DR KOUSHIK KR MONDAL

PGT, DEPT. OF GENERAL MEDICINE

R G KAR MEDICAL COLLEGE

DefinitionAn internationally agreed simple definition of Diabetic neuropathy for clinical

practice is

“the presence of symptoms and/or signs of peripheral

nerve dysfunction in people with diabetes after the

exclusion of other causes”

Boulton AJ et al. Diabetic neuropathies: a statement by

the American Diabetes Association. Diabetes Care. 2005 Apr;28(4):956-62.

Risk factors for the development of diabetic

neuropathy

Modifiable Risk Factors

Poor glycemic control (Elevated HbA1c)

Alcohol

Hypertension

Cigarette Smoking

Hypertriglyceridemia

Non-modifiable Risk Factors

• Obesity

• Older age

• Male sex

• Height

• Family h/o neuropathic disease

• Longer duration of diabetes

• Aldose reductase gene hyperactivity

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

2.Tesfaye S, Chaturvedi N, Eaton SE, et al. Vascular risk factors and

diabetic neuropathy. N Engl J Med 2005;352(4):341.

PATHOGENESISIncreased aldose reductase activity.

Auto oxidation of glucose

Non enzymatic glycation of protein(AGE)

Activation of protein kinase C

Oxidative stress

Reduced serum levels of nerve growth factor

Nerve ischemia/hypoxia.

CLASSIFICATION

1)IMPAIRED GLUCOSE TOLERANCE AND HYPERGLYCEMIC NEUROPATHY

2)GENERALIZED NEUROPATHIES:

-sensorimotor(most common)(DSPN)

-acute painful(insulin neuritis)

-autonomic

Contd………..

3)FOCAL AND MULTIFOCAL NEUROPATHIES:

-cranial

-thoracolumbar

-lumbosacral radiculoplexus

-focal limb

4)SUPERIMPOSED CIDP

Symptoms

-Numbness or feeling of walking in cotton

-Sharp shooting or stabbing pain(Ad fibre)

-Dull constant or boring pain.(C fibre)

-Tingling pins & needles

-Allodynia

-Autonomic dysfunction(resting

tachycardia,constipation,orthostatic hypotension etc)

SIGNS: Significant distal weakness is uncommon but EDB

weakness may be there(in DSPN).

Ankle reflexes are absent .

Sensory loss in a length related distribution with the toes and feet being most affected.

Loss or impairment of all sensory modalities with vibration sense often the first to go.

.

Investigation

NCV

quantitative sensory tests (QST) for vibration, tactile, thermal warming, and cooling thresholds

quantitative autonomic function tests (QAFT) revealing diminished heart rate variation with deep breathing, Valsalva maneuver, and postural testing & BP testing.

ScreeingNeuropathy symptom score could also be useful in

clinical practice.

The Michigan Neuropathy Screening Instrument (MNSI) is a 15-item questionnaire that can be administered to patients as a screening tool for neuropathy.

nerve impairment score of the lower limbs (NIS-LL).

The modified Neuropathic Disability Score.> 6

high chance of foot ulcer.

THE MODIFIED NEUROPATHIC DISABILITY

SCORE.

Devices for clinical screening.

Semmes-Weinstein monofilament

Assesses pressure perception when gentle pressure is applied to the handle sufficient to buckle the nylon filament.

One that exerts 10 g pressure, is most commonly used

Also referred as 5.07 monofilament .

Graduated Rydel-Seiffer tuning fork

Tactile circumferential discriminator

Neuropen

16–34% of patients with diabetes report painful

neuropathic symptoms and the prevalence is

greater in type 2 diabetes, women and South

Asians [Ziegler et al. 2009; Abbott et al. 2011].

The symptoms of painful diabetic neuropathy

(PDN) can be debilitating and can cause sleep

disturbances, anxiety and interfere with physical

functioning [Galer et al. 2000].

Pathophysiology of Neuropathic Pain Excitotoxicity(decrease disinhibited pain system)

Sodium channels-ectopic impulse generation

Ectopic discharge

Deafferentation

Central sensitization

maintained by peripheral input

become hyperresponsive (sensitized) to peripheral input

Chemical excitation of nonnociceptors

Ectopic transduction.

Physiology of Pain Perception

Injury

Descending Pathway

PeripheralNerve

Dorsal RootGanglion

C-Fiber

A-delta Fiber

AscendingPathways

Dorsal Horn

Brain

Spinal Cord

• Glutamate

• Substance P

• Brandykinin

• Prostaglandins

Pain Initiators

• Serotonin

• Endorphins

• Enkephalins

• Dynorphin

Pain Inhibitors

The Neurochemicals of Pain

Types of painful neuropathiesAcute (< 6 months)

Truncal neuropathy.

cachectic neuropathy-Acute, painful,wt.loss,poor control of DM

Insulin neuritis -Acute painful, weight loss, good control of DM

Painful 3rd cranial nerve palsy.

Easy to treat.

Chronic(> 6 months)

Distal symmetrical painful sensorimotorpolyneuropathy

Entrapment neuropathies

Difficult to treat.

Symptoms of Neuropathic Pain

Symptom Description (example)

Spontaneous symptoms

– Spontaneous pain1 Persistent burning, intermittent shock-like or

lancinating pain

– Dysesthesias2 Abnormal unpleasant sensations

e.g. shooting, lancinating, burning

– Parasthesias2 Abnormal, not unpleasant sensations e.g. tingling

Stimulus-evoked

symptoms

– Allodynia2 Painful response to a non-painful stimulus

e.g. warmth, pressure, stroking

– Hyperalgesia2 Heightened response to painful stimulus e.g.

pinprick, cold, heat

– Hyperpathia2 Delayed, explosive response to any painful stimulus

1.Baron. Clin J Pain. 2000;16:S12-S20.2. Merskey H et al. (Eds) In: Classification of Chronic Pain: Descriptions of Chronic Pain Syndromes and Definitions of Pain Terms. 1994:209-212.

Evaluation

The diagnosis of PDN is primarily clinical, based on history of neuropathic pain and confirmatory examination findings, establishing deficits associated with neuropathy. Although one might argue that confirming neuropathy using tests which assess large fibre deficits (loss of sensation, monofilament exam, reflexes) are not relevant to painful symptoms which are driven principally by small fibre damage. (Ad & C Fibre)Recent guidance has clearly stipulated that QSTs should not be used as standalone tests for the diagnosis of neuropathic pain [Backonja et al. 2013].

Diabetic Neuropathy- Pain Assessment Scales

Due to the subjective nature of the symptoms reported by patients, these scales may not produce consistent results and may lack the sensitivity to track any objective changes in neuropathy status.

Skin biopsies which measure intraepidermal nerve fibre density have been used to diagnose and assess neuropathy [Bakkers et al. 2014]

Corneal confocal microscopy has been proposed as a reliable, noninvasive marker of neuropathy that may be used to objectively assess neuropathy in PDN [Shy et al. 2003]

Loss of cutaneous nerve fibers that stain positive for the neuronal antigen protein gene product 9.5 in sensoryneuropathy. A, Normal epidermal fibersin the back. B, Slightly reduced density and swelling in the proximal thigh. C, Complete clearance in calf. (From McArthur JC, Stocks EA, Hauer P. Epidermal nerve fiber density: normative reference range and diagnostic efficiency. Arch Neurol 1998;55:1513-1520.)

Goals of Pain Management

Treat/prevent recurrence of pain-causing condition

Reduce pain

Improve physical/psychologic function

Improve quality of life

1.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.

Diabetes Control and Complication Trial (DCCT; 1995) –(5y) intensive management reduces neuropathy by 64%

Benefit persisted for 8 years .

BRAIN

Pharmacologic Agents Affect Pain Differently

Descending Modulation

Central SensitizationPNS

Local Anesthetics

Anticonvulsants

Opioids

AnticonvulsantsOpioidsNMDA-Receptor AntagonistsTricyclic/SNRI Antidepressants

AnticonvulsantsOpioidsTricyclic/SNRI Antidepressants

CNSSpinalCord

Peripheral

Sensitization

DorsalHorn

USP DI Volume I: Drug Information for the Healthcare Professional. 27th ed. Greenwood Village, CO: Thomson Micromedex; 2007.

Tricyclic antidepressants

Advantages Well documented efficacy in treatment of DPN. Recommended as first-line agents for all neuropathic pain

DisadvantagesUnacceptable 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

Duloxetine (SNRI)

Pharmacokinetics:

• 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.)

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).

Evidence-based

guideline: Treatment of

painful diabetic

neuropathy

Gabapentin Gabapentin, alpha -2-delta subunit voltage-gated calcium-

channel antagonist --reduces excitatory neurotransmitter release from hyperexcited neurons (e.g. glutamate, Substance P)

Dose titration required to achieve optimal level

Optimal dosage 1800mg/day in PDN

Analog of GABA, binds to alpha 2 delta subunit of voltage gated calcium channels.

Pregabalin

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

conc. 2.5 times more potent -

Drug-Drug interactions No Known drug-drug interactionsOral antacids reducebioavailability by 20 – 30 %

Dosage (starting dose)2 times a day (75 to 150 mg/day), Pregebalin SR (150, 300 mg / day)

3 times a day (300 to 900 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

Comparative Adverse Event Profile

Adverse Events* Pregabalin Gabapentin

Dizziness 10.7 17.1%

Somnolence 8.3 19.3%

Peripheral

Edema

0.6 1.7%

Ataxia 7.1 12.5%

Weight Gain 1.2 2.9%

*Gabapentin & Pregabalin Product Monograph

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.

Opioid Opioids act at two sites: They reduce pain signal

transmission by activating pre-synaptic opioid receptors. This leads to reduced intracellular cAMP concentration, decreased calcium ion influx and thus inhibits the release of excitatory neurotransmitters (glutamate, substance P).

At the post-synaptic level, opioid-receptor binding evokes a hyperpolarisation of the neuronal membrane which decreases probabilty of the generation of an action potential

Weak opioids(e.g. tramadol, codeine)

Strong opioids(e.g. morphine, oxycodone, fentanyl)

Dextromethorphan(Uncompetitive NMDA receptorantagonist

Distinguishing Dependence, Tolerance, and AddictionPhysical dependence: withdrawal syndrome arises

if drug discontinued, dose substantially reduced,or antagonist administered

Tolerance: greater amount of drug needed to maintain therapeutic effect, or loss of effect over time

Addiction (psychological dependence): psychiatric disorder characterized by continued compulsive use of substance despite harm

Opioids.

Dextromethorphan, morphine sulfate, tramadol, an oxycodoneshould 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.

Evidence-based guideline: Treatment

of

painful diabetic neuropathy

Topical and physical treatment

Topical nitrate-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

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.

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 Lidocaine 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.

Evidence-based guideline: Treatment

of

painful diabetic neuropathy

Nonpharmacologicmodalities ?

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

Future direction… Xenon402, a novel Nav1.7 sodium channel blocker:

found to be effective in erythromelalgia.

Small molecule angiotensin II type 2 receptor (AT2R) antagonists

EMA401

α-Conotoxins selective for GABA(B) receptor dependent inhibition of N-type Ca(2+) channels] ziconotide(Z160)

DIABETIC NEUROPATHY MANAGEMENT- ALGORITHM

• Improve metabolic control

• Explanation, empathy

• Set realistic targets

Confirm dx&exclude non diabetic etiologies

Max tolerated therapy

Pain Clinic referral oradmission

Lignocaine infusionAcupuncture

Add Tramadol if breakthrough pain

Add Tramadol if breakthrough pain

Still symptoms

Pregabalin

Duloxetine

GTN Spray

LignocainePatches

Consider referral to Acupuncture

Add Gabapentin

No response

Add Amitriptyline10mg & titrate

Persistent pain after max tolerated dose

Try PregabalinTry GTN SprayLignocaine Patches Try Pregabalin

Try GTN Spray Lignocaine Patches

Gabapentin 100-300mg od increasing as necessary

Topical Rx

Capsaicin

Acute onset

Age <80 yrs

Insidious onset

Age >80 yrs

Amitriptyline 10mg

Titrate dose

Max 100mg od

Gabapentin

300mg bd-2 days

300mg tds – 2 days

CT 600mg tdsSE

Factors to consider in choosing First –Tier Agents

Factor Recommended Avoid

Medical co morbidities

Glaucoma

Orthostatic phenomena

Cardiac or

electrocardiographic

abnormality

Hypertension

Renal insufficiency

Hepatic insufficiency

Falls and balance issues

Any other first tier agent

Any other first tier agent

Any other first tier agent

Any other first tier agent

Any other first tier agent

Any other first tier agent

Any other first tier agent

TCA s

TCA s

TCA s

TCA s

Duloxetine

Pregabalin,TCAs

Factors to consider in choosing first tier agents

Factor Recommended Avoid Psychiatric

comorbidities

Depression

Anxiety

Suicidal ideation

Somatic issues

sleep

Other factors

Cost

Weight gain

Edema

Duloxetine,TCAs

Any other first tier agent

Duloxetine,Pregabalin

Any first tier agent

TCA s oxycodoneCR

Duloxetine,

oxycodoneCR

Any other first tier agent

oxycodoneCR

pregabalin

TCAs , oxycodone CR

Duloxetine,Pregabalin

TCAs,Pregabalin

Pregabalin

Adverse effect…

Conclusion… 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 PDN 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.

Is it ‘‘diabetic neuropathy’’ or ‘‘neuropathy in a diabetic patient’’?

Think if-

Rapidly progressive

Prominent motor abnormality.

Asymmetrical

Motor>sensory

Large>small fiber involvement

Monoclonal gammopathy in serum

CSF protein>100 gm/dl

Elevated ESR,+ RF or ANA

F/H/O neuropathy