summary on neuropathic pain in diabetes and its management

1. Understanding and
pharmacotherapy of
Diabetic neuropathy

2. I take for granted
that you know
the basics.
What seems to be
right today may
be wrong tomorrow.
What the mind
doesn’t know the
eyes don’t see!
Oh, come with old Khayyam,
and leave the Wise to talk;
One thing is certain, that Life flies;
One thing is certain, and the Rest is Lies;
The Flower that once has blown forever dies.
Myself when young did eagerly frequent Doctor
and Saint,
and heard great Argument About it and about;
but evermore came out by the same door as in I
went.
With them the Seed of Wisdom did I sow, And with
my own hand labour'd it to grow:
And this was all the Harvest that I reap'd ---
'I came like Water and like Wind I go.'
-(Omar Khayyam 11th Century)

3. Diabetic Neuropathy

4. Incidence of Diabetic Neuropathy
as a proportion of all diabetics 20 years after diagnosis
No neuropathy
10%
Asymptomatic
40%
Symptomatic
50%

5. Classification of diabetic neuropathy
Diffuse
• Distal symmetric
sensorimotor neuropathy
-large fiber
-small fiber
• Autonomic
• Symmetric proximal lower
limb motor neuropathy
(Amyotrophy)
Focal
• Mononeuropathies
• Entrapment
neuropathies
• Truncal neuropathy
• Cranial neuropathy
• Focal amyotrophy.

6. Diagnosis of polyneuropathy
3 challenges
• Clinical signs & symptoms are due to
polyneuropahy.
• Categorisation of polyneuropathy
• Etiology- history, investigations- lab,
immunological, histological, genetic.
• 25 – 30% - cause not identified.

7. Evaluation of polyneuropathy
• History
• Clinical examination.
• Electrophysiological testing –
extension of clinical examination
• Laboratory investigations.

8. Clinical characteristics
• Polyneuropathies of many different etiologies
have similar signs & symptoms.
• Though the features are common the patterns
are different.
• The clinical features result from
Lack of function – negative symptoms & signs
abnormal function – positive symptoms & signs

9. Clinical characteristics
• Clinical course – acute,
subacute
chronic progressive,
remitting and relapsing forms
• Distribution of involvement
distal Vs proximal
symmetrical Vs asymmetrical
Upper limb Vs lower limb
predominance.

10. Clinical characteristics
•Types of fiber involvement
Motor, large sensory, small
sensory, autonomic
•Inheritance – family history.
•History of exposure to toxins
and drugs, concomittant
illness.

11. Neurological manifestations
negative positive
Motor Weakness, atrophy,fatigue
reduced tone
Fasciculations,
cramps
myokymia
Reflex Hypo or areflexia _
Small fiber Decrease of pain &
temperature sensation,
Loss of visceral pain
sensation
Foot ulceration
Spontaneous dull
burning pain
hyperesthesia
parasthesia

12. Neurological manifestations
negative positive
Large fiber Decreased proprioception
Decreased vibration sense
Reduction of touch pressure
sensibility
Sensory ataxia
Postural tremor
Paraesthesias
Sharp tingling pain (A
delta type)
Autonomic Orthostatic hypotension
Arrythmia
Gastroparesis
Constipation, Impotence
Urinary retention, Decreased
sweating
Hypertension
Neuropathic diarrhoea
Osteoarthropathy

13. Axonal Vs Demyelination(Clinical)
Demyelinating Axonal
Muscle atrophy Slight Severe
Weakness Severe Severe
Reflexes Global areflexia Knee & UL
preserved
Sensory signs Motor > sensory Significant

14. Risk factors
For Painful
neuropathy
• Hyperglycemia
• Hypertension
• Dysmetabolic
syndrome
HT+DM+IHD+DYSLIPIDEMIA
For painless
neuropathy
•Greater height
•Male gender
•Smoking
•Total abstinence
from alcohol
•High HbA1C

15. Underlying Mechanisms
Agreement not yet reached on exact causal relationship
between insulin imbalance and nerve damage.
The relative importance and inter-relationship of the
various mechanisms is the subject of ongoing research
and debate.

16. Physical manifestations
• Nerve fibres degenerate
• Blood vessels supplying the nerves are ‘grossly
diseased’
Any theory needs to account for both

17. Pathways of action
• Polyol pathway
• Triose phosphate effects
• Failure of nerve growth & repair mechanism
• Fatty acid metabolism

18. Polyol Pathway
• Polyol = Polyhydroxy alcohols
• High blood glucose
• Nerve cell and capillary membranes have insulin-
independent glucose transport.
• High intra-cellular glucose levels
• Conversion of glucose to sorbitol in nerve cells by aldose
reductase enzyme
• Sorbitol cannot cross membranes and therefore
accumulates

19. Polyol Pathway
• Consequences of high sorbitol concentration:
• Osmotic damage to nerve cells
• reduction in nerve myoinositol
• Inhibition of nitric oxide (NO) production
• Aldose reductase competes for NADPH
• NO is vasodilator
• Increased production of free radicals
• Superoxide, hydrogen peroxide, hydroxyl
• Formed during mitochondrial respiration
• Increased oxidative stress (proteins, lipids, DNA)

20. Polyol Pathway
• Treatment possibilities
• Aldose reductase inhibitors
• Supplemental myoinositol
• Nitric oxide stimulation/sensitisation
• Vasodilators
• Antioxidants

21. Triose phosphates
• High intracellular glucose leads increased production
of triose phosphates
• Activation of protein kinase C (PKC) via DAG
• Damages capillaries (permeability, contractility)
• Damages nerve function
• Non-enzymic reaction with proteins & DNA
• Advanced Glycation End-products (AGEs)
• Damage to capillaries and nerve fibres
• Specific cellular AGE receptors
• Protein cross-linking

22. Natural history of diabetic
neuropathy and clinical signs
and symptoms with
pathological background.
• With increasing stage of
neuropathy, there is a
progressive loss of nerve fibers
that convey sensation.
• When the fibers undergo
degeneration or impaired
remyelination, they release
impulse of positive symptoms.
• With progression of disease,
negative symptoms of sensory
loss are increased

23. Types of painful neuropathies
Acute (< 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 sensorimotor
polyneuropathy
• Entrapment
neuropathies
• Difficult to treat.

24. Clinical features –
Distal symmetrical painful sensorimotor
polyneuropathy
• Burning, superficial pain. Hypoalgesia in
later stages.
• Defective thermal sensation.
• Impaired vasomotion
• Defective autonomic function
• Intact DTR and power till late stages.
• Progressive with increasing duration of
diabetes.
• Related to glycemic control &
complications.

25. Clinical features –
Truncal neuropathy
• Truncal polyneuropathy
• Rare
• Occur in long standing
DM
• “Bandlike” Painful
symptoms in thoracic root
distribution
• Motor involvement-
muscle herniation –
asymmetric bulge in
abdominal wall
• Truncal
radiculopathy
• Acute onset of pain
in a radicular
pattern
• Asymmetrical pain
• Patchy sensory loss
is a clue to the
diagnosis.

26. Clinical features Insulin neuritis
• Acute painful, occurs 1 month after
insulin /OHA.
• Due to rapid glycemic control.
• Nerves in these patients are under
general hypoxia and use glucose
under anaerobic conditions.
• Once glucose is normalised in blood
and nerves, glucose is no longer
available and the nerves undergo
degeneration.

27. Insulin neuritis- contd..,
•Burning pain, paraesthesia, allodynia
with nocturnal exacerbation.
•Depression is a feature.
•No weight loss.
•Sensory loss is mild. No motor signs.
•Complete resolution in 1 year.

28. Clinical features - Cachectic neuropathy
• In patients with a poor control of DM.
• Wt.loss is prominent.
• Severe burning pain- continuous or
intermittent.
• Subjective feeling of swollen limb.
• Allodynia is common- nocturnal exacerbation.
• Sensory loss is mild.
• No motor signs.

29. Cranial nerve palsy
• Most common mononeuropathy
• Acute pain in the orbit, ptosis,
opthalmoplegia, pupil spared.
• Usually unilateral
• Complete recovery in 3 months.
• Vascular etiology suggested.
• 6th & 7th cranial nerve involvement are
described.

30. Peripheral Autonomic Dysfunction
•Contributes to the following
symptoms/signs:
• Neuropathic arthropathy (Charcot foot)
• Aching, pulsation, tightness, cramping, dry
skin, pruritus, edema, sweating
abnormalities
• Weakening of the bones in the foot leading
to fractures

31. Investigations
• Clinical examination – measuring
thermal & vibration threshold.
• Routine hemogram
• Plasma Glucose estimation-Glycemic
control
• HbA1C levels
• Electrodiagnostic testing.- Nerve
conduction studies, Quantitative Sensory
Testing (QST)

32. Investigations
• Nerve biopsy

33. Morphology- nerve biopsy
• Nerve biopsy – invasive procedure with
definite morbidity.
• Sural nerve most commonly used.
• Routine biopsy is controversial.
• To rule out other causes like vasculitis etc.,.
• Light & electron microscopic studies are
necessary.
• Can be done pre and post treatment to
assess response

34. Section of a sural nerve from a patient with
diabetic neuropathy

35. Morphology- Skin punch biopsy
• Small nerve visualisation – assessment of
cutaneous nerve fibers obtained from 3mm
skin punch biopsy – promising in DSP.
• Immunohistochemistry- antibody to general
neuronal marker protein gene product
9.5.(PGP 9.5)
• The relationship between epidermal nerve
fibers and clinical scores is nonlinear.
• Reappearance is a marker for diffuse
peripheral nerve regeneration and recovery.
• At present not advocated for routine
evaluation

36. Skin Biopsy PGP 9.5 staining

37. Bench To Bed side

38. Bench To Bed side
• Diabetic Peripheral Neuropathy Pain refractory to initial
therapies
• Diabetic Peripheral Neuropathy Pain in the presence of
comorbidity
• Non Diabetic Neuropathy in a patient with diabetes
mellitus
• Rational Polypharmacy DPNP

39. Bench To Bed side
• Diabetic Peripheral Neuropathy Pain refractory to initial
therapies
• Diabetic Peripheral Neuropathy Pain in the presence of
comorbidity
• Non Diabetic Neuropathy in a patient with diabetes
mellitus
• Rational Polypharmacy DPNP

40. Pharmacological Treatment of
DPNP by Drug Class
Class
• SNRI ( highly specific inhibition of serotonin
and Norepinephrine reuptake)
• Alpha 2 delta ligands ( modulate voltage –
gated Calcium channels )
• TCAs( inhibit reuptake of serotonin and
Norepinephrine)
• Opioids ( block mu opiod receptors)
• Topical agents
• Agents to AVOID ( never use)
Individual agents
• Duloxetine, Venlafaxine
• Pregabalin ( Lyrica), gabapentin.
• Tertiary ( amitriptyline); secondary (
desipramine)
• Tramadol, oxycodone CR, morphine;
methadone levorphanol;hydromorphone
• Capsaicin; lidocaine
• Meperidine, propoxyphene;NSAIDs; acetaminophen, amitriptyline( for
patients > 60 years); vitamin B6 (>250 mg/d due to its potiential for
neurotoxicity) pentazocine ( due to CNS toxicity and reversal of its analgesic
effect.)

41. AEDs
Carbamazepine
1. FDA approved for Trigeminal
Neuralgia
2. Side effects
Oxcarbazepine
1. One study for NeP
2. Hyponatremia – monitoring of
serum sodium required
3. Rash – 4 %
4. Few Drug-drug interaction
Levetiracetam
1. No controlled studies
Tiagabine
1. No controlled studies
Lamotrigine
1. Rash 10%
2. 2nd-line
3. Insomnia
Topiramate
1. Negative results (3 - / 1 +)
2. Weight loss (10-20%)
3. Cognitive impairment
4. Nephrolithiasis (1.5%)
Valproate
1. Nausea
2. Sedation
3. Fatal Hepatotoxicity - Enzymes
4. Hair loss
5. Hematologic effect (Platelet)
6. Drug-drug interactions

42. Agent type Reasons for recommendation Agent name
First line > 2 RCTs in DPN Duloxetine,oxycodone CR,
pregabalin, TCAs
Second line 1 RCT in DPN; > 1 in other Carbamazepine, gabapentin
painful neuropathies lamotrigine, tramadol,
venlafaxine ER
Topical Mechanism of action Capsaicin, lidocaine
Others > RCTs in other painful Bupropion, citalopram
neuropathies or other methodone, paroxetine,
evidence phenytoin, toriramate.
Recommendation for First- and Second- Line
Agents for DPNP

43. Bench To Bed side
• Diabetic Peripheral Neuropathy Pain refractory to
initial therapies
• Diabetic Peripheral Neuropathy Pain in the presence
of comorbidity
• Non Diabetic Neuropathy in a patient with diabetes
mellitus
• Rational Polypharmacy for DPNP

44. Factors to consider in choosing First –Line 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 line agent
Any other first line agent
Any other first line agent
Any other first line agent
Any other first line agent
Any other first line agent
Any other first line agent
TCA s
TCA s
TCA s
TCA s
Duloxetine
Pregabalin,TCAs

45. Factors to consider in choosing first line agents
Factor Recommended Avoid
Psychiatric comorbidities
Depression
Anxiety
Suicidal ideation
Somatic issues
sleep
Erectile dysfunction
Other factors
Cost
Drug interactions
Weight gain
Edema
Duloxetine,TCAs
Any other first line agent
Duloxetine,Pregabalin
Any other first line agent
Second line agent
Venlafaxine
TCA s oxycodone CR
Oxycodone, Pregabalin
Duloxetine, oxycodoneCR
Any other first line agent
oxycodoneCR pregabalin
oxycodoneCR
TCAs , oxycodone CR
All first line agents
Duloxetine,Pregabalin
Duloxetine,TCAs
TCAs,Pregabalin
Pregabalin

46. Bench To Bed side
• Diabetic Peripheral Neuropathy Pain refractory to
initial therapies
• Diabetic Peripheral Neuropathy Pain in the presence
of comorbidity
• Non Diabetic Neuropathy in a patient with diabetes
mellitus
• Rational of Poly pharmacy

47. Bench To Bed side
• Diabetic Peripheral Neuropathy Pain refractory to
initial therapies
• Diabetic Peripheral Neuropathy Pain in the presence
of comorbidity
• Non Diabetic Neuropathy in a patient with diabetes
mellitus
• Rational Polypharmacy in DPNP

48. Rational Polypharmacy for
Diabetic Peripheral Neuropathic Pain
First- line Add-on therapy Avoid
Agents
SNRIs alpha 2 delta ligands, opioids, topical agents other SNRIs, TCAs
tramadol
alpha 2 SNRIs, TCAs, opioids, tramadol, topicals other alpha 2 delta
Delta
TCAs alpha 2 delta, opioids, topicals SNRIs, tramadol
Opioids SNRIs, alpha 2 delta, TCAs, topicals Other opioids
Tramadol alpha 2 delda, opioids, topicals SNRIs, TCAs
Topical SNRIs, alpha 2 delda, TCAs, Opioids, tramadol None
Topicals

49. Decrease
Inflammatory
Response
NSAIDs,
Local Anesthetics,
Steroids
Decrease Conduction
Gabapentin,
Carbamazepine,
Local Anesthetics,
Opioids
Prevent
Centralization
COX 2,
Opioids,
Ketamine,
-2 Agonists.
Increase
Inhibition
TCA’s, SSRI’s,
Clonidine
Modify Expression
Anxiolytics
Mechanistic Approach To Pain Therapy

50. Other Agents - Topical and
Transdermal Drug Delivery Systems
Systemic activity
Applied away from painful site
Serum levels necessary
Systemic side effects
Peripheral tissue activity
Applied directly over painful site
Insignificant serum levels
Systemic side effects unlikely
Topical
(lidocaine patch 5%)
Transdermal
(fentanyl patch)

51. Based on Class I and Class II evidence,
capsaicin cream is probably effective in
lessening the pain of PDN.
Based on Class I evidence, isosorbide dinitrate
spray is probably effective for the treatment of
PDN.

52. Neuropathic Pain: Nonpharmacologic
Treatment Options
 Cognitive-behavioral strategies
– Meditation
– Imagery
– Biofeedback
– Relaxation therapy
 Physical rehabilitation
 Acupuncture
 Transcutaneous electrical nerve
stimulation

53. Religion, Spirituality and Chronic Pain
• Organized religion reduced chronic
pain
• Spirituality without affiliated regular
worship attendance increased
chronic pain prevalence
• Individuals with chronic pain are
more likely to use prayer, spiritual
support for coping

54. Summary
• Diabetic neuropathic pain is a disease, not a symptom
• “Rational” polypharmacy is often necessary
• combining peripheral and central nervous system agents
enhances pain relief
• Treatment goals include:
• balancing efficacy, safety, and tolerability
• reducing baseline pain and pain exacerbations
• improving function and QOL
• New agents and new uses for existing agents offer
additional treatment options

55. Thank You