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Neuropathic pain understanding and management
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- 2. I take forgranted that you know the basics. What seems to be right today may be wrong tomorrow. What the mind doesn’t know the eyes don’t see! Oh, come with old Khayyam, and leave the Wise to talk; One thing is certain, that Life flies; One thing is certain, and the Rest is Lies; The Flower that once has blown forever dies. Myself when young did eagerly frequent Doctor and Saint, and heard great Argument About it and about; but evermore came out by the same door as in I went. With them the Seed of Wisdom did I sow, And with my own hand labour'd it to grow: And this was all the Harvest that I reap'd --- 'I came like Water and like Wind I go.' -(Omar Khayyam 11th Century)
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- 4. Incidence of DiabeticNeuropathy as a proportion of all diabetics 20 years after diagnosis No neuropathy 10% Asymptomatic 40% Symptomatic 50%
- 5. Classification of diabeticneuropathy Diffuse • Distal symmetric sensorimotor neuropathy -large fiber -small fiber • Autonomic • Symmetric proximal lower limb motor neuropathy (Amyotrophy) Focal • Mononeuropathies • Entrapment neuropathies • Truncal neuropathy • Cranial neuropathy • Focal amyotrophy.
- 6. Diagnosis of polyneuropathy 3challenges • Clinical signs & symptoms are due to polyneuropahy. • Categorisation of polyneuropathy • Etiology- history, investigations- lab, immunological, histological, genetic. • 25 – 30% - cause not identified.
- 7. Evaluation of polyneuropathy •History • Clinical examination. • Electrophysiological testing – extension of clinical examination • Laboratory investigations.
- 8. Clinical characteristics • Polyneuropathiesof many different etiologies have similar signs & symptoms. • Though the features are common the patterns are different. • The clinical features result from Lack of function – negative symptoms & signs abnormal function – positive symptoms & signs
- 9. Clinical characteristics • Clinicalcourse – acute, subacute chronic progressive, remitting and relapsing forms • Distribution of involvement distal Vs proximal symmetrical Vs asymmetrical Upper limb Vs lower limb predominance.
- 10. Clinical characteristics •Types offiber involvement Motor, large sensory, small sensory, autonomic •Inheritance – family history. •History of exposure to toxins and drugs, concomittant illness.
- 11. Neurological manifestations negative positive MotorWeakness, atrophy,fatigue reduced tone Fasciculations, cramps myokymia Reflex Hypo or areflexia _ Small fiber Decrease of pain & temperature sensation, Loss of visceral pain sensation Foot ulceration Spontaneous dull burning pain hyperesthesia parasthesia
- 12. Neurological manifestations negative positive Largefiber Decreased proprioception Decreased vibration sense Reduction of touch pressure sensibility Sensory ataxia Postural tremor Paraesthesias Sharp tingling pain (A delta type) Autonomic Orthostatic hypotension Arrythmia Gastroparesis Constipation, Impotence Urinary retention, Decreased sweating Hypertension Neuropathic diarrhoea Osteoarthropathy
- 13. Axonal Vs Demyelination(Clinical) DemyelinatingAxonal Muscle atrophy Slight Severe Weakness Severe Severe Reflexes Global areflexia Knee & UL preserved Sensory signs Motor > sensory Significant
- 14. Risk factors For Painful neuropathy •Hyperglycemia • Hypertension • Dysmetabolic syndrome HT+DM+IHD+DYSLIPIDEMIA For painless neuropathy •Greater height •Male gender •Smoking •Total abstinence from alcohol •High HbA1C
- 15. Underlying Mechanisms Agreement notyet reached on exact causal relationship between insulin imbalance and nerve damage. The relative importance and inter-relationship of the various mechanisms is the subject of ongoing research and debate.
- 16. Physical manifestations • Nervefibres degenerate • Blood vessels supplying the nerves are ‘grossly diseased’ Any theory needs to account for both
- 17. Pathways of action •Polyol pathway • Triose phosphate effects • Failure of nerve growth & repair mechanism • Fatty acid metabolism
- 18. Polyol Pathway • Polyol= Polyhydroxy alcohols • High blood glucose • Nerve cell and capillary membranes have insulin- independent glucose transport. • High intra-cellular glucose levels • Conversion of glucose to sorbitol in nerve cells by aldose reductase enzyme • Sorbitol cannot cross membranes and therefore accumulates
- 19. Polyol Pathway • Consequencesof high sorbitol concentration: • Osmotic damage to nerve cells • reduction in nerve myoinositol • Inhibition of nitric oxide (NO) production • Aldose reductase competes for NADPH • NO is vasodilator • Increased production of free radicals • Superoxide, hydrogen peroxide, hydroxyl • Formed during mitochondrial respiration • Increased oxidative stress (proteins, lipids, DNA)
- 20. Polyol Pathway • Treatmentpossibilities • Aldose reductase inhibitors • Supplemental myoinositol • Nitric oxide stimulation/sensitisation • Vasodilators • Antioxidants
- 21. Triose phosphates • Highintracellular glucose leads increased production of triose phosphates • Activation of protein kinase C (PKC) via DAG • Damages capillaries (permeability, contractility) • Damages nerve function • Non-enzymic reaction with proteins & DNA • Advanced Glycation End-products (AGEs) • Damage to capillaries and nerve fibres • Specific cellular AGE receptors • Protein cross-linking
- 22. Natural history ofdiabetic neuropathy and clinical signs and symptoms with pathological background. • With increasing stage of neuropathy, there is a progressive loss of nerve fibers that convey sensation. • When the fibers undergo degeneration or impaired remyelination, they release impulse of positive symptoms. • With progression of disease, negative symptoms of sensory loss are increased
- 23. Types of painfulneuropathies Acute (< 6 months) • Truncal neuropathy. • cachectic neuropathy-Acute, painful,wt.loss,poor control of DM • Insulin neuritis -Acute painful, weight loss, good control of DM • Painful 3rd cranial nerve palsy. • Easy to treat. Chronic(> 6 months) • Distal symmetrical painful sensorimotor polyneuropathy • Entrapment neuropathies • Difficult to treat.
- 24. Clinical features – Distalsymmetrical painful sensorimotor polyneuropathy • Burning, superficial pain. Hypoalgesia in later stages. • Defective thermal sensation. • Impaired vasomotion • Defective autonomic function • Intact DTR and power till late stages. • Progressive with increasing duration of diabetes. • Related to glycemic control & complications.
- 25. Clinical features – Truncalneuropathy • Truncal polyneuropathy • Rare • Occur in long standing DM • “Bandlike” Painful symptoms in thoracic root distribution • Motor involvement- muscle herniation – asymmetric bulge in abdominal wall • Truncal radiculopathy • Acute onset of pain in a radicular pattern • Asymmetrical pain • Patchy sensory loss is a clue to the diagnosis.
- 26. Clinical features Insulinneuritis • Acute painful, occurs 1 month after insulin /OHA. • Due to rapid glycemic control. • Nerves in these patients are under general hypoxia and use glucose under anaerobic conditions. • Once glucose is normalised in blood and nerves, glucose is no longer available and the nerves undergo degeneration.
- 27. Insulin neuritis- contd.., •Burningpain, paraesthesia, allodynia with nocturnal exacerbation. •Depression is a feature. •No weight loss. •Sensory loss is mild. No motor signs. •Complete resolution in 1 year.
- 28. Clinical features -Cachectic neuropathy • In patients with a poor control of DM. • Wt.loss is prominent. • Severe burning pain- continuous or intermittent. • Subjective feeling of swollen limb. • Allodynia is common- nocturnal exacerbation. • Sensory loss is mild. • No motor signs.
- 29. Cranial nerve palsy •Most common mononeuropathy • Acute pain in the orbit, ptosis, opthalmoplegia, pupil spared. • Usually unilateral • Complete recovery in 3 months. • Vascular etiology suggested. • 6th & 7th cranial nerve involvement are described.
- 30. Peripheral Autonomic Dysfunction •Contributesto the following symptoms/signs: • Neuropathic arthropathy (Charcot foot) • Aching, pulsation, tightness, cramping, dry skin, pruritus, edema, sweating abnormalities • Weakening of the bones in the foot leading to fractures
- 31. Investigations • Clinical examination– measuring thermal & vibration threshold. • Routine hemogram • Plasma Glucose estimation-Glycemic control • HbA1C levels • Electrodiagnostic testing.- Nerve conduction studies, Quantitative Sensory Testing (QST)
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- 33. Morphology- nerve biopsy •Nerve biopsy – invasive procedure with definite morbidity. • Sural nerve most commonly used. • Routine biopsy is controversial. • To rule out other causes like vasculitis etc.,. • Light & electron microscopic studies are necessary. • Can be done pre and post treatment to assess response
- 34. Section of asural nerve from a patient with diabetic neuropathy
- 35. Morphology- Skin punchbiopsy • Small nerve visualisation – assessment of cutaneous nerve fibers obtained from 3mm skin punch biopsy – promising in DSP. • Immunohistochemistry- antibody to general neuronal marker protein gene product 9.5.(PGP 9.5) • The relationship between epidermal nerve fibers and clinical scores is nonlinear. • Reappearance is a marker for diffuse peripheral nerve regeneration and recovery. • At present not advocated for routine evaluation
- 36. Skin Biopsy PGP9.5 staining
- 37. Bench To Bedside
- 38. Bench To Bedside • Diabetic Peripheral Neuropathy Pain refractory to initial therapies • Diabetic Peripheral Neuropathy Pain in the presence of comorbidity • Non Diabetic Neuropathy in a patient with diabetes mellitus • Rational Polypharmacy DPNP
- 39. Bench To Bedside • Diabetic Peripheral Neuropathy Pain refractory to initial therapies • Diabetic Peripheral Neuropathy Pain in the presence of comorbidity • Non Diabetic Neuropathy in a patient with diabetes mellitus • Rational Polypharmacy DPNP
- 40. Pharmacological Treatment of DPNPby Drug Class Class • SNRI ( highly specific inhibition of serotonin and Norepinephrine reuptake) • Alpha 2 delta ligands ( modulate voltage – gated Calcium channels ) • TCAs( inhibit reuptake of serotonin and Norepinephrine) • Opioids ( block mu opiod receptors) • Topical agents • Agents to AVOID ( never use) Individual agents • Duloxetine, Venlafaxine • Pregabalin ( Lyrica), gabapentin. • Tertiary ( amitriptyline); secondary ( desipramine) • Tramadol, oxycodone CR, morphine; methadone levorphanol;hydromorphone • Capsaicin; lidocaine • Meperidine, propoxyphene;NSAIDs; acetaminophen, amitriptyline( for patients > 60 years); vitamin B6 (>250 mg/d due to its potiential for neurotoxicity) pentazocine ( due to CNS toxicity and reversal of its analgesic effect.)
- 41. AEDs Carbamazepine 1. FDA approvedfor Trigeminal Neuralgia 2. Side effects Oxcarbazepine 1. One study for NeP 2. Hyponatremia – monitoring of serum sodium required 3. Rash – 4 % 4. Few Drug-drug interaction Levetiracetam 1. No controlled studies Tiagabine 1. No controlled studies Lamotrigine 1. Rash 10% 2. 2nd-line 3. Insomnia Topiramate 1. Negative results (3 - / 1 +) 2. Weight loss (10-20%) 3. Cognitive impairment 4. Nephrolithiasis (1.5%) Valproate 1. Nausea 2. Sedation 3. Fatal Hepatotoxicity - Enzymes 4. Hair loss 5. Hematologic effect (Platelet) 6. Drug-drug interactions
- 42. Agent type Reasonsfor recommendation Agent name First line > 2 RCTs in DPN Duloxetine,oxycodone CR, pregabalin, TCAs Second line 1 RCT in DPN; > 1 in other Carbamazepine, gabapentin painful neuropathies lamotrigine, tramadol, venlafaxine ER Topical Mechanism of action Capsaicin, lidocaine Others > RCTs in other painful Bupropion, citalopram neuropathies or other methodone, paroxetine, evidence phenytoin, toriramate. Recommendation for First- and Second- Line Agents for DPNP
- 43. Bench To Bedside • Diabetic Peripheral Neuropathy Pain refractory to initial therapies • Diabetic Peripheral Neuropathy Pain in the presence of comorbidity • Non Diabetic Neuropathy in a patient with diabetes mellitus • Rational Polypharmacy for DPNP
- 44. Factors to considerin choosing First –Line Agents Factor Recommended Avoid Medical co-morbidities Glaucoma Orthostatic phenomena Cardiac or electrocardiographic abnormality Hypertension Renal insufficiency Hepatic insufficiency Falls and balance issues Any other first line agent Any other first line agent Any other first line agent Any other first line agent Any other first line agent Any other first line agent Any other first line agent TCA s TCA s TCA s TCA s Duloxetine Pregabalin,TCAs
- 45. Factors to considerin choosing first line agents Factor Recommended Avoid Psychiatric comorbidities Depression Anxiety Suicidal ideation Somatic issues sleep Erectile dysfunction Other factors Cost Drug interactions Weight gain Edema Duloxetine,TCAs Any other first line agent Duloxetine,Pregabalin Any other first line agent Second line agent Venlafaxine TCA s oxycodone CR Oxycodone, Pregabalin Duloxetine, oxycodoneCR Any other first line agent oxycodoneCR pregabalin oxycodoneCR TCAs , oxycodone CR All first line agents Duloxetine,Pregabalin Duloxetine,TCAs TCAs,Pregabalin Pregabalin
- 46. Bench To Bedside • Diabetic Peripheral Neuropathy Pain refractory to initial therapies • Diabetic Peripheral Neuropathy Pain in the presence of comorbidity • Non Diabetic Neuropathy in a patient with diabetes mellitus • Rational of Poly pharmacy
- 47. Bench To Bedside • Diabetic Peripheral Neuropathy Pain refractory to initial therapies • Diabetic Peripheral Neuropathy Pain in the presence of comorbidity • Non Diabetic Neuropathy in a patient with diabetes mellitus • Rational Polypharmacy in DPNP
- 48. Rational Polypharmacy for DiabeticPeripheral Neuropathic Pain First- line Add-on therapy Avoid Agents SNRIs alpha 2 delta ligands, opioids, topical agents other SNRIs, TCAs tramadol alpha 2 SNRIs, TCAs, opioids, tramadol, topicals other alpha 2 delta Delta TCAs alpha 2 delta, opioids, topicals SNRIs, tramadol Opioids SNRIs, alpha 2 delta, TCAs, topicals Other opioids Tramadol alpha 2 delda, opioids, topicals SNRIs, TCAs Topical SNRIs, alpha 2 delda, TCAs, Opioids, tramadol None Topicals
- 49. Decrease Inflammatory Response NSAIDs, Local Anesthetics, Steroids Decrease Conduction Gabapentin, Carbamazepine, LocalAnesthetics, Opioids Prevent Centralization COX 2, Opioids, Ketamine, -2 Agonists. Increase Inhibition TCA’s, SSRI’s, Clonidine Modify Expression Anxiolytics Mechanistic Approach To Pain Therapy
- 50. Other Agents -Topical and Transdermal Drug Delivery Systems Systemic activity Applied away from painful site Serum levels necessary Systemic side effects Peripheral tissue activity Applied directly over painful site Insignificant serum levels Systemic side effects unlikely Topical (lidocaine patch 5%) Transdermal (fentanyl patch)
- 51. Based on ClassI and Class II evidence, capsaicin cream is probably effective in lessening the pain of PDN. Based on Class I evidence, isosorbide dinitrate spray is probably effective for the treatment of PDN.
- 52. Neuropathic Pain: Nonpharmacologic TreatmentOptions Cognitive-behavioral strategies – Meditation – Imagery – Biofeedback – Relaxation therapy Physical rehabilitation Acupuncture Transcutaneous electrical nerve stimulation
- 53. Religion, Spirituality andChronic Pain • Organized religion reduced chronic pain • Spirituality without affiliated regular worship attendance increased chronic pain prevalence • Individuals with chronic pain are more likely to use prayer, spiritual support for coping
- 54. Summary • Diabetic neuropathicpain is a disease, not a symptom • “Rational” polypharmacy is often necessary • combining peripheral and central nervous system agents enhances pain relief • Treatment goals include: • balancing efficacy, safety, and tolerability • reducing baseline pain and pain exacerbations • improving function and QOL • New agents and new uses for existing agents offer additional treatment options
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