SECTION II • DIABETIC NEUROPATHIES 114 However, despite 25 years of clinical trials with ARIs in diabetic neuropathy, only epalrestat is currently available in Japan. Most of the early trials can be summarized as: • Too small. Drug effect inadequate to inhibit nerve sorbitol accumulation; • Too few. Inadequate numbers of subjects randomized; • Too short. Many trials only lasted weeks or months for a chronic disease of many years duration; • Too late. Targeting a pathogenetic mechanism is not likely to be effective when the complication is well established; • Too toxic. A number of ARIs were withdrawn in phase III due to hepatic or renal toxicity. Antioxidants Increased free radical production and a reduced ability to neutralize free radicals due to nicotinamide adenine dinucleotide (NADH) depletion, partly the result of non-enzymatic glycation and polyol pathway hyperactivity supports the role of oxidative stress in the pathogenesis of neuropathy. Studies with the antioxi- dant alpha-lipoic acid (LA) have provided evidence of potential efficacy with this agent for both symptoms and signs. Two large North American/European clin- ical trials of the efficacy of LA are in progress and should report in 2005. Gamma-linolenic acid (GLA) GLA can prevent abnormalities in essential fatty acid and prostanoid metab- olism. GLA treatment for one year in a randomized trial resulted in improve- ment in electrophysiology and deficits. A LA/GLA conjugate has produced impressive improvements in electrophysiological and neurochemical abnor- malities in experimental diabetic neuropathy but this has not been tested in diabetic patients. Inhibitors of glycation Non-enzymatic glycation occurs in diabetes and may be an important initiat- ing factor for nerve demyelination and may also interfere with axonal trans- port. Advanced glycation end products (AGE) can also absorb nitric oxide (NO) and impair nerve blood flow. Studies of aminoguanidine, an inhibitor of advanced glycation have shown no benefit in diabetic nephropathy and few data are available on this or other inhibitors of AGE formation in human dia- betic neuropathy. Protein Kinase C-β (PKC-β) inhibition Intracellular hyperglycaemia increases diacylglycerol levels and activates PKC-β formation, which alters expression of endothelial nitric oxide synthetase and vascular endothelial growth factor (VEGF). These changes are CHAPTER 13 • TREATMENTS OPTIONS associated with abnormalities in vascular function and PKC-β inhibitors have been shown to correct endothelial dependent relaxation, nerve perfusion deficits and conduction velocity in animal models. Preliminary phase II data suggest that treatment with a PKC-β inhibitor might ameliorate symptoms and neurological deficits in DPN. Phase III multicentre clinical trials are cur- rently in progress and will report in 2006. Vasodilators Treatment with angiotensin-converting enzyme inhibitors (ACE-Is) has been shown to improve electrophysiological measures of nerve function in mild neuropathy. The short-acting vasodilator isosorbide dinitrate has been shown to improve painful symptoms, but its effect on deficits and electrophysiology are unknown. Neutrophins Neurotrophic factors are important in the growth and development of neu- rones. These include insulin-like growth factor I and II and the neurotrophin family which includes nerve growth factor (NGF) and brain derived neuro- trophic Factor (BDNF). NGF is reduced in experimental diabetes and treat- ment with NGF corrects some aspects of sensory neuropathy related to small fibre dysfunction in diabetic rats. A promising phase II study showed an improvement in human diabetic neuropathy. However this was not con- firmed in a phase III study and therefore the clinical development of NGF was halted. Similarly, a small study with BDNF has also shown no benefit. SYMPTOMATIC MANAGEMENT Control of hyperglycaemia A number of small open label uncontrolled studies have suggested that achieving stable near-normoglycaemic control is helpful in the management of painful neuropathic symptoms. In an early study of continuous subcuta- neous insulin infusion (CSII) for four months in patients with painful neu- ropathy, relief of neuropathic symptoms was associated with an overall improvement of glycaemic control and a reduction in blood glucose flux. More recently patients with painful neuropathy were compared to those with painless neuropathy. Those with painful symptoms had poorer control, more excursions to hyper- and hypoglycaemic levels and greater blood glucose flux. Thus, it may be that the stability of glycaemic control is equally important to the level of overall normoglycaemia. Pharmacotherapy A large number of therapeutic agents have been used in the management of painful symptoms. There is little evidence to support the use of non-steroidal 115 SECTION II • DIABETIC NEUROPATHIES 116 anti-inflammatory drugs in symptomatic neuropathy. Moreover, these agents should be used with caution in neuropathic diabetic patients, many of whom may have renal impairment, a contraindication to non-steroidal drugs. Tricyclic drugs Several small randomized clinical trials have supported the use of these agents in the management of neuropathic pain. Putative mechanisms by which these drugs relieve pain include inhibition of norepinephrine and/or serotonin reuptake at synapses of central descending pain pathways. More recently, the antagonism of n-methyl-d-aspartate receptors has been shown to alleviate hyperalgaesia and allodynia. Most experience has been achieved with amitriptyline and imipramine. The dosage of either one of these two drugs required for symptomatic relief is sim- ilar, being 25–150 mg daily. In order to avoid undue drowsiness, the dose can be taken once a day in the evening. Desipramine is also a useful drug that may be better tolerated than amitriptyline. The usefulness of these agents was con- firmed in a systematic review performed by McQuay and colleagues. The major problem remains the frequency of side-effects which are predictable. Although drowsiness and lethargy are common, it is the anticholinergic side- effects, particularly dry mouth, that are the most troublesome. Selective serotonin-reuptake inhibitors (SSRIs) These agents inhibit pre-synaptic reuptake of serotonin but not norepineph- rine. Studies suggest that treatment with paroxetine but not fluoxetine is asso- ciated with significant pain relief. Similarly citalopram 40 mg/day is efficacious but less effective than imipramine. Their main advantage is lesser side-effects. Anticonvulsants Anticonvulsants have been used in the management of neuropathic pain for many years. In total there are 13 published trials of anticonvulsants of which only six are randomized controlled trials which show that, for those diabetic patients with painful neuropathy given anticonvulsants, the true risk of a reduction in pain relief is 2.3 times greater than with placebo (Fig 13.2). Only limited evidence exists for the efficacy of phenytoin and carbamazepine for diabetic neuropathy. Agranulocytosis has been reported with carbamazepine and must be monitored by obtaining blood counts at baseline and thereafter periodically to screen for bone marrow suppression and leucopenia. Oxcarbazepine is a second generation antiepileptic drug and like carba- mazepine, it blocks sodium channels, reducing hyperexcitability of peripher- al nerves. It has been effectively used in trigeminal neuralgia. There are cur- rently five randomized-controlled trials underway in Japan evaluating its effi- cacy in diabetic neuropathy. Gabapentin is now widely used for neuropathic CHAPTER 13 • TREATMENTS OPTIONS symptoms based on the results of a large controlled trial in symptomatic neu- ropathy where significant pain relief together with reduced sleep disturbance was reported using dosages of 900–3,600 mg daily. In a recent review of all the trials of gabapentin for neuropathic pain, it was concluded that dosages of 1,800–3,600 mg per day of this agent were effective. The side-effect profile also seems superior to that of the tricyclic drugs, though somnolesence is a prob- lem with higher doses. Pregabelin has been shown to be more efficacious than gabapentin with even lesser side effects. Lamotrigine has at least two anti- nociceptive properties and in a randomized placebo controlled study was shown to have efficacy in patients with neuropathic pain. Anti-arrhythmics Mexilitine is a class 1B antiarrhythmic agent and a structural analogue of lig- nocaine. Its efficacy in neuropathic pain has been confirmed in controlled tri- als using doses of up to 450 mg daily which are lower than those usually used for the treatment of cardiac arrhythmias. However, regular ECG monitoring is necessary and the long-term use of mexilitine cannot be recommended. 117 Fig. 13.2 Meta-analysis of six placebo controlled trials of anticonvulsants for pain in painful diabetic neuropathy. The dotted vertical line shows the combined relative risk estimate with the 95% confidence interval (CI). Here we can say, with 95% confidence, that for those given anticonvulsants the true population risk of a reduction in pain relief is 2.3 times greater than with placebo. combined (fixed) 12 510 Rosenstock 2004 Pregabalin Kochar 2002 Valproate Backonja 1998 Gabapentin Chadda 1978 Phenytoin Wilton 1974 Carbamazepine Rull 1969 Carbamazepine 2.31 (1.87, 2.85) 2.76 (1.50, 5.25) 3.43 (1.66, 7.93) 1.84 (1.30, 2.67) 2.80 (1.66, 5.05) 2.67 (1.48, 5.08) 1.87 (1.35, 2.84) SECTION II • DIABETIC NEUROPATHIES 118 Other agents Tramadol is an opioid-like centrally acting, synthetic non-narcotic analgesic which was shown to produce significant symptomatic relief in a randomized controlled trial of patients with painful diabetic neuropathy initially over six weeks which was maintained for at least six months. However, side-effects are relatively common and are similar to other opioid-like drugs. Similarly, two randomized trials have confirmed the efficacy of controlled release oxy- codone for neuropathic pain in diabetes. TOPICAL AND PHYSICAL TREATMENT Topical nitrate A recent placebo controlled study suggested that the local application to the feet of isosorbide dinitrate spray was effective in relieving overall pain and burning discomfort in painful diabetic neuropathy and has been confirmed by applying GTN patches to both lower limbs. Capsaicin This alkaloid depletes tissue of substance P and results in degeneration of epi- dermal nerve fibres. Therefore it is not surprising that several controlled stud- ies combined in a meta-analysis seem to provide some evidence of efficacy in diabetic neuropathic pain. However, true blinding of these studies has been questioned because of the local hyperalgesia experienced when applying the active drug. Furthermore, with the overt epidermal nerve fibre damage it causes one must question the ethical basis of promoting denervation in a foot which already has or will have sensory loss. Acupuncture A number of unmasked studies support the use of acupuncture and, in the most recent published report, benefits of acupuncture lasted for up to six months and reduced the use of other analgesics. OTHER PHYSICAL THERAPIES A number of other physical therapies have been proposed, though few have been rigorously tested in controlled clinical trials. Efficacy has been shown with percutaneous nerve stimulation and static magnetic field therapy, with no benefit with electrical socks. CHAPTER 13 • TREATMENTS OPTIONS Electrical spinal cord stimulation A case series of patients with severe painful neuropathy unresponsive to con- ventional therapy suggested efficacy of using an implanted spinal cord stim- ulator. This approach can only be recommended in very resistant cases as it is invasive, expensive, and unproven in controlled studies. FURTHER READING Backonja M, Glanzman RL. Gabapentin dosing for neuropathic pain: evidence from ran- domized placebo controlled clinical trials. Clin Ther 2003; 25: 81–104. Boulton, AJM. Treatment of symptomatic diabetic neuropathy. Diabet Metab Res Rev 2003; 19: S16–S21. McQuay H, Carroll D, Jadad AR, et al. Anticonvulsant drugs for the management of pain: a systematic review. BMJ 1995; 311: 1047–1052. 119 CURRENT ISSUES • Maintaining near-normoglycaemia prevents the development and retards the progression of DPN. • Despite 25 years of clinical trials with ARIs in diabetic neuropathy, only epalrestat is currently available in Japan. • Increased free radical production and a reduced ability to neutralize free radicals due to NADH leads to oxidative stress which is involved in the pathogenesis of neuropathy. • Preliminary phase II data suggest that treatment with a PKC-β inhibitor might ameliorate symptoms and neurological deficits in DPN. • Treatment with ACE-Is has been shown to improve nerve function in mild neuropathy. • A large number of therapeutic agents have been used in the management of painful symptoms. • Of 13 published trials of anticonvulsants only six are randomized controlled trials and show a risk reduction in pain relief 2.3 times greater than placebo. CHAPTER 14 MANAGEMENT GUIDELINES FOR DIABETIC PERIPHERAL NEUROPATHY AND FOOT ULCERATION Rayaz A. Malik MB.ChB, PhD, MRCP 121 DIABETIC NEUROPATHY In 1995 the Neurodiab, a subgroup of the European Association for the Study of Diabetes, suggested that there was a need for guidelines for the outpatient management of patients with diabetic neuropathy. Such guidelines were developed from an international consensus meeting attended by diabetolo- gists, neurologists, primary care physicians, podiatrists and diabetes specialist nurses. In brief, these guidelines agreed on a practical means of assessment (Table 14.1), classification (Table 14.2) and management (Table 14.3) of dia- betic patients presenting in an outpatient setting. More recently in 2004 and 2003 respectively, two detailed technical reviews have been published on somatic diabetic peripheral neuropathy (DPN)and autonomic (AN) diabetic neuropathy. On behalf of the American Diabetes Association a consensus report has emerged from these two lengthy reviews. It is agreed that the diabetic neuropathies are heterogeneous, affect different parts of the nervous system and may present with diverse clinical manifesta- tions. A simple clinical classification is proposed (Table 14.4). DPN is consid- ered to be a diagnosis of exclusion. The early recognition and appropriate management of neuropathy is thought to be important for a number of rea- sons: 1) non-diabetic neuropathies may be present in patients with diabetes; 2) a number of treatment options exist for symptomatic diabetic neuropathy; 3) up to 50% of DPN may be asymptomatic and patients are at risk of insensate injury to their feet; 4) AN may involve every system in the body; 5) AN causes substantial morbidity and increased mortality particularly if cardiovascular autonomic neuropathy is present. The diagnostic methods employed in diabetic neuropathy are varied and show considerable heterogeneity for both specificity and sensitivity. The American Academy of Neurology recently proposed a consensus statement on the use of quantitative sensory testing (QST) in the diagnosis of diabetic neuropathy. This assessment evaluated the clinical utility, efficacy, and safety of QST. Using a search strategy on MEDLINE, Current Contents, and their personal files, the authors identified 350 articles. No adequately powered class I studies and only a small number of class II and III studies demonstrated that QST probably identified small or large fibre sensory abnormalities in patients with diabetic neuropathy. They concluded that QST was a potentially useful tool for measuring sensory impairment for clinical and research studies but should not be the sole criteria used to diagnose pathology. Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment, Second Edition Edited by Richard Donnelly, Edward Horton Copyright © 2005 by Blackwell Publishing Ltd Table 14.1 Stage of diabetic peripheral neuropathy. Table 14.2 Neurological tests. SECTION II • DIABETIC NEUROPATHIES 122 Treatment should be directed at underlying pathogenetic mechanisms, although the benefits of this approach are limited at present (Table 14.5). Effective symptomatic treatments are available for the manifestations of DPN but treatments should take into account number needed to treat (NNT) and needed to harm (NNH) (Table 14.6). Stages of diabetic peripheral neuropathy Stage of neuropathy Characteristics No neuropathy No symptoms or signs Clinical neuropathy Chronic pain Burning, shooting, stabbing pains ± pins and needles; increased at night; absent sensation to several modalities; reduced/absent reflexes Acute pain Severe symptoms as above (hyperaesthesia common); may follow initiation of insulin in poorly controlled diabetes; signs minor or absent Painless with Numbness/deadness of feet or no symptoms; painless complete/partial injury; reduced/absent sensation; reduced thermal sensory loss sensitivity; absent reflexes Late complications Foot lesions; neuropathic deformity; non-traumatic amputation 1. Types of diabetic neuropathy: frequent, sensorimotor symmetrical neuropathy (mostly chronic, sensory loss or pain), autonomic neuropathy (history of impotence and possibly other autonomic abnormalities); rare, mononeuropathy (motor involvement, acute onset, may be painful), diabetic amyotrophy (weakness/wasting usually of proximal lower limb muscles). 2. Staging does not imply automatic progression to the next stage. The aim is to prevent, or at least delay, progression to the next stage. Neurological tests Pin prick test Use a disposable instrument, e.g. a disposable dressmaker’s pin. Do not use a hypodermic needle. Ask ‘Is it painful?’ not ‘Can you feel it?’ Light touch Use a consistent method, ideally a cotton wisp Vibration test Use a 128 Hz tuning fork, initially on the big toe Ankle reflex Compare the ankle reflex with the knee reflex Pressure perception Absence of sensation in the foot to a 10 g monofilament may be used to assess the risk of foot ulceration Table 14.3 Management of the stages of neuropathy. Table 14.4 Classification of diabetic neuropathy. CHAPTER 14 • MANAGEMENT GUIDELINES FOR DPN AND FOOT ULCERATION 123 Management of the stages of neuropathy Stage Key elements Referral No clinical neuropathy Education; glycaemic Chiropodist/podiatrist/ (Stage 0/1) control a diabetes specialist nurse Annual assessment Clinical neuropathy (Stage 2) Chronic painful If disabled, treatment Diabetologist/neurologist with tricyclic drugs; glycaemic control Acute painful Simple analgesics/ Diabetologist/neurologist tricyclic drugs/NSAIDs/ opiates; glycaemic control Painless/loss of Education, especially Appropriate member of sensation footcare; glycaemic footcare team according control to needs Diabetic amyotrophy Early referral Neurologist/diabetologist Late complications Emergency referral if Diabetologist/neurologist/ (Stage 3) lesions present; chiropodist/podiatrist/ otherwise referral diabetes specialist nurse within 4 weeks a If, in future, specific therapies become available for the treatment of early neuropathy, the guidelines will require amendment to provide advice on the separate diagnosis and management of people with no neuropathy (Stage 0) and those with subclinical disease (Stage 1). Guidelines for the Diagnosis and Outpatient Management of Diabetic Peripheral Neuropathy, Diabetic Medicine 1998; 15: 508–514. Classification of diabetic neuropathy Generalized symmetric polyneuropathies: • acute sensory • chronic sensorimotor • autonomic Focal and multifocal neuropathies: • cranial • truncal • focal limb • proximal motor (amyotrophy) • (co-existing chronic inflammatory demyelinating polyneuropathy [CIDP] ) Note: Clinicians should be alert for treatable neuropathies occurring in diabetic patients including CIDP, monoclonal gammopathy, vitamin B 12 deficiency etc. Table 14.5 Treatment of diabetic neuropathy based on the putative pathogenetic mechanisms. Copyright © 2005 American Diabetes Association. From Diabetes Care 2005; 28: 956–962. Reprinted with permission from The American Diabetes Association. SECTION II • DIABETIC NEUROPATHIES 124 Treatment of diabetic neuropathy based on the putative pathogenic mechanisms Abnormality Compound Aim of treatment Status of RCTs Polyol pathway? Aldose reductase Nerve sorbitol ↓ inhibitors Sorbinil Withdrawn (AE) Tolrestat Withdrawn (AE) Ponalrestat Ineffective Zopolrestat Withdrawn (marginal effects) Zenarestat Withdrawn (AE) Lidorestat Withdrawn (AE) Fidarestat Effective in RCTs, trials ongoing AS-3201 Effective in RCTs, trials ongoing Epalrestat Marketed in Japan myo-Inositol ↓ Myo-inositol Nerve myo-inositol Equivocal Oxidative stress α-Lipoic acid Oxygen free Effective in RCTs, trials radicals ↓ ongoing Nerve hypoxia Vasodilators NBF ↓ ACE inhibitors Effective in 1 RCT Prostaglandin Effective in 1 RCT analogs phVEGF 165 Angiogenesis? RCTs ongoing gene transfer Protein kinase C PKC-β inhibitor NBF ↓ RCTs ongoing (ruboxistaurin) C-peptide ↓ C-peptide NBF Studies ongoing Neurotrophism ↓ Nerve growth Nerve regeneration, Ineffective factor (NGF) growth BDNF Nerve regeneration, Ineffective growth LCFA Acetyl-L-carnitine LCFA Ineffective metabolism ↓ accumulation ↓ GLA synthesis ↓γ-Linolenic acid EFA metabolism Withdrawn (GLA) NEG Aminoguanidine AGE accumulation ↓ Withdrawn BDNF: brain-derived neurotrophic factor; NEG: non-enzymatic glycation; AGE: advanced glycation end products; EFA: essential fatty acids; LCFA: long-chain fatty acids; AE: adverse events; NBF: nerve blood flow; RCTs: randomized controlled trials. [...]... years of diagnosis of diabetes and 78% in those with disease duration >15 years • The prevalence of proliferative retinopathy is 2% in those within five years of onset of diabetes, rising to 16% in those with disease duration >15 years The higher prevalence of retinopathy in those diagnosed with diabetes over the age of 30 is partly due to the difficulty in determining the precise date of onset of disease... Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet 1998; 352: 837–853 UK Prospective Diabetes Study Group Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38 BMJ 1998; 317: 703–13 137 Vascular Complications of Diabetes: ... Intensive BP control reduces the risk of progression of retinopathy Even small reductions in BP translate into large clinical benefits FURTHER READING Diabetes Control and Complications Trial Research Group The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes N Engl J Med 1993; 329: 977–9 86 Klein, R, Klein BEK, Moss SE,... prevalence of retinopathy at the time of diagnosis of type 2 diabetes has been reported to be as high as 38% Four-year incidence of visual impairment in participants surviving and completing the follow-up examination Visual impairment at baseline Number of participants None (%) Mild (%) Moderate (%) Blind (%) 832 26 10 20 95.3 26. 9 10.0 0 2.8 42.3 10.0 0 1.4 15.4 30.0 0 0.5 15.4 50.0 100.0 Older-onset,... The incidence of proliferative retinopathy over a 4-year and 10-year period is 2–7% and 10–23%, respectively RISK FACTORS FOR DIABETIC RETINOPATHY Hyperglycaemia Chronic hyperglycaemia is the major risk factor in the development of diabetic retinopathy The US Diabetes Control and Complications Trial (DCCT) evaluated the rates of development of microvascular complications in two groups of type 1 diabetics... 26: 113–119 Vinik AI, Maser RE, Mitchell BD, Freeman R Diabetic autonomic neuropathy Diabetes Care 2003; 26: 1553–1579 Vascular Complications of Diabetes: Current Issues in Pathogenesis and Treatment, Second Edition Edited by Richard Donnelly, Edward Horton Copyright © 2005 by Blackwell Publishing Ltd SECTION III DIABETIC RETINOPATHY AND ASSOCIATED OPHTHALMIC DISORDERS Vascular Complications of Diabetes: ... prevalence of blindness in diabetic patients is approximately 2% Diabetic retinopathy accounts for between 8 and 12% of all registrable blindness (defined as a Snellen visual acuity of 6/ 60 or worse in the better eye) PREVALENCE OF DIABETIC RETINOPATHY Summary of findings from the WESDR: Onset of diabetes before age 30 years (Fig 15.1) • The prevalence of any retinopathy is 2% in those within two years of. .. rate of progression of retinopathy in those patients randomized to more intensively controlled BP Use of an angiotensin-converting enzyme inhibitor (ACE-I) may be particularly effective in reducing the progression of retinopathy, independently of BP reduction, especially in normotensive type 1 diabetics Age Diabetic retinopathy is rare under 10 years of age; only one case was seen in the first decade of. .. on the rate of progression of retinopathy In a small case-control study of type 2 diabetic patients by Dodson and Gibson, patients with maculopathy were followed-up over seven years and compared with a matched group of patients without maculopathy The group with maculopathy was found to have higher serum cholesterol levels (6. 6 vs 5.9 mmol/l), higher levels of the HDL2 subfraction (0. 46 vs 0.32 mmol/l)... years of diagnosis of diabetes and 98% in those with disease duration >15 years • The prevalence of proliferative retinopathy is 0% in those within five years of diagnosis of diabetes, rising to 67 % in those with disease duration >35 years 129 130 SECTION III • DIABETIC RETINOPATHY AND ASSOCIATED OPHTHALMIC DISORDERS Onset of diabetes after age 30 years (Fig 15.2) • The prevalence of any retinopathy . with diabetes over the age of 30 is partly due to the difficulty in determining the precise date of onset of disease. The prevalence of retinopathy at the time of diag- nosis of type 2 diabetes. the development of dia- betic retinopathy. The US Diabetes Control and Complications Trial (DCCT) evaluated the rates of development of microvascular complications in two groups of type 1 diabetics. control. Fig. 15.3 Four-year progression of retinopathy by quartile of HbA1 C and duration of diabetes at baseline in persons with (top) younger-onset diabetes; (centre) older- onset diabetes, taking