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