Insights in 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,

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

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

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 – 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

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