NEUROPATHIC PAIN

Summary Neuropathic pain – Nerve injury / compression Comprehensive assessment helps dignosis Multiple mechanisms Follow step ladder for drug treatment Treat Total Pain

Neuropathic Pain Definition: International Association for the Study of Pain defines Neuropathic pain as : “ pain initiated or caused by primary lesion or dysfunction of the nervous system” Also defined as ‘Pain in an area of absent sensation’

Classification of Neuropathic Pain Nerve Compression Nerve Injury CentralPeripheral Eg. Post-stroke pain Spinal Cord Compression peripheral neuropathy eg. post-herpetic neuralgia VisceralSomatic Plexopathies Sympathetic

Common Neuropathic Pain Situations Amputation - eg. Phantom limb pain Back, leg, and hip problems (Sciatica) CANCER and its treatment Diabetes Trigeminal neuralgia HIV infected or AIDS Herpes zoster virus infection Complex Regional Pain Syndromes Cerebro-Vascular Accident

Causes of Neuropathic pain in advanced Cancer Cancer Nerve compression / infiltration Plexopathy Spinal cord compression Thalamic tumour Anticancer treatment Chronic surgical incision pain Phantom limb pain Chemotherapy- peripheral neuropathy Radiation fibrosis - Plexopathy, neuralgia Debility Postherpetic neuralgia Concurrent disorders Diabetic neuropathy Post-stroke pain

Hallmarks of Neuropathic Pain Allodynia : Pain resulting from a stimulus that normally does not evoke pain.  Thermal or mechanical stimuli Hyperalgesia : Something that is normally painful is now more painful than usual  Exaggerated response to a normally painful stimulus  Pain within area of injury - Primary Hyperalgesia  Pain in surrounding undamaged area - Secondary Hyperalgesia

Clinical features of nerve pain Distribution: If peripheral nerve injury - neurodermatomal If central - larger area of abnormal sensation If Sympathetic component is present Pain felt in area of distribution of the vessel Vasomotor disturbances : redness, pallor, swelling Sweating abnormalities Motor and trophic changes - thinning of skin

What Does Patient Complain of ? Burning Numbness Paroxysmal Lancinating Shooting Raw Skin Feeling “ants crawling” “bag of worms”

Neuropathic Pain Hyperexcitability and spontaneous activity Central sensitization Nerve injury Dorsal horn NMDA and Glutamate mechanisms

Serotonin, noradrenaline

Chemical Excitation of Non-nociceptors beta

Mechanisms of Neuropathic Pain 1. Chemical Excitation of non-nociceptors 2. Recruitment of nerves outside the site of injury 3. Excitotoxicity 4. Excess Sodium channels 5. Ectopic discharge 6. De-afferentation 7. Central sensitization maintained by peripheral input 8. Sympathetic involvement 9. Ephaptic cross talk

Glutamate Substance P Excessive Sodium channels Excessive Calcium channels Decreased Potassium channels Nerve Growth Factor, Nitric-oxide Present mainly in Dorsal Horn Cells Increased Stimulation causes ‘Wind up’ Phenomena Increased Excitation leads to Persisting pain Agents which increase NMDA Receptor activity: Central Sensitisation - Role of NMDA Receptor

NERVE INJURY DRUG NEUROCHEMICAL ANATOMICAL INCREASE IN SURVIVAL FACTORS CELL DEATH ALTERATION OF TROPHIC FACTOR EXPRESION SYMPATHETIC SWITCH IN EXITATORY PEPTIDES SPROUTING INCREASE OF INHIBITORY PEPTIDES CHANGE IN RECEPTOR EXPRESSION INCREASE IN NITRIC OXIDE SYNTHASES CHANGE IN ION CHANNEL ALL THE ABOVE LEADS TO PHYSIOLIGICAL CHANGES LIKE REDUCTION IN PRESYNASPTIC INHIBITION ECTOPIC DISCHARGES

NERVE INJURY DORSAL HORN NEUROCHEMICAL ANATOMICAL REDUCTION IN GABA AND GABA RECEPTORS TERMINAL ATROPHY REDUCTION IN OPIOD RECEPTORS CELL LOSS GLIA CELL ACTIVATION APOPTOSIS INCREASE IN CYTOKINES INCREASE IN IMMEDIATE EARLY GENES INCREASE IN TRANSCRIPTION SIGNALS ALL THESE ABOVE CHANGES CAUSES INCREASED WINDUP, LONG TERM POTENTIATION REDUCED INHIBITORY CONTROLE IN DORSAL HORNS

Recruitment Neuroanatomical Reorganisation Recruitment to adjacent segments Nerve injury + recruitment of nerves outside site of injury State of Hyperalgesia - Primary and secondary

Ectopic Discharge Discharge of impulses from Areas of nerve which normally should not be discharging

1. Comprehensive Assessment Look for clinical features : Allodynia - pain on touch, cant bear a draft on skin, even clothes provoke hyperesthesia Sensory deficit, numbness. Hyperalgesia. Occasional sympathetic component Increased skin temperature, sweating Patients exhausted, demoralised, sleepless.

ALTERED EXCITABILITY VOLTAGE SENSITIVE NA+ CHANNELS HAVE BEEN SHOWN ACCUMALATE IN NEUROMA NERV ENDINGS & IN PATCHES OF DEMYELINATION AXONAL NEURAL MEMBRANE UNDER MYELIN NORMALLY CONTAINS A VERY LOW DENSITY NA+ CHANNELS B’CAUSE MYELIN SUPPRESS THEIR INSERTION DEMYELINATION, SPROUTING, ENDBULB FORMATION REMOVE THIS SUPPRESSION PERMITTING EXCESS CHANNEL INSERTION

Opioids NSAIDs Sodium-channel blockade Lidocaine Enhanced descending Inhibition Tricyclics SSRIs Alpha2- adrenergic agonists Tramadol Activation of GABA inhibitory system Baclofen Inhibition of glutamate excitatory system Ketamine Amantidine Anticonvulsants Carbamazepine Valproate Gabapentin Pregabalin Clonazepam Mechanism-based therapy

2. Management of Neuropathic pain Explanation Analgesics : specific for neuropathic pain other drugs : Non-opioids & Opioids Interruption of pain pathways. Physical therapy : Heat or cold pads, TENS Psychological and modification of way of life

Step 1 Step 2 Step 3 Step 4 Step 5 Coticosteroid For Nerve Compression Tricyclic antidepressant or anti-epileptic Tricyclic anti depressant and anti-epileptic NMDA - receptor -channel blocker Invasive Techniques Treatment of Neuropathic Pain Try Opioids first in cancer or severe non-cancer pain

Corticosteroid INFLAMMATORY NEUROPATHIC PAIN BONE PAIN PAIN FROM BOWEL OBSTRUCTION PAIN FROM LYMPHOEDEMA HEADACHE WITH RAISED ICT ACTION Inhibits PG production—Decreses inflammation—Decreases cappilary permeability—reducing peritubular oedema Membrane stabilization---Decreases Neuronal excitability Dexamethasone – Oral or Injection I.V mg/day for 3 days and continue with oral drug in diminishing dose

After Corticosteroid Nerve T T

Step 1 - Opioids In Neuropathic pain related to Cancer : More than one pain often present Try opioids first 50% of pain may be reduced with opioids helps reduce dose of specific neuropathic pain drugs

Step 2 - TriCyclic Antidepressants Amitryptiline : Particularly in burning type of pain Action : Prevention of reuptake of serotonin& Norad Alfa adrenergic blockade Na channel effect, NMDA antagnsm Start with 10 to 25 mg at night and increase every third day up to 75 to 100 mg if necessary Side effects - sedation, constipation, urinary retention, heart block aggravated Other TCAs -

Step 2 / Step 3 - Anticonvulsants Preferred for shooting lancinating type of pain Action : Suppress spontaneous neuronal discharges & hyperexcitability Depress the exitatory pathways, Facilitates the inhibitory mechanisms Drugs used: Carbamazepine, sodium valproate Carbamazepine : mg/day increased every third day by 100 mg up to mg/day Side effects : gastric irritation, sedation, giddiness, ataxia, confusion

Anticonvulsants GABAPENTIN &PREGABALIN ACTION- Act on neither GABA nor Na channels Modulate the cellular Ca influx into nociceptive neurons by binding to vlotage gated Ca channels preferred in Post Herpetic Neuralgia & Diabetic neuropathy less side effects Expensive Dose of Gabapentin: Start with 200 to 300 mg/day, increase up to 1200 to 1800 mg/ day in divided doses. Dose of Pregabalin : Start with 75 mg 12Qh, increase by adding 75mg every 3 to 4 days, upto 300 mg Q12h

NMDA Receptor Antagonists Oral Ketamine : Injectable form: given mixed in sweetened beverage Starting dose : 0.25 to 0.5 mg/kg (approximately 25mg /adult dose) hourly - gradually increased Side effects : delirium, hallucinations, nightmares

Systemic Local Anaesthetics Action- Blocking the Na channels Ex-Lidocaine,Mexilitine Autonomic drugs Alfa2 Agonist- Clonidine Alfa1 Antagonist- Prazocin,Terazocine Othrs like CAPSAICIN CREAM

Interventional Techniques Sympathetic Blockade eg. Lumbar Sympathetic block for pelvic or lower limb pain (e.g. Ca cervix) Stellate Ganglion block for upper limb pain as in Ca Breast Trigger Point Injections Somatic Nerve Block Neurolytic block Epidural

What should be the aim of our treatment ? To improve quality of life !

Total Pain Physical Spiritual Psychological Social Non-Physical Components of Pain