VASCULAR COMPLICATIONS OF DIABETES - PART 6 doc

In total there are 13 published trials of anticonvulsants of whichonly six are randomized controlled trials which show that, for those diabeticpatients with painful neuropathy given anti

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 besummarized 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 effectivewhen 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• Too toxic A number of ARIs were withdrawn in phase III due to hepatic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 radicalsdue 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 dant alpha-lipoic acid (LA) have provided evidence of potential efficacy with thisagent 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

antioxi-Gamma-linolenic acid (GLA)

GLA can prevent abnormalities in essential fatty acid and prostanoid olism GLA treatment for one year in a randomized trial resulted in improve-ment in electrophysiology and deficits A LA/GLA conjugate has producedimpressive improvements in electrophysiological and neurochemical abnor-malities in experimental diabetic neuropathy but this has not been tested indiabetic patients

metab-Inhibitors of glycation

Non-enzymatic glycation occurs in diabetes and may be an important 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

initiat-of advanced glycation have shown no benefit in diabetic nephropathy and fewdata 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 activatesPKC-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 havebeen shown to correct endothelial dependent relaxation, nerve perfusiondeficits and conduction velocity in animal models Preliminary phase II datasuggest that treatment with a PKC-β inhibitor might ameliorate symptomsand 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 beenshown to improve electrophysiological measures of nerve function in mildneuropathy The short-acting vasodilator isosorbide dinitrate has been shown

to improve painful symptoms, but its effect on deficits and electrophysiologyare unknown

Neutrophins

Neurotrophic factors are important in the growth and development of rones These include insulin-like growth factor I and II and the neurotrophinfamily 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 smallfibre dysfunction in diabetic rats A promising phase II study showed animprovement in human diabetic neuropathy However this was not con-firmed in a phase III study and therefore the clinical development of NGF washalted Similarly, a small study with BDNF has also shown no benefit

subcuta-Pharmacotherapy

A large number of therapeutic agents have been used in the management ofpainful 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 agentsshould be used with caution in neuropathic diabetic patients, many of whommay 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 thesedrugs relieve pain include inhibition of norepinephrine and/or serotoninreuptake at synapses of central descending pain pathways More recently, theantagonism of n-methyl-d-aspartate receptors has been shown to alleviatehyperalgaesia and allodynia

Most experience has been achieved with amitriptyline and imipramine Thedosage 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 firmed in a systematic review performed by McQuay and colleagues Themajor 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

con-Selective serotonin-reuptake inhibitors (SSRIs)

These agents inhibit pre-synaptic reuptake of serotonin but not rine Studies suggest that treatment with paroxetine but not fluoxetine is asso-ciated with significant pain relief Similarly citalopram 40 mg/day is efficaciousbut less effective than imipramine Their main advantage is lesser side-effects

norepineph-Anticonvulsants

Anticonvulsants have been used in the management of neuropathic pain formany years In total there are 13 published trials of anticonvulsants of whichonly six are randomized controlled trials which show that, for those diabeticpatients 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 fordiabetic neuropathy Agranulocytosis has been reported with carbamazepineand must be monitored by obtaining blood counts at baseline and thereafterperiodically 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 rently five randomized-controlled trials underway in Japan evaluating its effi-cacy in diabetic neuropathy Gabapentin is now widely used for neuropathic

cur-CHAPTER 13 • TREATMENTS OPTIONS

symptoms based on the results of a large controlled trial in symptomatic ropathy where significant pain relief together with reduced sleep disturbancewas reported using dosages of 900–3,600 mg daily In a recent review of all thetrials of gabapentin for neuropathic pain, it was concluded that dosages of1,800–3,600 mg per day of this agent were effective The side-effect profile alsoseems superior to that of the tricyclic drugs, though somnolesence is a prob-lem with higher doses Pregabelin has been shown to be more efficacious thangabapentin with even lesser side effects Lamotrigine has at least two anti-nociceptive properties and in a randomized placebo controlled study wasshown to have efficacy in patients with neuropathic pain

neu-Anti-arrhythmics

Mexilitine is a class 1B antiarrhythmic agent and a structural analogue of 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 usedfor the treatment of cardiac arrhythmias However, regular ECG monitoring

lig-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

SECTION II • DIABETIC NEUROPATHIES

118

Other agents

Tramadol is an opioid-like centrally acting, synthetic non-narcotic analgesicwhich was shown to produce significant symptomatic relief in a randomizedcontrolled trial of patients with painful diabetic neuropathy initially over sixweeks which was maintained for at least six months However, side-effects arerelatively common and are similar to other opioid-like drugs Similarly, tworandomized 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 thefeet of isosorbide dinitrate spray was effective in relieving overall pain andburning 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 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 indiabetic neuropathic pain However, true blinding of these studies has beenquestioned because of the local hyperalgesia experienced when applying theactive drug Furthermore, with the overt epidermal nerve fibre damage itcauses one must question the ethical basis of promoting denervation in a footwhich already has or will have sensory loss

epi-Acupuncture

A number of unmasked studies support the use of acupuncture and, in themost recent published report, benefits of acupuncture lasted for up to sixmonths and reduced the use of other analgesics

OTHER PHYSICAL THERAPIES

A number of other physical therapies have been proposed, though few havebeen rigorously tested in controlled clinical trials Efficacy has been shownwith 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 ventional therapy suggested efficacy of using an implanted spinal cord stim-ulator This approach can only be recommended in very resistant cases as it

con-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;

• 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, neurolodiabetolo-gists, 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 DPNbut 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

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:

• 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 B12deficiency 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

phVEGF165 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

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.

Table 14.6 Oral symptomatic therapy of painful neuropathy Copyright © 2005

American Diabetes Association From Diabetes Care 2005; 28: 956–962 Reprinted with

permission from The American Diabetes Association.

CHAPTER 14 • MANAGEMENT GUIDELINES FOR DPN AND FOOT ULCERATION 125

FOOT ULCERATION

It is agreed that diabetic foot ulcers pose a great burden on both the patientand the health care systems of many countries A multifactorial approach withthe input of many different specialists is advocated in diagnosing and treatingdiabetic patients with foot ulceration An International Consensus on theDiabetic Foot, resulting in a worldwide network of professionals involved inthe management of diabetic patients with foot problems, has emerged

Prophylactic foot care has been shown to decrease patient morbidity,utilization of expensive resources, and risk for amputation and prematuredeath In 2005 the Diabetes Committee of the American Orthopaedic Footand Ankle Society has recently developed guidelines for the implementation

of such prophylactic foot care Screening and treatment algorithms arebased on an evaluation of neuropathy, skin integrity, ulcer history, defor-mity and vascular insufficiency Treatment includes paring of calluses,debridement of infected or nonviable tissue, dressings, and off-loading withpatient education and provision of appropriate orthoses/footwear Timelyspecialty assistance and cross referral to a vascular surgeon, orthopaedicsurgeon, podiatrist, diabetologist, infectious disease consultant and radiol-ogist is encouraged

Oral symptomatic therapy of painful neuropathy

NNT = Numbers needed to treat to achieve pain relief in 1 patient

NNH = Numbers needed to treat to harm 1 patient

CI = Confidence Interval

ND = Not determined