Insights in 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

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 – PGE2 helps 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,