new look at painful neuropathy

1. Insights in Painful Neuropathy
Sanjeev Kelkar
Secretary DFSI

2. Insights in Painful Neuropathy
• Chronic neuropathic pain – 20% of a diabetic
cohort with more than 10 years duration
(Poncelet)
• Frequency of chronic painful neuropathy
similar in T1 and T2 diabetes (Tentolouris)
• Associated with depression, frustration (of both
patient and the physicians)

3. Insights in Painful Neuropathy
• Chronic painful neuropathy associated with A
delta and C fibers – not always integral to
autonomic neuropathy
• In both T1 and T2 16 to 20% coexisted with or
without autonomic neuropathy (Tentolouris)
• General assumption – small fiber europathy and
autonomic invariably coexist

4. Insights in Painful Neuropathy
• Painful neuropathy seems to be associated
with higher vibration perception thresholds
lower cold detection threshold and
higher heat pain threshold
• Correlations are highly statistically
significant (Lea Sorensen)
• Reminiscent of painful painless syndrome

5. Insights in Painful Neuropathy
• Special Forms of Painful Neuropathy
Diabetic Neuropathic Cachexia – pain,
weight loss, depression; age > 50 years,
more in males, present in both T1 ad T2, is
self limiting in about 2 years duration

6. Insights in Painful Neuropathy
• Special Forms of Painful Neuropathy
Thoracic particularly left sided radiculopathy,
unsettling due to suspicions of CHD, needs to be
differentiated from IGT neuropathy, usually a
duration of more than 6 months after the initial
control of hyperglycemia is established, cardiac
investigation negative for CHD,

7. Insights in Painful Neuropathy
• Special Forms of Painful Neuropathy
Insulin Neuritis, settles after control is obtained,
Hypoglycemic Neuropathy,
Neuropathy at diagnosis, settles with control
Infarction in a major nerve trunk producing pain,
limited to the area of distribution mononeuritis
multiplex, by far more common in diabetes

8. Therapy of Painful Neuropathy
• Generally not well rewarding
• Patient can be helped, relief to some extent is
possible, psychological support important
• Tight glucose control – a must
• Available choices be judged on the basis of NNT
– ie Number Needed to Treat,
• NNH – number needed to produce adverse
reaction
• Drug interactions – important consideration

9. Therapy of Painful Neuropathy
• NNT – ie Number Needed to Treat to
achieve 50% relief in one patient
• The lower the number the more predictably
effective the therapy is
• eg; Aspirin – high NNT
• Statins – low NNT
• Insulin in CHD and infarction – low NNT

10. Therapy of Painful Neuropathy
• NNH – ie Number Needed to Treat to meet
1st
adverse reaction in a patient
• The higher the number the more predictably
safe the drug would be
• eg; Aspirin – lower NNH
• Statins – high NNH
• Insulin in CHD and infarction – low but
easy to manage NNH

11. Therapeutic Options for
Painful Neuropathy
• TCAs – tricyclic antidepressants
• NNT – 2 to 3, Amitriptiline and
desipramine reign
• Amitriptiline – 10 mg q HS to 150 mg q HS
weekly increments in doses. helps
depression, insomnia

12. Therapeutic Options for
Painful Neuropathy
• TCAs – tricyclic antidepressants
• NNT – 2 to 3, Amitriptiline, and desipramine
reign
• Desipramine – 10 to 100 mg q HS, greater
tolerability,
• Fluoxitine – antidepressant, morning dosing
modest, equivocal on nerve
• Duloxitine – May work, doubtful
1.

13. Therapeutic Options for
Painful Neuropathy
• Antiepileptics – Sudden lancinating pains
considered epileptic equivalent,
• Phenytoin, Carbamazepine
• Phenytoin – better avoided, ineffective, side
reactions, drug interactions
• Carbamazepine – Personal experience satisfactory,
works well with Amitriptiline
100 mg OD to about 200 mg tid best tolerated
range

14. Therapeutic Options for
Painful Neuropathy
• Carbamazepine – does not seem to fare better in
comparison with TCAs and Gabapentine
• Gabapentine - Emerging therapy, 1st
line choice,
well tolerated,
• Head to head trial with Amitriptiline –
Fares better and more frequent pain relief in sub-
maximal tolerated dose, cost and multi dose
regime a problem

15. Therapeutic Options for
Painful Neuropathy
• Pregabalin – Congener of Gabapentine
• Comparable to Gabapentine
• Non saturable absorption, equal effect
• Definite and frequent dizziness and
somnolence seem to weigh against the
relative side effect free nature of
gabapentine

16. Therapeutic Options for
Painful Neuropathy
• NSAIDs – simpler first line, common sense
defence, if effective; nephropathy
• Opioid like analgesics –
Tramadol - NNT 3.1, clinically moderately
effective, higher levels of side effects in
nearly 50% of cases,
Dextromethorphan – 100% side effects,
moderate benefits

17. Therapeutic Options for
Painful Neuropathy
• Mexiletine 150 mg / day for 3 days, 300 mg per day for 3
days, then 10 mg / kg body weight / day, may worsen
arrhythmia
• Alfa Lipoic Acid – 600 mg IV effective, possible in
routine practice? effectivity orally doubtful since he half
life is only 3 minutes
• GLA – Creates a non inflammatory, non thrombotic,
vasodilatory effect at tissue level, a major trial in US
seems to be disapointing
• Promoted as nerve nutrient,

18. Diabetic Neuropathy
Evidence for halting progression, causing reversal
• 3rd
hope –
• Control of oxidative stress
• Alpha lipoic acid – a thiol replenishing and redox
modulating agent
• Anti oxidant actions:
Metal chelating activity
ROS scavenging
Regenerating endogenous antioxidants like
glutathione, Vit C & E
Repair of proteins, DNA and lipids

19. Diabetic Neuropathy
Evidence for halting progression, causing reversal
• 3rd
hope –
• Control of oxidative stress
• Shown to be effective in ameliorating both somatic and
autonomic neuropathy in diabetes in European trials
• Stimulates skeletal muscle glucose uptake and changes
NADH / NAD+
& GSH GSSG ratios
• Currently large trial in USA
(Ziegler et al, 1995, 1997, 1999, Roy et al, 1997)

20. Diabetic Neuropathy
Evidence for halting progression, causing reversal
• 4th
hope –
• Control of oxidative stress – gamma linolenic acid
• Serves as an important constituent of neuronal membrane
phospholipids
• Serves as a substrate of PGE2– PGE2helps preserve blood
flow to the nerves
• Metabolism of GLA impaired in diabetes
• Multi-center double blind placebo controlled trial by Keen
et al, 1993, showed significant improvement in clinical and
electrophysiologic testing

21. Therapeutic Options for
Painful Neuropathy
• Capsiacin - .075% cream, depletes substance P,
counterirritation, equivocal
• Anodyne Therapy – supposed to release NO,
vasodialates, difficult to accept as theory, Works
well in practice – many happy over the results
• TENS – Transcutaneous Electrical Nerve
Stimulation - 30 minutes of shocks, Pain returns
after one week of stopping therapy

22. Therapeutic Options for
Painful Neuropathy
• PENS – Percutaneous Electrical Nerve
Stimulation – Invasive, punctures soft tissues of
foot with acupuncture like needles 1 to 3 cms
Profound reduction of pain, increased physical
activity, improved sleep quality
Practical obstacles: Invasive, results are as yet
preliminary, difficult to initiate and maintain in a
clinical setting

23. Therapeutic Options for
Painful Neuropathy
• NEVER FORGET INSULIN –
• FOR GOOD CONTROL, FOR A LARGE
NUMBER OF ACTIONS BENEFICIAL TO
TISSUE PRSERVATION,
• Several strong evidences to suggest insulin helps
preserve the integrity of nerves and even restores
the function in at least the early stages

24. Therapeutic Options for
Painful Neuropathy
• Never forget to rule out non diabetic causes -
compressive neuropathy, B12, Alcoholic, nutritional,
auto immune neuropathy
• Coexistence calls for relief of compression
• The non compressive will remain, need
explanations prior to surgical intervention

25. Therapeutic Options for
Painful Neuropathy
• Talk to the patient
• Explain what to expect, limitations of therapy
• Support them
• Sometimes multitherapy helps,