new look at painful neuropathy

1. Insights in Painful Neuropathy
Sanjeev Kelkar
Head Project Management Group
Secretary DFSI
PAN India update Switzerland,
6th
of October 2007

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. Drugs in phase 3 trial with promise
• Lacosamide 400 to 600 mg
Superior to placebo
Reduced 2.5 points on Likert pain scale
• Evidence based recommendations –
Tier 1 > 2 RCTs – Duloxetine, TCAS,
pregabalin, oxycodon,

12. Drugs in phase 3 trial with promise
• Tier 2 - 1 RCT, Gabapentine, Venlafaxine
• Tier 2 - > 1 RCT, Carbamezapine,
Lamotorgine, Tramadol,
• Tier 3 - > 1 RCT in other painful
neuropathy or other evidence – Topiramate,
Lidocaine patch, Capsiscin

13. Drugs with promise
• Recombinant NGF, IGF 1 like growth factors,
Acetyl carnitine have shown some promise
• IVIg in lumbosacral plexopathy since it is
believed to have some auto immune basis
• Clonidine patches in DPN
• Complex regional pain syndrome or
sympathetically mediated pain is a difficult
problem, clonidine would be ideal but does not
seem to help to that extent

14. Therapeutic Options for
Painful Neuropathy
• TCAs – tricyclic antidepressants
• NNT – 2 to 3, Amitriptiline and desipramine
reign,
• Nortryptiline, 50 to 150 mg / d, single or divided
doses, sympathomimetic effects ++,
• Amitriptiline – 10 mg q HS to 150 mg q HS
weekly increments in doses. helps depression,
insomnia

15. Therapeutic Options for
Painful Neuropathy
• TCAs – tricyclic antidepressants
• NNT – 2 to 3, Amitriptiline, and desipramine
• Desipramine – 10 to 100 mg q HS, greater
tolerability,
• Other TCAs – Maprotiline, Clomipramine,
1.

16. Therapeutic Options for
Painful Neuropathy
• Selective serotonin reuptake inhibitors
Fluoxetine, Paroxetine, Venlafaxine, Citalopram
• Fluoxetine – Non sedative antidepressant,
morning dosing, 20 to 60 mg, modest, equivocal
on nerve
• Venlafaxine, - structurally different
antidepressant, 25 to 75 mg immediate release,
225 for sustained release
1.

17. Therapeutic Options for
Painful Neuropathy
• Duloxetine – Anti depressant, Dual reuptake
inhibitor, FDA approved for DPN, May work,
some doubtful, some think well of this drug, 30
to 120 mg up titrated slowly
• May cause initial nausea, works by enhancing
NE, Sero uptake within the inhibiting pain
pathways, thereby reducing the central pain
processing
1.

18. Therapeutic Options for
Painful Neuropathy
• Antiepileptics – Sudden lancinating pains
considered epileptic equivalent,
• Phenytoin, Carbamazepine, Topiramate, Valproic acid
• 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

19. Therapeutic Options for
Painful Neuropathy
• Topiramate – Adjuntive to other pain relief drugs,
Reduces epileptiform disharges by blocking the
sensitive Na channels and enhancing the activity
of GABA receptors 25 mg / d increased to up to
400 mg for , PN, Agitation anxiety, weight loss
above 100 mg dose
• Valproic acid – desperate cases, high on side
effect

20. Therapeutic Options for
Painful Neuropathy
• Carbamazepine – reduces the excitability
and increases membrane stability, build the
dose from 100mg to 900 to 1600 mg if
tolerated, phenitoin acts the same way, far
less predictably effective
• Oxcarbazepine – 600 mg / d
• Does not seem to fare better in comparison
with TCAs and Gabapentine,

21. Therapeutic Options for
Painful Neuropathy
• Gabapentine - Emerging therapy, 1st
line choice,
well tolerated,
• Binds to alfa 2 d subunit of N type CCB
• Dose range – 2100 to 3600 to 6000 mg
• Not tolerated beyond 900 mg, cost a consideration
• 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

22. Therapeutic Options for
Painful Neuropathy
• Pregabalin – Congener of Gabapentine, reduces
excitatory neurotransmitter release, binds to
voltage gated Ca+ channels, 150 to 600 mg / d
• 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

23. 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

24. Therapeutic Options for
Painful Neuropathy
• NSAIDs – simpler first line, common sense
defence, if effective; nephropathy
• Opioid like analgesics –
Tramadol – 12.5 mg, qid, NNT 3.1, centrally
acting analgesic, NE Sero uptake mildly inhibited
clinically moderately effective,
higher levels of side effects in nearly 50% of
cases,

25. Therapeutic Options for
Painful Neuropathy
• Dextromethorphan – 100% side effects,
moderate benefits
• Methadone, 1 to 15 mg, oxycodon 30 to 60
mg, Ketamine
• Morphine, Pethidine in extreme cases

26. Therapeutic Options for
Painful Neuropathy
• Mexiletine – oral congener of lidocaine, 150 mg /
day for 3 days, 300 mg per day for 3 days, then 10
mg / kg body weight / day, useful in lancinating,
dysesthetic pain, may worsen arrhythmia
• Lidocaine administration – IV5 mg / kg body
weight over 30 minutes by infusion pump; Ct
ECG monitoring, resuscitative equipment must,
drowsiness, dysarthria may take long hours to
respond, 5% patches 12 hourly, AE minimal
• Both reduce spontaneous evoked discharges

27. Therapeutic Options for
Painful Neuropathy
• 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 disappointing
• Promoted as nerve nutrient,

28. Diabetic Neuropathy
• Alpha lipoic acid – a thiol replenishing and redox
modulating agent
Metal chelating activity
ROS scavenging
Regenerating endogenous antioxidants like
glutathione, Vit C & E
Repair of proteins, DNA and lipids

29. Diabetic Neuropathy
• 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)

30. Diabetic Neuropathy
• 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

31. 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

32. 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

33. Therapeutic Options for
Painful Neuropathy
• Lamotrigine, an anti epileptic, works on pre-
synaptic glutamate release, recommended in
refractory cases 50 mg / d increased slowly by 100
mg biweekly, till the dose of 600 mg is reached,
useful in coexisting bipolar depression

34. Medical Co-morbidities and the
Therapeutic Options
• Important contraindication –
• Glaucoma, post hypotension, DCM, sexual
dysfunction – TCAs
• Hypertension Venlafaxine
• Renal insufficiency – Duloxetine, adjust for
oxycodon, pregabalin,
• Dizziness – Pregabalin, TCAs
• Hepatic Insufficiency - Duloxetine

35. Medical Co-morbidities and the
Therapeutic Options
• Major depression, generalized anxiety disorder,
suicidal ideation – oxycodon,
• Major depression, peripheral edema, weight gain –
Pregabelin
• Cost considerations TCAs recommended

36. 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

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

38. 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