Insights in Painful Neuropathy

Sanjeev Kelkar

Secretary DFSI

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)

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

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

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

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,

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

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

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

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

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

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

1.

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

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

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

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

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,

Diabetic NeuropathyEvidence 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

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)

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

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

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

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

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

Therapeutic Options for Painful Neuropathy

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