1362576458 new look at painful neuropathy

Insights in Painful Neuropathy

Sanjeev KelkarHead Project Management GroupSecretary DFSIPAN India update Switzerland, 6th of October 2007


• 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)


• 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


• 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


• 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


• 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,


• 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

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


• 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


• 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

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,

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

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

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


• TCAs – tricyclic antidepressants• NNT – 2 to 3, Amitriptiline, and desipramine• Desipramine – 10 to 100 mg q HS, greater

tolerability, • Other TCAs – Maprotiline, Clomipramine,

1.


• 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.


• 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.


• 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


• 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


• 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,


• 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


• 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


• 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


• 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,


• Dextromethorphan – 100% side effects, moderate benefits

• Methadone, 1 to 15 mg, oxycodon 30 to 60 mg, Ketamine

• Morphine, Pethidine in extreme cases


• 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


• 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,

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

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)

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


• 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


• 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


• 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

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

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


• 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


• Talk to the patient• Explain what to expect, limitations of therapy• Support them• Sometimes multitherapy helps,


• 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

Health & Medicine

1362576458 new look at painful neuropathy