in up to 50% of cases, is one of the most important complications of diabetes. All diabetic patients, regardless of their type of diabetes, duration of diabetes, or age, require careful clinical examination of the lower extremities and feet at least once a year.
Until recently, in the management of neuropathic pain, there have been few well-designed, placebo-controlled studies. However, in recent years, a number of well-designed clinical trials have confirmed the efficacy of a number of therapies that are outlined above. Unfortunately, it is not possible to predict which therapy might be of greatest benefit to a particular patient. The tricyclic and anticonvulsant agents remain firstline drugs for the management of painful symptoms, although some new classes of drugs are showing promise. Patients who fail to respond to the medications listed in this review might be considered for referral to a pain clinic or a neurologist.
Any patient with diabetic neuropathy should be considered to be at potential risk of foot ulceration or injury and should receive preventive education and referral to a podiatrist as necessary.
Andrew J.M. Boulton, MD, DSc(Hon), FRCP, is a professor of medicine at the University of Manchester, U.K., and the University of Miami in Miami, Fla.
Note of disclosure: Dr. Boulton has received honoraria for speaking engagements or consulting fees from Pfizer and Eli Lilly. These companies manufacture drugs for treatment of neuropathic pain.
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