Diabetic Neuropathy

Dr Shahjada Selim
Department of Endocrinology
BSMMU, Bangladesh
email: selimshahjada@gmail.com
info@shahjadaselim.com
Diabetic Neuropathy can be defined as-

The presence of symptoms and/or

signs of nerve dysfunction
in people with diabetes after other
causes have been excluded.
 Diabetic Neuropathy: Problem statement

• All forms of diabetes of sufficient duration are

vulnerable
• May coincide with CIDP, vit B12 deficiency,
alcoholic neuropathy, endocrine neuropathies.
• Additional causes in 10% to 55% of patients
with DM.
• Prevalence estimates from 5% to 100%.
• Can occur with IGT and metabolic syndrome
without hyperglycemia.
• Most common form of neuropathy in the
developed countries.
• More hospitalizations than all diabetic
complications
• 50% to 75% of nontraumatic amputations.
• Weakness and ataxia, likelihood of falling 15
times unaffected.
• 25% had symptoms, 50% had neuropathy after
ankle reflex or vibration test.
• 90% positive on sophisticated tests of autonomic
function or peripheral sensation.
• Major morbidity is foot ulceration, gangrene,
limb loss.
• Amputation risk 1.7-fold , 12-fold if deformity
(consequence of neuropathy), 36-fold if h/ o
ulceration.
 Risk Factors For The Development Of
Diabetic Neuropathy
Modifiable Risk Factors
• Poor glycemic control (Elevated HbA1c)
• Hypertension
• Cigarette Smoking
• Alcohol
• Hypertriglyceridemia

Harati Y. Diabetic Neuropathies: Unanswered Questions. Neurol Clin 25 (2007) 303–317

Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med
2005;352(4):341.
 Risk Factors For The Development Of Diabetic Neuropathy

Non-modifiable Risk Factors

• Obesity
• Older age
• Male sex
• Height
• Family h/o neuropathic disease
• Longer duration of diabetes
• APOE genotype
• Aldose reductase gene hyperactivity
• Angiotensin-converting enzyme genotype
Harati Y. Diabetic Neuropathies: Unanswered Questions. Neurol Clin 25 (2007) 303–317
Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med
2005;352(4):341.
 STAGING
• No- no symptoms or signs of neuropathy
• N1- asymptomatic, only signs of neuropathy
• N2- symptomatic neuropathy
• N3- disabling polyneuropathy.
 Distal Symmetrical Polyneuropathy

A. Acute sensory neuropathy

• Burning discomfort in feet, hyperesthesiae,
deep aching pain
• Sharp, stabbing or “electric shock” like
sensations in lower limbs.
• Weight loss, depression, erectile
dysfunction
• Nocturnal exacerbation, clothes irritating
hyperesthetic skin.
 Distal Symmetrical Polyneuropathy

A. Acute sensory neuropathy

• Allodynia on sensory testing, a normal motor
exam, reduced ankle reflexes.
• Poor glycemic control, may follow an episode
of ketoacidosis
• Associated with weight loss & eating disorders
• May develop after sudden improvement of
glycemic control? (Insulin neuritis)
• Blood glucose flux in genesis of neuropathic pain .
• Degeneration of myelinated & unmyelinated fibers
• More common in DM with mitochondrial tRNA
mutation at 3243 (Suzuki , 1997)
• Neural ischemia by sudden improvement of
glycemic control, “steal” effect with arteriovenous
shunting
• In management, stable blood glucose control is
most important.
• Onset acute or subacute, severe symptoms resolve
in less than a year
 Chronic Sensorimotor Neuropathy (DPN)

• Most common DN, 3/4th of all DN.

• Sensory predominant, autonomic correlate with severity
• Minor involvement of distal muscles of lower
extremities.
• Sensory stocking-glove distribution
• Length-dependent pattern.
• Advanced- sensation impaired over chest & abdomen -
wedge-shaped area.
Large-fiber Neuropathy
• Painless paresthesias beginning at the toes and feet,

• Impaired vibration & JPS

• Diminished reflexes.

• Ataxia secondary to sensory deafferentation.

• Often asymptomatic, sensory deficit on

examination.
Small-fiber Neuropathy
• Deep, burning, stinging, aching pain; allodynia to light
touch.
• Pain & temp impaired, relative preservation of vibration
& JPS & DTR
• Often accompanied by autonomic neuropathy

• May develop soon after onset of T1DM.

• Distal joint destruction (acrodystrophic neuropathy).

• Chronic foot ulceration (4% to 10%) due to unnoticed tissue

damage, vascular insufficiency, secondary infection
• Neuropathic arthropathy(Charcot joint ) in patients with foot
ulcers & autonomic impairment
• Small joints of feet.

• Diabetic pseudotabes - lancinating pains, loss of JPS , diabetic

pupillary abnormalities (pseudo-Argyll Robertson pupils).
 Diabetic Autonomic Neuropathy

• Correlates with severity of somatic neuropathy.

• Subclinical impairment CVS , GI , GU dysfunction
• Orthostatic hypotension, resting tachycardia, diminished
heart-rate response to respiration
• Vagal denervation of heart- high resting pulse & loss of
sinus arrhythmia.
• Painless or silent myocardial infarction.
 Investigations Recommended

• Urinalysis for protein/glucose/microscopy-for evidence of

nephropathy.
• HbA1c/glucose
• Urea and electrolytes
• LFT including GGT
• Thyroid function tests
• Serum protein electrophoresis
• Vitamin B 12 levels.
• Assess symptoms - muscle weakness, muscle cramps, prickling,
numbness or pain, vomiting, diarrhea, poor bladder control and
sexual dysfunction
• X-ray
• Ultrasound
• GI motility abnormalities of esophagus, stomach,
gallbladder, bowel, fecal incontinence.
• Delayed gastric emptying - nausea, early satiety,
postprandial bloating.
• Diabetic diarrhoea due to small-intestinal involvement,
at night, paroxysmal.
• Constipation due to colonic hypomotility is more
common than diarrhoea.
• Bacterial overgrowth may occur.
• Impaired bladder sensation - first symptom of GU
dysfunction.
• Bladder atony - prolonged intervals between voiding,
urinary retention, overflow incontinence.
• Void every few hours to prevent urinary retention.
• Impotence is often first manifestation in men , occurring
in more than 60%.
• Both erectile failure and retrograde ejaculation.
• Impotence usually associated with distal symmetrical
polyneuropathy.
• Sudomotor abnormalities - distal anhidrosis, facial and
truncal sweating, heat intolerance.
• Gustatory sweating - profuse sweating in face following
food .
• Pupillary abnormalities - constricted pupils with sluggish
light reaction, in 20% .
• Blunted response to hypoglycemia - inadequate
sympathetic & adrenal response - unawareness of
hypoglycemia –complicates intensive insulin treatment
 Proximal Diabetic Neuropathy (Diabetic
Amyotrophy or Lumbosacral Radiculoplexopathy)

• Diabetic proximal neuropathy,. Diabetic amyotrophy,

thoracic radiculopathy, and proximal or diffuse lower
extremity weakness -different presentations of
involvement of roots or proximal nerve segments.
• Asymmetrical weakness and wasting of pelvifemoral
muscles may occur abruptly or stepwise in individuals
with diabetes older than 50 .
• May develop with long-standing NIDDM during poor
metabolic control and weight loss, but can occur in mild
and well-controlled diabetics or be presenting feature.
• Unilateral severe pain in the lower back, hip, and
anterior thigh heralds onset
• Within days to weeks, weakness of proximal and, to a
lesser extent, distal lower-extremity muscles (iliopsoas,
gluteus, thigh adductor, quadriceps, hamstring, and
anterior tibialis).
• Opposite leg affected after days to months.
• Reduced or absent knee and ankle jerks.
• Weight loss in more than half & more than nondiabetic
lumbosacral radiculoplexopathy.
• Pain recedes before power improves.
• Recovery takes up to 24 months due to slow axonal
regeneration, mild to moderate weakness may persist.
• EMG-low-amplitude femoral nerve motor responses,
fibrillation potentials in thoracic and lumbar paraspinal
muscles, active denervation in affected muscles.
• Neuroimaging should be considered when lumbar root,
cauda lesions, or structural lumbosacral plexopathy
suspected .
• No effect of corticosteroids in recovery of motor deficit.
 Truncal Neuropathy
• T4 -T12 radiculopathy - pain or dysesthesias in
distribution.
• Bulging of abdominal wall due to weakness of abdominal
muscles
• In isolation or with lumbosacral radiculoplexopathy.
• Can mimic intraabdominal, intrathoracic, or intraspinal
disease, zoster .
• May persist for several months before resolution within 4
to 6 months.
• EDX - active denervation in paraspinal and abdominal
muscles,
• Focal anhidrosis in area of pain with thermoregulatory
sweat test.
 LIMB MONONEUROPATHY
• Nerve infarction or entrapment.

• Infarction- abrupt onset of pain , variable weakness and atrophy.

Median, ulnar, fibular n. commonly affected.
• Entrapment more common than infarction.
• EDX - axonal loss in nerve infarction ; conduction block or
slowing in entrapment.
• DM in 8% to 12% of patients with CTS.
• Aggravation of ischemia in nerves with chronic endoneurial
hypoxia.
 Multiple Mononeuropathies
• Mononeuritis multiplex- replaced as rarely due to
inflammation
• Involvement of two or more nerves
• Onset abrupt in one nerve, other nerves are
involved sequentially
• Multiple mononeuropathies involving proximal
nerves considered cause of amyotrophy.
• Infarction results occlusion of vasa nervorum.
• Systemic vasculitis be considered in D/D
 Cranial Mononeuropathies
• 3 rd nerve palsy is most common
• Pupillary sparing, from ischemic infarction of the
centrifascicular oculomotor axons
• Peripheral pupillary motor fibers spared due to
collateral circulation
• 4th , 6th, 7th nerves also affected.
• Bell palsy- higher frequency of diabetes.
• Rhinocerebral mucormycosis and “malignant”
external otitis
 Comparison of features of mononeuropathies, entrapment
syndromes and distal symmetric polyneuropathy

Vinik et al , Diabetic Neuropathy in Older Adults. Clin Geriatr Med 24 (2008) 407–435
Is it ‘‘Diabetic Neuropathy’’ or ‘‘Neuropathy In
A Diabetic Patient’’?
Think if-
• Rapidly progressive
• Prominent motor abnormality or cranial nerve
involvement
• Disproportionate large fiber abnormalities.
• Involvement of the entire lower limbs without
neuropathy of the distal upper limb.
• More often sensory symptoms and findings in the
hands
 Signs
• Scores to assess clinical signs pioneered by Dyck,
who first described the NDS and later the Neuropathy
Impairment Score (NIS).
• A modified NDS used in several studies , can be used
in community
• Shown to be best predictor of foot ulceration and best
neuropathic end point in a large prospective
community study
• The maximum NDS is 10, with a score of 6 or more
being predictive of foot ulcer risk.
Neuropen
• Assesses pain using both a Neurotip at one end of the “pen” and a
10-g monofilament at other end.
• Was shown to be sensitive device for assessing nerve function
when compared with the simplified NDS
 Electrophysiology
• NCV is only gradually diminished by DPN, with
estimates of a loss of 0.5m/ s/ year.
• Sensitive but nonspecific index on onset
• Detecting subclinical deficits.
• Trace the progression.
• Changes related to glycemic control.
• Can reflect pathology in large axons (Atrophy,
demyelination,loss of density)
• Can improve with effective therapy
Amplitudes, area, and duration. Peak
Strong correlation (r 0.74; P 0.001) between
myelinated fiber density and whole-nerve sural
amplitude in DPN
Loss of SNAP amplitude at a rate of 5% per year in
DPN over 10-year period
• Total area of the SNAP and CMAP suggested as
means of assessing contribution of slower conducting
fibers,
• Area alone, or with peak amplitude, can be used to
estimate temporal dispersion and conduction block.
 Diagnostic tests of Autonomic Neuropathy
Resting heart rate
>100 bpm is abnormal.
 Beat-to-beat HRV
At rest and supine heart rate by ECG while patient breathes at
6/m
Difference of >15 bpm - normal, <10 bpm - abnormal.
 Lowest normal value for the expiration-to-inspiration ratio of
the R-R interval is 1.17 in 20–24 years of age.
Heart rate response to standing
R-R interval measured at beats 15 and 30 after standing.
Normally, tachy F.B. reflex brady. The 30:15 ratio is 1.03.
• Heart rate response to the Valsalva maneuver
 Exhales into manometer to 40 mmHg for 15 s
 Healthy subjects develop tachy & peripheral
vasoconstriction during strain & overshoot brady, rise
in BP with release.
 The ratio of longest R-R to shortest R-R should be 1.2.
• Systolic blood pressure response to standing
 Sys BP measured supine. Patient stands, BP aft 2 m.
 Normal response- fall of <10 mmHg,
 Borderline - fall of 10–29 mmHg
 Abnormal - fall of >30 mmHg with symptoms
• Diastolic blood pressure response to isometric exercise
 Squeeze handgrip dynamometer to a max . Then squeezed at
30% max for 5 min.
 N response for diastolic BP is a rise of >16 mmHg in the other
arm.
• ECG QT/QTc intervals
The QTc should be 440 ms.
• Neurovascular flow
 Using noninvasive laser Doppler measures of peripheral
sympathetic responses to nociception.
• Radionuclide Cardiac Imaging
 123-I-metaiodobenzylguanidine (MIBG)
 11-C-hydroxyephedrine
 Management of Diabetic Neuropathy
Symptomatic management
1) Exclude nondiabetic causes
● Malignant disease (e.g., bronchogenic carcinoma)
● Metabolic
● Toxic (e.g., alcohol)
● Infective (e.g., HIV infection)
● Iatrogenic (e.g., isoniazid, vinca alkaloids)
● Medication related (chemotherapy, HIV treatment)
2) Explanation, support, and practical measures (e.g., bed cradle to lift bed,
clothes off hyperesthetic skin)
3) Assess level of blood glucose control profiles
4) Aim for optimal stable control
5) Consider pharmacological therapy
 Control Of Hyperglycemia
• Open-label uncontrolled studies suggested near normoglycmia
helpful in painful neuropathic symptoms.
• Stability of glycemic control equally important to level of
achieved control.
• Lack of appropriately designed controlled studies

• Generally accepted that intensive diabetes therapy aimed at

near normoglycemia should be first step in the treatment of any
form of DN.
• Duckworth et al.(2009)( 6y) no benefit for new neuropathy

• Action to Control Cardiovascular Risk in Diabetes

(ACCORD) trial- (10,000 patients) -new cases of
neuropathy significantly reduced intensive group
• ADVANCE trial –( 11,000 patients)- (5y) not significantly
affected by intensive control
• Diabetes Control and Complication Trial (DCCT; 1995) –
(5y) intensive management reduces neuropathy by 64%
• Benefit persisted for 8 years after DCCT
 Pharmacotherapy
• No evidence to support NSAIDs.
Tricyclic drugs
• Several RCTs supported these agents in neuropathic pains.
Mechanisms
 Inhibition of NE &/or 5-HT reuptake at synapses of central
descending pain control systems
 Antagonism of NMDA rec mediating hyperalgesia &
allodynia .
 Rapid onset, suggests a mode of action not primarily relief of
depression.
• use is restricted because of the frequency and severity of side
effects.
• Most experience with amitriptyline and imipramine.
• Can be taken once a day in the evening.
• Desipramine also useful drug ,better tolerated than
amitriptyline
• Side effects
 Drowsiness and lethargy
 Anticholinergic side effects, particularly dry mouth
• In cases of painful neuropathy resistant to tricyclic
drugs, combination with major tranquilizers
• Amitriptyline and transcutaneous electrotherapy
described in failed monotherapy.
• Superior to that of tricyclic monotherapy plus sham
electrotherapy
SSRIs
• inhibit presynaptic reuptake of 5HT, not NE.

• Paroxetine but not fluoxetine associated with

significant pain relief.
• Citalopram 40 mg/day was confirmed to be efficacious
in relieving neuropathic pain, but less effective than
imipramine
• Side effects are less common with SSRIs.
Anticonvulsants.
• Used for many years
• Limited evidence for phenytoin and carbamazepine in DN
• Gabapentin now widely used
• In a large controlled trial, significant pain relief 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
• Lamotrigine - antiepileptic agent with at least two antinociceptive
properties.
• In a randomized placebo controlled study, Eisenberg et al
confirmed
the efficacy of this agent in patients with neuropathic pain.
Antiarrhythmics
• Mexilitine is a class 1B antiarrhythmic , structural analog of
lignocaine.
• Efficacy in neuropathic pain confirmed in controlled trials and
reviewed by Dejgard et al. and Jarvis and Coukell.
• The dosage used in trials (up to 450 mg daily) is lower than that
used for arrhythmias;
• Regular ECG monitoring necessary

• Long-term use of mexilitine cannot be recommended.

Other agents
• Tramadol - opioidlike, centrally acting, nonnarcotic analgesic.
• Although first trial was 6 weeks’ duration, subsequent follow-up
study suggested symptomatic relief could be maintained for at
least 6 months
• Side effects common , similar to other opioid-like drugs.

• Similarly, two randomized trials have confirmed the efficacy of

controlled-release oxycodone for neuropathic pain in diabetes
• Opioids such as oxycodone may be considered as add-on
therapies for patients failing to respond to nonopioid medications.
 Topical and physical treatment
Topical Nitrate
• A recent study suggested local application feet of isosorbide
dinitrate spray was effective in relieving overall pain & burning
discomfort
Capsaicin
• Alkaloid, in red pepper, depletes substance P and reduces
chemically induced pain.
• Several controlled studies combined in meta-analyses seem to
provide some evidence of efficacy in diabetic neuropathic pain
• Only recommended for up to 8 weeks of treatment
• Useful in localized discomfort.
Acupuncture
Unmasked studies support its use .
In recent report, benefits lasted 6 months, reduced use of other
analgesics
Conduct of potential blinded studies of acupuncture is
problematic; although a placebo response is possible with
acupuncture
Other physical therapies.
Percutaneous nerve stimulation
Static magnetic field therapy .
Electrical spinal cord stimulation.
 A case series of patients with severe painful neuropathy
unresponsive to conventional therapy suggested efficacy of using
an implanted spinal cord stimulator.
 Evidence-based guideline:
Treatment of
painful diabetic neuropathy

Anticonvulsants
• If clinically appropriate, pregabalin should be offered for the
treatment of PDN (Level A).
• Gabapentin and sodium valproate should be considered for the
treatment of PDN (Level B).
• There is insufficient evidence to support or refute the use of
topiramate for the treatment of PDN (Level U).
• Oxcarbazepine, lamotrigine, and lacosamide should probably not be
considered for the treatment of PDN (Level B).

Valproate may is potentially teratogenic, be avoided in women of childbearing age. Due to weight gain and potential worsening of glycemic control,
this drug is unlikely to be the first treatment choice for PDN.
Antidepressants

• Amitriptyline, venlafaxine, and duloxetine should be considered

for the treatment of PDN (Level B). Data are insufficient to
recommend one of these agents over the others.

• Venlafaxine may be added to gabapentin for a better response

(Level C).

• There is insufficient evidence to support or refute the use of

desipramine, imipramine, fluoxetine, or the combination of
nortriptyline and fluphenazine in the treatment of PDN (Level U).
Opioids
 Dextromethorphan, morphine sulfate, tramadol, an oxycodone
should be considered for the treatment of PDN (Level B). Data
are insufficient to recommend one agent over the other

 The use of opioids for chronic nonmalignant pain has

gained credence over the last. Both tramadol and
dextromethorphan were associated with substantial adverse
events (e.g., sedation, nausea, and constipation).

 The use of opioids can be associated with the development

of novel pain syndromes such as rebound headache.

 Chronic use of opioids leads to tolerance and frequent

escalation of dose.
Other pharmacologic agents

• Capsaicin and isosorbide dinitrate spray should be considered for

the treatment of PDN (Level B).
• Clonidine, pentoxifylline, and mexiletine should probably not be
considered for the treatment of PDN (Level B).
• The Lidoderm patch may be considered for the treatment of PDN
(Level C).
• There is insufficient evidence to support or refute the usefulness of
vitamins and -lipoic acid in the treatment of PDN (Level U).
• Although capsaicin has been effective in reducing pain in PDN
clinical trials, many patients are intolerant of the side effects,
mainly burning pain on contact with warm/hot water or in hot
weather.
 Nonpharmacologic modalities ?

• Percutaneous electrical nerve stimulation should be

considered for the treatment of PDN (Level B).

• Electromagnetic field treatment, low-intensity laser

treatment, and Reiki therapy should probably not be
considered for the treatment of PDN (Level B).

• Evidence is insufficient to support or refute the use of

amitriptyline plus electrotherapy for treatment of PDN
(Level U).
 Summary Of Recommendations

V. Bril, J. England, G.M. Franklin, et al. Evidence-based guideline: Treatment of painful diabeticneuropathy : Report of the American Academy of Neurology, the
American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation .Neurology 76 May 17,
2011
 Autonomic Neuropathy
• Head of bed elevated 6 to 10 inches.
• Prevents salt & water losses during night and combat supine
hypertension.
• Two cups of strong coffee or tea with meals
• Frequent small meals
• Daily fluid intake (>20 oz/day) and salt ingestion (10-20 g/day).
• Elastic body stockings may be beneficial by reducing the venous
capacitance in bed but poorly tolerated.
• Plasma volume expansion can by fludrocortisone (0.1-0.6 mg/day).
• NSAlDs, which inhibit prostaglandin synthesis, ibuprofen, 400 mg
QID
• Phenylpropanolamine (25-50 mg TDS), once used to manage OH
• Midodrine, an α1-adrenergic agonist,causes vasoconstriction, also
effective.
• Subcutaneous recombinant human erythropoietin effective in
some patients with OH & anemia.
• Octreotide may improve OH by splanchnic vasoconstriction.
• Delayed gastric emptying relieved with metoclopramide
• Diabetic diarrhea treated with short courses of tetracycline or
erythromycin
• Clonidine reported to reduce troublesome diarrhea.
 Pathogenetic Treatments And
Prevention
Aldose Reductase Inhibitors.
• The first clinical trials of ARIs in DN took place 25
years ago, and currently only one agent is available in
one country (Epalrestat in Japan) .
• Most of the early trials can be summarized as:

● Too small. ● Too few ● Too short. ● Too late.

TREATMENT OF DIABETIC NEUROPATHY BASED ON PATHOGENETIC
MECHANISMS

From boulton a, vinik, a, arezzo j, et al. American diabetes association: position statement: diabetic neuropathies. 2005.
Antioxidants
• α -LA - potential efficacy for both symptoms &
modifying natural history . (ALADIN II, ALADIN III,
SYDNEY)
• Two large North American/European clinical trials of of
α -LA are in progress
• γ-LA (GLA) , component of evening primrose oil, can
prevent abnormalities in diabetes and in essential fatty
acid and prostanoid metabolism
• GLA treatment for 1 year in a randomized trial resulted
in improvement in electrophysiology and deficits
Neutrophins
As a result of contradictory results from clinical trials, the clinical
development of NGF was halted,
Inhibitors of glycation
 Studies of aminoguanidine, which inhibits the formation of
AGEs, mainly focused on nephropathy
Few data are available on aminoguanidine or other inhibitors of
AGE formation in clinical neuropathy
PKC inhibition
 Intracellular hyperglycemia increases DAG levels, which activates
PKC formation
Preliminary data suggest that treatment with a PKC- inhibitor
might ameliorate measures of nerve function in DPN . Multicenter
trials are currently in progress
Vasodilators
• Treatment with ACE inhibitors has been shown to
improve electophysiological 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
 Take Home Message
• Diabetic neuropathy occurs in about 45% patients with Diabetes
Mellitus
• Metabolic and Vascular factors are implicated in pathogenesis.
• Most common type is distal symmetrical sensorimotor
polyneuropathy
• Exclude nondiabetic etiologies
• Stabilize glycemic control
• Tricyclic drugs (eg, amitriptyline 25 to 150 mg before bed)
• Anticonvulsants (eg, gabapentin, typical dose 1.8 g/day)
• Opioid or opioid-like drugs (eg, tramadol or controlled
release oxycodone)
• Drugs targeting pathogenic process are in development and may
be available in near future.
 References
• Katirji B, Koontz D. Disorders of Peripheral Nerves. In:
Bradley’s Neurology in Clinical Practice. 5th Edition.
• Harrison’s Principles of Internal Medicine. 18th Edition.
• Harati Y. Diabetic Neuropathies: Unanswered Questions.
Neurol Clin 25 (2007) 303–317.
• Vinik A I et al. Diabetic Autonomic Neuropathy. Diabetes
Care, Volume 26, Number 5, May 2003
• Boulton AJM. Diabetic Neuropathies:A statement by the
American Diabetes Association. Diabetes Care, Volume 28,
Number 4, April 2005.
• Vinik AI et al. Diabetic Neuropathy in Older Adults. Clin
Geriatr Med 24 (2008) 407–435.
 Features of Diabetic Neuropathy
• Common complication affecting up to 50%
patients with DM

• Diagnosed in the presence of 2 abnormal

symptoms or signs

• Frequently asymptomatic & mostly untreatable

• Requires careful examination/assessment to

detect (NDS, NSS)
 .........Features of Diabetic Neuropathy

• Affects quality of life (pain, depression)

• Patients with DN are 15 times more likely to

have LL amputation

• Foot problems are the commonest reason for in-

patient admission

• Death most frequently due to cardiovascular

disease
 What causes Diabetic Neuropathies?
 Metabolic factors - such as high blood
glucose, long duration of diabetes,
abnormal blood fat levels, and possibly
low levels of insulin

 Neurovascular factors, leading to

damage to the blood vessels that carry
oxygen and nutrients to nerves

 Autoimmune factors that cause

inflammation in nerves

 Mechanical injury to nerves

 Lifestyle factors, such as smoking or

alcohol use
 Burden of Diabetes Neuropathy

• Cost to the Patient: pain

loss of function
depression
loss of independence
loss of earnings

• Cost to the Health Care Service: GP, community/OP/IP

services

• Cost to society: Number of patients growing

of Diabetes (Diabetic Capital of
World)
Workforce
Welfare system

• Increasing prevalence across all age groups

 Etiology & Pathophysiology

• Alterations in nerve blood flow

• Schwann cell dysfunction: Primary

demyelination, secondary segmental
demyelination due to impairment of axonal
control of myelination, remyelination, SC
proliferation, atrophy of denervated bands of
SC, basal lamina hypertrophy.
 ...........Etiology & Pathophysiology

• Neuronal degeneration & progressive

impairment of regeneration (esp. thin
myelinated fibres)

• Neuronal damage caused by hyperglycaemia

(activation of the polyol p’way, synthesis of
AGE products, excess activation of PKC-driven
p’ways, microangiopathy of the vasa nervorum)

• Oxidative stress
Pathophysiology-biochemical and vascular factors

www.plymouthdiabetes.org.uk/
 Types of Diabetic Neuropathy

• Sensorimotor: Acute reversible (hyperglycaemic neuropathy)

Persistent Symmetrical*
Focal & Multifocal

• Autonomic: Gustatory sweating

Postural hypotension
Gastroparesis
Diabetic diarrhoea
Neuropathic bladder
ED
Neuropathic oedema
Charcot arthropathy
 Risk Factors

• Modifiable: Glycaemic control

Dyslipidemia
Hypertension
BMI
Smoking
Excessive alcohol
Prevention/delaying the onset of DM

• Non-modifiable: Age of onset of diabetes

Duration of DM
Genetic factors
Presence of other complications of DM
 Management of
Diabetic Neuropathy
Goals of Neuropathic Pain Management

Treat/prevent recurrence of pain-causing condition

Reduce pain

Improve physical/psychologic function

Improve quality of life

Diabetic Neuropathy- Pain Assessment
Scales
Neuropathic Pain: Nonpharmacologic
Treatment Options
 Cognitive-behavioral strategies
– Meditation
– Imagery
– Biofeedback
– Relaxation therapy
 Physical rehabilitation
 Acupuncture
 Transcutaneous electrical nerve
stimulation
DIABETIC NEUROPATHY MANAGEMENT
- ALGORITHM
 APPROACHES TO THE MANAGEMENT
OF NEUROPATHIC PAIN

Monotherapy Combinations Additional

Measures
First-line TCA Low-dose TCA+
AE Paracetamol
Anti-epileptic
(AE) Acupuncture
Second-line Alternative Opioid with TCA
Physiotherapy
antidepressant or AE
Opioid
Capsaicin
Third-line Alternative Intrathecal drug
opioids delivery
Neuromodulation
 Management of Diabetic
Peripheral Neuropathy
Parameters
Tight glucose control
Tricyclic antidepressants (TCA’s)
Serotonin reuptake inhibitor (SSRI’s)
Antiepileptic drugs (AED’s)
Methylcobalamin
Significance
Can reverse the changes but only if the neuropathy
and diabetes is recent in onset.
e.g. Amitriptyline, Nortriptyline
Effective but suffer from multiple side effects that
are dosage dependent
e.g. Fluoxetine, Paroxetine, Sertraline and
Citalopram
FDA not approved, no more efficacious than
placebo in several controlled trials.
e.g. Gabapentin & Pregabalin
Emerging as first line treatment for painful
neuropathy.
Exerts neuroprotective effects, regenerates myelin
sheath
Managing Neuropathic Pain: New Approaches For Today's Clinical Practice
Charles E. Argoff, MD, www.medscape.com
Latest Guidelines on Neuropathy
Management

Neurology® 2011;76:1–1
Summary of Recommendations
 Guidelines – At a Glance
• Pregabalin is established as effective and should be offered
for relief of PDN (Level A).
• Venlafaxine, duloxetine, amitriptyline, gabapentin,
valproate, opioids (morphine sulfate, tramadol, and
oxycodone controlled-release), and capsaicin are probably
effective and should be considered for treatment of PDN
(Level B).
• Other treatments have less robust evidence or the evidence
is negative.
• Effective treatments for PDN are available, but many have
side effects that limit their usefulness, and few studies have
sufficient information on treatment effects on function and
QOL.

Neurology® 2011;76:1–1
Pregabalin in the management of
DPNP
 How does Pregabalin work???

Pregabalin binds with high affinity to the

alpha2-delta site ( voltage-gated calcium
channels) in Neurons

Reduces the calcium-dependent release of

several neurotransmitters (Glutamate ,
Substance P)

Increases neuronal GABA levels

Reduces neuropathic pain & also exerts

anticonvulsive and anxiolytic effects
 Pregabalin

FDA approved indications –

– Management of neuropathic pain associated with
diabetic peripheral neuropathy
– Management of postherpetic neuralgia
– Adjunctive therapy for adult patients with partial
onset seizures
– Management of fibromyalgia
 Pregabalin – From Clinical Experience

• Accepted First line therapy in the management of DPN.

• More than 140 clinical studies and 20 studies

exclusively in DPN support the use of Pregabalin in
Neuropathy management.

• Daily dosages of Pregabalin (150mg / 300 mg) in

divided dosages; B.I.D or T.I.D) reduces at least 50% of
pain score in DPN patients.
 Pregabalin from the clinical trials…

• More than 2000 patients on Pregabalin therapy actually had a relief

from the DPN.

• The dosage schedule for the all the trials was 150 mg (B.I.D) as
initial dose and 600 mg (B.I.D) as the maximum dose per day.

• Pregabalin offered superior profile in terms of efficacy & safety

when compared with the placebo as well as other comparative
drugs.

Thus,
Pregabalin 150 mg – 600 mg/day in divided dosages is the effective dose
for the treatment of Diabetic Peripheral Neuropathy…
 Pregabalin 600 mg dose…

• Trial Method - 12 weeks randomized, double-blind, placebo-controlled trial.

• Interventions – 82 patients received Pregabalin 300 mg BID & 85 patients

were on Placebo.

• Outcomes –
– Primary – Change in mean pain score (MPS) from daily pain diaries (11-point scale).
– Secondary - Weekly MPS and proportion of responders

Research article, Joseph C Arezzo* et.al, BMC Neurology 2008, 8:33 doi:10.1186/1471-2377-8-33
 Results –
Weekly least-squares mean pain scores

Improvement in the Pregabalin group was evident at week 1 and this improvement was
maintained at every weekly time point through week 13
Research article, Joseph C Arezzo* et.al, BMC Neurology 2008, 8:33 doi:10.1186/1471-2377-8-33
 Results –
Responder rate

49% patients in Pregabalin group responded to ≥50% reduction in mean pain score from
baseline to endpoint as compared to 23% in placebo group.

Research article, Joseph C Arezzo* et.al, BMC Neurology 2008, 8:33 doi:10.1186/1471-2377-8-33
 Results -
Global improvement

CGIC – Clinical Global Impression of Change scales PGIC – Patient Global Impression of Change scales

On both the clinician-rated and the patient-rated instruments, there was a response favoring
Pregabalin compared with placebo
Research article, Joseph C Arezzo* et.al, BMC Neurology 2008, 8:33 doi:10.1186/1471-2377-8-33
 Conclusion
• Pregabalin 600 mg/d (300 mg BID) effectively reduced
pain & was well tolerated.

Research article, Joseph C Arezzo* et.al, BMC Neurology 2008, 8:33 doi:10.1186/1471-2377-8-33
 Pregabalin across all dosage range…

• Trial method – Data pooled across seven double blind, randomized,

placebo-controlled trials using Pregabalin

• Intervention – Pregabalin 150, 300, and 600 mg/day administered

TID or BID.

• Treatment duration – 5 to 13 weeks

ROY FREEMAN, MD, et.al, Diabetes Care 31:1448–1454, 2008
 Results –
Change in least-squares mean pain score

Significant reductions in end point least-squares mean pain score were observed for all three
dosages of Pregabalin i.e.150, 300, and 600 mg/day

ROY FREEMAN, MD, et.al, Diabetes Care 31:1448–1454, 2008

 Results -
Proportion of patients meeting improvement from
baseline in mean pain score

Significant improvements from baseline was observed for all three dosages of Pregabalin i.e.150,
300, and 600 mg/day
ROY FREEMAN, MD, et.al, Diabetes Care 31:1448–1454, 2008
 Results –
Survival curve analysis

The median time to onset of a sustained (≥ 30% at end point) 1-point improvement was 4 days in
patients treated with Pregabalin 600 mg/day, 5 days in patients treated with Pregabalin 300 mg/day,
13 days in patients treated with Pregabalin 150 mg/day, and 60 days in patients receiving placebo.

ROY FREEMAN, MD, et.al, Diabetes Care 31:1448–1454, 2008

 Conclusion…
• Treatment with Pregabalin across its effective dosing
range i.e. 150 – 600 mg/day (B.I.D or T.I.D) is associated
with significant, dose-related improvement in pain in
patients with DPN.

ROY FREEMAN, MD, et.al, Diabetes Care 31:1448–1454, 2008

 Pregabalin for the treatment of painful diabetic peripheral
neuropathy: a double-blind, placebo-controlled trial.

• Trial method – Randomized, double-blind, placebo- controlled,

parallel-group, multicenter trial

• Intervention –146 patients were randomized to receive placebo (n = 70)

or Pregabalin 300 mg/day (n = 76).

• Treatment duration – 8 weeks

• Outcomes- Mean pain score from daily patient diaries (11-point

numerical pain rating scale).

Rosenstock J, Tuchman M, LaMoreaux L, Sharma U et.al, Pain. 2004 Aug;110(3):628-38.

 Results –
Effect on Mean Weekly Pain scores in
DPN

Pregabalin produced significant improvements for mean pain scores; mean sleep interference scores;
and Total Mood Disturbance versus placebo

Rosenstock J, Tuchman M, LaMoreaux L, Sharma U et.al, Pain. 2004 Aug;110(3):628-38.

 Conclusion…
• Pregabalin was safe and effective in decreasing pain
associated with DPN, and also improved mood, sleep
disturbance, and quality of life.

Rosenstock J, Tuchman M, LaMoreaux L, Sharma U et.al, Pain. 2004 Aug;110(3):628-38.

 Along with that, Pregabalin Sustained
Release…
• Increased patient compliance – Reduces the pill burden in
polypharmacy.

• Round the clock pain management – 24 hour steady therapeutic

concentration.

• Lesser dose escalation and dose titration – Higher responder rate.

• Improved quality of life – No breakthrough events during night,

no morning tingling sensation.

• Improved work efficiency during the production hours of day –

Lesser or negligible events of drowsiness during the day hours.
 Overall…
• Pregabalin is safe and efficacious in the management of
Diabetic Peripheral Neuropathy.

• From various clinical trials Pregabalin improved mean

pain score & also improved mood, sleep disturbance,
and quality of life.

• The effective dosage range of Pregabalin established

from the clinical trials is 150 mg to 600 mg per day in
divided dosages.

• Pregabalin SR enhances patient compliance

112
 Pregabalin better than Gabapentin….
Feature Pregabalin Gabapentin
Tmax 1 h., Pregebalin SR (3-4 hr) 3.5 h.
Absorption Fast Slow
Oral Bioavailability > 90 % independent of dose 35% - 57 % dependent of dose
Plasma concentrations Predictable & Linear Unpredictable & non-linear
Potency based on Plasma
2.5 times more potent -
conc.
Oral antacids reduce
Drug-Drug interactions No Known drug-drug interactions
bioavailability by 20 – 30 %
2 times a day (75 to 150 mg/day), 3 times a day (300 to 900
Dosage (starting dose)
Pregebalin SR (150, 300 mg / day) mg/day)
Overall Pharmacokinetic More stable Less stable
At high dosage Fast absorption Less absorption
Onset of action 1 – 2 days ≥ 9 days
Dose increases Non – linear Linear and predictable
Protein binding Varied Predictable levels
Antidepressants in
DPNP
• USP DI Volume I: Drug Information for the Healthcare Professional. 27th ed. Greenwood Village, CO:
Thomson Micromedex; 2007.
Compared with placebo, Amitriptyline reduced
pain to a similar extent whether patients
were not depressed or were depressed
 Tricyclic antidepressants
• Advantages
– Well documented efficacy in treatment of PHN and DPN.
– Recommended as first-line agents for all neuropathic pain by many
practitioners

• Disadvantages
Unacceptable side effects like
• Anticholinergic effects: Dry mouth, constipation, blurred vision,
urinary retention, dizziness, tachycardia, memory impairment
• Sedation
• Alpha-1-adrenergic effects: Orthostatic hypotension / syncope
• Cardiac conduction delays/heart block: Arrhythmias, Q-T
prolongation
• Other side effects: Weight gain, excessive perspiration, sexual
dysfunction
SNRI – AN OVERVIEW
 Duloxetine
MOA
1. Neurotransmitter synthesis

2. Neurotransmitter storage

3. Vesicle transport
4. Vesicle fusion and Neuro-
transmitter release

5. Autoreceptor binding

6. Receptor binding

DULOXETINE NEUROTRANSMITTER
ACTS HERE REUPTAKE
 Duloxetine

Pharmacokinetics:

•Well-absorbed after oral doses

•Peak plasma levels occur in 6 hours

•An elimination half-life is 16 hours

•Preferred in elderly patients and those with cardiac disease

•Use cautiously in patients with any hepatic insufficiency &

in renally impaired patients. (should be initiated at a lower dose
& then increased gradually.)
 Advantages of Duloxetine Over
Gabapentin
• At monotherapy with Duloxetine results in a 30 to 50%
reduction in pain, a multi-drug regime may be helpful.

• Duloxetine - Has anti - depressant & central pain

inhibitory actions. It is used as OD or BD. Higher dose is
even taken OD.

• Proven beneficial in neuropathic pain. Dose should by

OD or BD.
 Serotonin Reuptake Inhibitors
• Advantages:
– selective and are better tolerated than TCAs, with fewer associated side
effects and toxicities.

• Disadvantages:
– FDA not approved
– Except Duloxetine which is a SNRI all the other agents in this group
are believed to be less efficacious in the treatment of neuropathic pain
and are not regarded as first-line agents
– Though the SNRI duloxetine has recently received FDA approval for
use in DPNP it has poor efficacy in the treatment of PHN
 Methylcobalamin in
Management of Diabetic
Neuropathy
• Despite of symptomatic treatment with Drugs there are
still some treatment gaps which needs to be addressed –

1. Regeneration of Myelin Sheath of Neuron

2. Long-term neuropathy management

127
 Methylcobalamine
Vitamin B12 deficiency

Methylcobalamin is the
active form of vitamin
B12 acting as a cofactor
for methionine synthase Demyelination (destruction or
loss of the myelin sheath)
which damages the neurons

Methylcobalamin
Methylcobalamin

Helps
Helpsin inthe
theformation
formationofofmyelin
myelin
(component
(componentof ofmyelin
myelinsheath).
sheath).
Promotes
Promotesnerve
nerveregeneration
regeneration&&
improves
improvestransmission.
transmission.
128
 Methylcobalamine from Clinical
Evidences…
• 7 randomized controlled trials from June 1954 to
July 2004 was evaluated & reviewed

– Both the vitamin B12 combination and pure

methylcobalamin had beneficial effects on somatic
symptoms, such as pain and paresthesia.

– methylcobalamin therapy improved autonomic

symptoms.

– Leads to symptomatic relief

Acta Neurol Taiwan. 2005 Jun;14(2):48-54.
Effect of mecobalamin on diabetic neuropathies.
Beijing Methycobal Clinical Trial Collaborative
Group
• Methylcobalamine after twelve weeks after the
treatment –
– 73% improvement in spontaneous pain
– 75% improvement in numbness of limbs

• Hypoesthesia, hotness, coldness, oral dryness and

dysuria showed better response than the controls group

• Also benefited nerve reflection and conduction velocity

Mecobalamin might be worthy of use as a safe

agent in the treatment of diabetic neuropathies
Zhonghua Nei Ke Za Zhi. 1999 Jan;38(1):14-7.
 Role of Methylcobalamine in Neuropathy
• Improves symptoms related to Neuropathy such as1
– Paraesthesia
– Burning pain

• Increases synthesis of Lecithin, major component of

myelin sheath

• Regenerates myelin sheath and thus protects nerve

axons and peripheral nerves

• Excellent tolerability and no known toxicity.

131
Acta Neurol Taiwan. 2005 Jun;14(2):48-54.
Nitroglycerine Spray in
Management of DPNP
 Nitroglycerin – Place in therapy
• Vasodilation due to nitric oxide, a derivative of
glyceryl-trinitrate, may explain its analgesic effects,
while stimulation of angiogenesis in the blood vessels
supplying the nerves could explain the temporal
increase in the analgesic effects
 Glyceryl trinitrate spray in the management of painful diabetic
neuropathy: a randomized double blind placebo controlled cross-over
study.

• Trial method – Randomized, double-blind, placebo- controlled, cross-over trial

• Intervention – 48 patients were randomized to receive placebo (group A) or

GTN (group B).

• Treatment duration – 10 weeks

• Outcomes- Patients of group B observed significant improvement in all pain

scores compared to group A (p<0.001). The numbers needed to treat (NNT)
calculated on VAS as pain parameters came out to be 4. The drug was well
tolerated by all the patients except palpitation and headache for some days in
five patients.

• Conclusion- GTN spray, a well tolerated drug, provides significant

improvement in painful diabetic neuropathy.

Diabetes Res Clin Pract. 2007 Aug;77(2):161-7

 Summarizing…
• Neuropathy is a multifactorial problem.

• Neuropathy - The most common complication and greatest source

of morbidity and mortality in diabetes patients.

• Despite advances in the understanding of the metabolic causes of

neuropathy, treatments have been limited by side effects and lack of
efficacy.

• The unmet needs of DPN has to be addressed and needs to be

managed with either the new convincing formulations of existing
molecules or with the newer agents to have a control.
THANK YOU