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1362576458 new look at painful neuropathy

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new look at painful neuropathy

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1362576458 new look at painful neuropathy

  1. 1. Insights in Painful Neuropathy Sanjeev Kelkar Head Project Management Group Secretary DFSI PAN India update Switzerland, 6th of October 2007
  2. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 37. Therapeutic Options for Painful Neuropathy • Talk to the patient • Explain what to expect, limitations of therapy • Support them • Sometimes multitherapy helps,
  38. 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

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