neuropathic pain-update - ssrao

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NEUROPATHIC PAIN DR.S.SREENIVASARAO MD,C.C.P.P.M, ASSIST PROFESSOR, DEPT.OF ANAESTHESIA, S.V.R.R.G.G.H.&S.V.M.C, TIRUPATI

WHAT IS PAIN………?:

WHAT IS PAIN………? DEFINITION : “ An unpleasant sensory and emotional experience associated with actual or potential damage or described in terms of such damage” - International Association for the Study of Pain, 1979 PAIN IS SUBJECTIVE REACTION TO AN OBJECTIVE STIMULUS WHAT THE PATIENT SAYS – “HURTS”

PAIN -TYPES:

PAIN -TYPES NEUROPATHIC COMPONENT N C O O C M I P C O E N P E T N I T V E YES NO YES MIXED NOCICEPTIVE NO NEUROPATHIC DYSFUNCTIONAL

NOCICEPTIVE PAIN :

NOCICEPTIVE PAIN NOCICEPTIVE PAIN NOXIOUS STIMULUS HEAT,COLD MECHANICAL FORCE CHEMICAL IRRITANTS PAIN AUTONOMIC RESPONSE WITHDRAWAL REFLEX ADAPTIVE HIGH THRESHOLD PAIN EARLY WARNING SYSTEM PROTECTIVE WOLF.CJ.CLIN.INVEST.-120:3742:2010

INFLAMMATORY PAIN :

INFLAMMATORY PAIN SPONTANEOUS PAIN PAIN HYPERSENSITIVITY INFLAMMATORY PAIN INFLAMMATION PERIPHERAL INFLAMMATION POSITIVE SYMPTOMS TISSUE DAMAGE ADAPTIVE LOW THRESHOLD PAIN TENDERNESS PRAMOTES REPAIR(PROTECTIVE) WOLF.CJ.CLIN.INVEST.-120:3742:2010

PATHOLOGICAL PAIN :

PATHOLOGICAL PAIN SPONTANEOUS PAIN EVOKED PAIN PAIN HYPERSENSITIVITY PERIPHERAL NERVE DAMAGE PATHOLOGICAL PAIN NEUROPATHIC PAIN NEURAL LESION POSITIVE & NEGATIVE SYMPTOMS INJUR Y STROKE ABNORMAL CENTRAL PROCESSING MALADAPTIVE LOW THRESHOLD DISEASE STATE OF NS WOLF.CJ.CLIN.INVEST.-120:3742:2010

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50 years old with 15 years of diabetic histoy complaining of numbness and tingling both lower limbs,loss of sensation below the knee joint- according to patient words he feels as amputated person,it is difficult to wear and catchhold the sliippers since 5 years. What may be the reason?

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40years old,he devoloped the painfull vesicles with burning sensation at his 5 th intercostal region transversly,treated by the loacl physcian, vesicles subsided with in two weeks,after that he devoloped pain to touch at the vesicles area and he is unable wear a shirt without that discomfort. What may be the reason?

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20 years old,who underwent hernioplasty at left inguinal region 6 months back, now he complains of very painfull to touch at the incissional area. What may be the reason?

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As an anaesthetist we are all facing the problem of resistance for repeated spinal anaesthesia from the patients especially females who are coming for second c/s section All resistant patients complains of pain& tenderness and backache at the needle puncture area. What may be the reason?

Neuropathic Pain:

Neuropathic Pain Definition:older 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’

New definition:

New definition NeuPSIG(2008) “ Pain arising as a direct consequence of a lesion or disease affecting the somatosensory system ” IASP(2011) “ Pain caused by a lesion or disease of the somatosensory system ”

PAIN QUALITIES:

PAIN QUALITIES Burning Paroxysmal Prickling Numbness “ants crawling ” Shock

Why should every doctor know Neuropathic pain?:

Why should every doctor know Neuropathic pain? Nep is common in the population ,peak incidence in the elderly. Nep is a common cause of severe pain Nep is assisiated with -- comarbities(depression,anxiety,sleep disorders) -- disability Impaired QOL Loss of work productivity 1.torrence et all,2.smith et all,3.bouhassia et all,4.dieleman et all,5.freyhagen et all,6.argoff et all,7.jensen et all,8.doth et all,9.gore et all

CLASSIFICATION(OLDER):

CLASSIFICATION(OLDER) PERIPHERALNeP NERVE,PLEXUS,ROOT CENTRAL NeP SPINAL CORD BRAIN STEM THALAMUS CEREBRAL CORTEX

Classifications of neuropathic pain(new) :

Classifications of neuropathic pain(new) Symptoms and Signs: Pain quality Sensory loss Sensory gain Mechanisms : Ectopic discharges Loss of inhibition Peripheral sensitization Central sensitization Locati on : Peripheral (nerve, plexus, dorsal root ganglion, root) Central (spinal, brainstem, thalamus, cortex) Etiology : Trauma Ischemia or hemorrhage Inflammation Neurotoxic Neurodegeneration Paraneoplastic Metabolic Vitamin deficiency Cancer

Definitions of common features suggestive of neuropathic pain :

Definitions of common features suggestive of neuropathic pain Paresthesia -- An abnormal sensation, whether spontaneous or evoked Dysesthesia --An unpleasant sensation, whether spontaneous or evoked Hypoesthesia --Decreased sensitivity to stimulation (tactile or thermal; both are frequent) Hyperesthesia -- Increased sensitivity to stimulation (tactile or thermal; both are rare) Hypoalgesia --Diminished pain response to a normally painful stimulus Hyperalgesia --An increased response to a stimulus that is normally painful Allodynia -- Pain due to a stimulus that does not normally activate the nociceptive system

Components of neuropathic pain.:

Components of neuropathic pain. Pain Spontaneous pain Provoked pain Continuous Intermittent Allodynia Hyperalgesia Mechanical Thermal

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Identified causes of pain . Possible underlying causes of pain in (1) all patients pooled (n = 2,436) and (2) the patients with a LANSS pain score ≥ 12 (n = 1,163). Patients may have multiple underlying pathologies. DN: diabetic neuropathy, TS: trigeminal syndrome (neuralgia); Ca: cancer, LP: lumbar pain, OP: osteoporosis; MS: multiple sclerosis, PHN: post-herpetic neuralgia, CRPS: complex regional pain syndrome; SM: Syringomyelia; CCS: carpal canal syndrome; pCVA: post-cerebrovascular accident; Alc: alcohol abuse; PSL: post-surgical lesions; PTL: post-traumatic lesion; OA: osteoarthritis . Hans et al. BMC Public Health 2007 7 :170 doi:10.1186/1471-2458-7-170 open, multicentre, observational survey investigated how physicians diagnose neuropathic pain (NeP) by applying the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale, and how neuropathic pain conditions are managed in daily practice in Belgium . Spontaneous pain was present in 96.5% Evoked pain was mostly present as allodynia (40.3%), hyperalgesic symptomatology only (10.3%), mixed allodynic/hyperalgesic symptoms (47.0%). Touch-evoked allodynia was most common71.7%

RANDAMIZED CONTROLE TRIALS & AETIOLOGIES:

RANDAMIZED CONTROLE TRIALS & AETIOLOGIES VELERIA MARTINEZ 2009

NEUROPATHIC PAIN SYNDROMES:

NEUROPATHIC PAIN SYNDROMES PRIMARY NeP SECONDARY NeP PERIPHERAL NeP TRIGEMINAL NEURALGIA ERYTHROMETALGIA EXTREME PAROXYSMAL PAIN SYNDROME DEGENERATIVE DISC DISEASE WITH RADICULAR PAIN IN NECK & LOW BACKACHE DM,CANCER POSTHERPETIC CRPS11 CENTRAL NeP NOT YET IDENTIFIED MULTIPLE SCLEROSIS POST STROKE PAIN SPC INJURY TRAUMATIC BRAIN INJURY SYRINGOMYLIA

IN NEUROPATHIC PAIN:

IN NEUROPATHIC PAIN

PERIPHERAL SENSITIZATION:

PERIPHERAL SENSITIZATION TISSUE DAMAGE INFLAMMATION SYMPATHETICO TERMINALS SENSITIZING “SOUP” HYDROGEN IONS HISTAMINE PURINES LEUKOTRIENS NORADRENALINE POTASSIUM IONS CYTOKINES NGF BRADYKININ PROSTAGLANDINS 5HT NEUROPEPTIDES DECREASED THRESHOLD OF NOCICEPTORS ECTOPIC DISCHARGES ABNORMAL ACCUMULATION OF SODIUM CHANNELS ADAPTED FROM SIDDAL,COUSINS;BRIDENBAUGH EDS;NEURAL BLOCKADE ;1998;675-699

PERIPHERAL SENSITIZATION:

PERIPHERAL SENSITIZATION CHANGES IN THE NOCICEPTOR FUNCTION,CHEMISTRY,STRUCTURE SPONTANEOUS FIRING OF NOCICEPTORS(AFTER DICHARGES) INCREASE IN THE MAGNITUDE & DURATION OF THE RESPONSE OF NOCICEPTORS FOR THE SUPRATHRESHOLD STIMULUS REDUCTION IN THE THRESHOLD FOR ACTIVATION OF NOCICEPTORS

CENTRAL SENSITIZATION:

CENTRAL SENSITIZATION

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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 Sensitization - Role of NMDA Receptor

NMDA RECEPTORS:

NMDA RECEPTORS + + + + + + + + + Mg Ca Ca Ca Ca BLOCKED BY Mg IONS AT RESTING MEMBRANE POTENTIAL

NMDA RECEPTORS:

NMDA RECEPTORS + + + + + + + + + Mg Ca Ca Ca Ca DEPOLARIZATION BY A δ & C FIBER INPUT

NMDA RECEPTORS:

NMDA RECEPTORS + + + + + + + + + Mg Ca Ca Ca Ca Mg ION DISPLACED IN VOLTAGE DEPENDENT MANNER GLUTAMATE BINDS TO ACTIVATED RECEPTOR

NMDA RECEPTORS:

NMDA RECEPTORS + + + + + + + + + Mg Ca Ca Ca Ca CAUSES INWARD Ca ION FLUX PHOSPHORYLATION OF NMDA RECEPTOR CAUSES DECREASED Mg BLOCKADE AT PHYSIOLOGIC RESTING POTENTIAL Ca Ca Ca Ca Ca CENTRAL SENSITIZATION

Central sensitization:

Central sensitization GLUTAMATE SUBSTANCE-P IL16,IL-6,8 TNF α SERATONINE NE DOPAMINE IL-4,10 PRO-NOCICEPTORS ANTI-NOCICEPTORS IMBALANCED NOCICEPTION

CROSS TALK:

CROSS TALK SENSITIZED NOCICEPTOR Aδ,C LOW THRASHOLD MECHANORECEPTOR A β WDR NEURON PAIN HYPEREXCITABLE DORSAL HORN NEURON PNS CNS

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SITE OF INJURY-CHANGES

PATHOLOGICAL CHANGES--SITES:

PATHOLOGICAL CHANGES--SITES HYPR EXCITABILITY OF NOCICEPTIVE NEURON DRG DRG INJURY C FIBRE A β GLUTAMATE PEPTIDES SP PHENOTYPIC CHANGES PHENOTYPIC CHANGES MICROGLIAL ACTIVATION REDUCTION OF SEGMENTAL INHIBITION OF GABA,GLYCINE AP DP ALTERATION OF INHIBITORY CONTROLE ECTOPIC CHANGES ECTOPIC CHANGES

MECHANISMS--SITES:

MECHANISMS--SITES HYPR EXCITABILITY OF NOCICEPTIVE NEURON DRG CENTRAL SENSITIZATION GENE REGULATION MICROGLIAL ACTIVATION REDUCTION OF SEGMENTAL INHIBITION OF GABA,GLYCINE INHIBITION OF TRANSMISSION ALTERATION OF INHIBITORY CONTROLE EXCITABILITY DESENSITIZATION

Mechanisms of Neuropathic Pain:

Mechanisms of Neuropathic Pain PERIPHERAL EFFECTS CENTRAL EFFECTS ECTOPIC & SPONTANEOUS DISCHARGES EPHAPTIC CONDUCTION ALTERATIONS IN ION CHANNEL EXPRESSION COLLATERAL SPROUTING OF PRIMARY AFFERENT NEURONS SPROUTING OF SYMPATHETIC NEURONS IN DRG NOCICEPTOR SENSITIZATION CENTRAL SENSITIZATION SPINAL REORGNIZATION CORTICAL REOGANIZATION CHANGES IN INHIBITORY PATHWAYS

CLINICAL MANIFESTATIONS OF NP:

CLINICAL MANIFESTATIONS OF NP CLINICAL MANIFESTATION PROBABLE MECHANISMS SENSORY LOSS DAMAGE TO THE NOCICEPTIVE SYSTEM ONGOING PAIN ECTOPIC ACTIVITY LOSS OF INHIBITION HYPERLAGESIA ALLODYNIA PERIPHERAL SENSITIZATION AND PHENOTYPIC SWITCH OF MYLINATED A-BETA FIBERS CENTRAL SENSITIZATION DISINHIBITION AND ENHANCED RELEASE OF NEUROTRANSMITTERS DESCENDING FACILITATION COURTESY –TREED RD

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It is almost like the old story about the six blind men and the elephant. They all came to different results from their examination. “A wall!” “A snake!” “A spear!” “A tree!” “A fan!” “A rope!” They told the prince: “We are sorry. But we cannot agree on what an elephant is like. We each touched the same animal. But to each of us the animal is completely different.” The prince spoke gently, “The elephant is a very large animal. Its side is like a wall,Its trunk is like a snake,Its tusks are like spears. Its legs are like trees. Its ears are like fans. And its tail is like a rope. So you are all right. But you are all wrong, too. For each of you touched only one part of the animal. To know what an elephant is really like, you must put all those parts together.” We can all agree that the nervous system is very large and its disorders are quite complex. We need to put all the information we have together in order to most effectively understand it & treat it UNDERSTANDING OF NEUROPATHIC PAIN

MANAGEMENT:

MANAGEMENT DEFINE THE DIAGNOSIS GRADING THE NP PHARMACOLOGICAL NONPHARMOCOLOGICAL SURGICAL NEWER THEURAPEUTIC MANAGAMENT

DIAGNOSIS:

DIAGNOSIS LOCATION OF PAIN INTENSITY OF PAIN SCREENING TOOLS BY SIGNS & SYMPTOMS SENSORY TESTING MOTOR TESTING INVESTIGATIONS ROUTINE SPECIFIC

LOCATION OF PAIN –PAIN MAPPING:

LOCATION OF PAIN –PAIN MAPPING Examples of pain drawings of neuropathic pain patients with (A) radicular pain of the right C6 dermatome and (B) painful polyneuropathy A B BURNING VAS-8/10 14-10-2012

INTENSITY OF PAIN:

INTENSITY OF PAIN

NEUROPATHIC PAIN SCREENING TOOLS:

NEUROPATHIC PAIN SCREENING TOOLS IDENTIFY POTENTIAL PATIENTS WITH NeP , POTENTIALLY BY NON SPECIALISTS FOR FURTHER ASSESSMENT SENSITIVITY--66-85%, SPECIFICITY--74-90% EASY TO USE DO NOT REPLACE THE CLINICAL JUDJEMENT

NEUROPATHIC PAIN SCREENING TOOLS:

NEUROPATHIC PAIN SCREENING TOOLS LANSS DN4 NPQ PAIN DETECT ID PAIN PRICKING,TINGLING ELECTRIC SCHOCK,SHOOTING HOT,BURNING NUMBNESS PAIN EVOKED BY LIGHT TOUCH PAINFULL COLD,FREENING PAIN AUTONOMIC CHANGES BRUSH ALLODYNIA RAISED SOFT TOUCH THRESHOLD RAISED PINPRICK THRESHOLD MODIFIED FROM BENNET et al PAIN 2007.127,199-203

SCREENIG OF NP-PAIN DETECT:

SCREENIG OF NP-PAIN DETECT 1.BURNING PAIN? 2.TINGLING OR PRICKLING(ELECTRIC) ? 3.SENSITIVE TO TOUCH(CLOTHES) ? 4.PAINFULL TO COLD OR HOT(BATH) ? 5.SHOOTING PAIN,ELECTRIC SHOCK? 6.NUMBNESS? 7.PAIN WITH LIGHT PRESSURE ? VERY STRONG —5 STRONG —4 MODERATE —3 SLIGHT —2 HARDLY NOTICED —1 NEVER —0

SENSORY TESTING:

SENSORY TESTING Summary of tools assessing sensory functi ons Fiber Type Sensation Clinical Testi ng Instrument Aβ Touch Vibration Fingers, a piece of cott on wool, or a soft brush Tuning fork (64 or 128 Hz) Aδ Pinprick, sharp pain Cold Wooden cocktail sticks Cold object (20°C) C Warmth Warm object (40°C)

Sensory abnormalities found in patients with neuropathic pain:

Sensory abnormalities found in patients with neuropathic pain Quantitative Qualitative Spatial Temporal Hypoesthesia Allodynia Poor localization Abnormal latency Hyperesthesia Paresthesia Abnormal radiation Aftersensation Hypoalgesia Dysesthesia Summation Hyperalgesia

MOTOR ASSESSMENT:

MOTOR ASSESSMENT Motor assessment Muscle strength, Tonus, Coordination and fluidity of movements Examination of tendon reflexes Examination of cranial nerves Muscle wasting

investigations:

investigations Routine investigations Special investigations Neurophysiologic testing Quantitative sensory testing (QST) Autonomic function testing Skin biopsy Bone scintigraphy , Bone densitometry, Nerve or sympathetic ganglion blockade Serum immunoelectrophoresis Specific serum antibody tests

Neurophysiologic testing:

Neurophysiologic testing Neurophysiologic testing, principally nerve conduction studies and electromyography, Slowing in maximum NCVs or loss of CMAP or SNAP amplitudes, indicative of peripheral nerve disease either focally or generally, occur as a consequence of large fiber dysfunction

Quantitative sensory testing (QST) :

Quantitative sensory testing (QST) Measures sensory thresholds for Pain, Touch, Vibration, and Hot and cold temperature sensations Specific fiber functions can be assessed: A δ -fibers with cold and cold-pain detection thresholds, C-fibers with heat and heat-pain detection thresholds, And large fiber (A β -) functions with vibration detection thresholds.

Quantitative sensory testing (QST) :

Quantitative sensory testing (QST) Elevated sensory thresholds correlate with sensory loss and lowered thresholds occur in allodynia and hyperalgesia In asymptomatic patients, abnormal QST thresholds suggest subclinical nerve damage QST is a psychophysical test and therefore is dependent upon patient motivation, alertness, and concentration .

Autonomic function testing:

Autonomic function testing Neuropathic pain frequently have signs & symptoms of autonomic dysfunction Dry eyes or mouth, Skin temperature and color changes Sweating abnormalities, Orthostatic hypotension, Heart rate responses to deep breathing, Edema, These tests study skin temperature, and sudomotor, baroreceptor,vasomotor, and cardiovagal functions

Autonomic function testing:

Autonomic function testing A semiquantitative composite autonomic symptoms score (CASS), composed of the results of sudomotor, cardiovagal, and adrenergic testing The most useful tests being The quantitative sudomotor axon reflex test (QSART), Thermoregulatory sweat test, Heart rate responses to deep breathing, Valsalva ratio, and Surface skin temperature

Skin biopsy:

Skin biopsy Epidermal nerve fiber density and morphology, A reduced density of epidermal nerve fibers is seen in small-fiber neuropathies - diabetic neuropathy, and impaired glucose tolerance neuropathy The skin biopsy findings were found to be a more sensitive measure than QSART or QST in diagnosing neuropathy in patients with burning feet and normal NCVs The loss of epidermal small fibers is not specific for the presence of neuropathic pain

LEPROSY & SMALL FIBER NEUROPATHY:

LEPROSY & SMALL FIBER NEUROPATHY Punch skin biopsy & IENF analysis was performed in 16 patients with leprosy(Lund c et al 2007) Statistically significant reduction in IENF density compared to control skin biopsies(p<0.001) Complete depletion of IENF in 6 patients

OTHER TESTS:

OTHER TESTS Bone scintigraphy, Bone densitometry, Nerve or sympathetic ganglion blockade. Serum immunoelectrophoresis can be helpful in painful polyneuropathies associated with monoclonal gammopathies and acquired amyloid polyneuropathy Specific serum antibody tests are valuable in painful neuropathies associated with neoplasia, celiac disease, and human immunodeficiency virus

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Percentage of patients undergoing one or more additional tests in relation to the underlying pathology in patients with LANSS ≥ 12 (n = 1,163) Number of tests Pathology 0 1 2 3 4 5 6 Diabetic neuropathy (n = 89) 6.7 46.1 19.1 10.1 11.2 6.7 0.0 Cancer (n = 27) 0.0 14.8 7.4 29.6 33.3 11.1 3.7 Lumbar problem (n = 84) 5.9 9.5 19.1 35.7 20.2 9.5 0.0 Osteoporosis (n = 3) 0.0 0.0 33.3 66.7 0.0 0.0 0.0 PHN (n = 98) 55.1 19.4 14.3 9.2 0.0 1.0 1.0 Multiple sclerosis (n = 22) 9.1 27.3 18.1 22.7 13.6 9.09 0.00 Post-traumatic lesion (n = 62) 6.4 19.3 19.3 17.7 20.9 16.1 0.0 Thalamic syndrome (n = 1) 0.0 0.0 0.0 0.0 0.0 100. 0.0 CRPS (n = 51) 11.8 13.7 25.5 17.6 23.5 7.8 0.0 Alcohol (n = 17) 11.8 29.4 29.4 11.8 17.7 0.0 0.0 Syringomyelia (n = 6) 16.7 50.0 16.7 0.00 0.00 16.7 0.0 Post-surgical lesion (n = 34) 8.8 17.6 26.5 20.6 14.7 5.9 5.9 CCS (n = 31) 3.2 74.2 16.1 3.2 3.2 0.0 0.0 Osteoarthritis (n = 17 ) 11.8 5.9 23.5 17.6 23.5 11.8 5.9 Post-CVA (n = 24) 12.5 25.0 37.5 16.7 4.2 4.2 0.0 Others (n = 119) 13.4 25.2 21.8 20.2 10.9 6.7 1.7 Abbreviations: PHN: post-herpetic neuralgia; Post-CVA: post-cerebrovascular accident; CRPS: complex regional pain syndrome; CCS: carpal canal syndrome Hans et al. BMC Public Health 2007 7 :170 doi:10.1186/1471-2458-7-170

GRADING SYSTEM:

GRADING SYSTEM CRITERIA TO BE EVALUATED FOR EACH PATIENT 1.PAIN WITH DIFFERENT NEUROANATOMICALLY PLAUSIBLE DISTRIBUTION 2.A HISTORY OF A REEVANT LESION OR DISEASE AFFECTING THE PERIPHERAL OR CENTRAL SOMATOSENSORY SYSTEM 3.DEMONSTRATION OF THE DISTINCT NEUROANATOMICALLY PLAUSIBLE DISTRIBUTION BY ATLEAST ONE CONFIRMATORY TEST 4.DEMONSTRATION OF THE RELEVANT LESION OR DISEASE BY ATLEAST ONE CONFIRMATORY TEST

GRADING SYSTEM:

GRADING SYSTEM DEFINITE NeP---1-4 (ALL) PROBABLE NeP---1&2 + EITHER 3 OR 4 POSSIBLE NeP-----1&2 WITHOUT CONFIRMATORY EVIDENCE FROM 3 OR 4

NONPHARMACOLOGICAL MANAGEMENT:

NONPHARMACOLOGICAL MANAGEMENT

NONPHARAMACOLOGICAL:

NONPHARAMACOLOGICAL Modification of the sensory aspects of pain without recourse to drugs involves the following strategies: Simple measures - Heat, ice, massage, Manipulative therapies (e.g. chiropractic, osteopathy), Physiotherapy Treating the primary cause - Improve diabetic control Supplement thiamine; reduce/stop alcohol consumption Surgery for disc prolapses or spinal stenosis Nerve translocation surgery (e.g. carpal tunnel release)

NONPHARAMACOLOGICAL:

NONPHARAMACOLOGICAL Stimulating inhibitory mechanisms Acupuncture TENS Electrical peripheral nerve or dorsal column or central (deep-brain) stimulation Inhibition or prevention of ascending nerve transmission in the peripheral nervous system, in the dorsal root ganglion or spinal cord: Nerve blocks, Neurolysis or Rhyzolysis

NONPHARAMACOLOGICAL:

NONPHARAMACOLOGICAL Alter pain processing at the cortical level . Cognitive therapies, Biofeedback, Hypnosis, Meditation. It is currently unclear the exact way in which these therapies alter sensation, but is assumed to involved both descending inhibition and alteration of sensitivity to ascending stimulus.

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PHARMACOLOGOCAL

Stepwise pharmacologic management of neuropathic pain (NP)--iasp :

Stepwise pharmacologic management of neuropathic pain (NP)-- iasp Step 1 Assess pain and establish the diagnosis of NP ; if uncertain about the diagnosis, refer to a pain specialist or neurologist Establish and treat the cause of NP ; if uncertain about availability of treatments addressing NP etiology, refer to appropriate specialist Identify relevant comorbidities (e.g., cardiac, renal, or hepatic disease, depression, gait instability) that might be relieved or exacerbated by NP treatment, or that might require dosage adjustment or additional monitoring of therapy Explain the diagnosis and treatment plan to the patient, and establish realistic expectations

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Step 2 Initiate therapy of the disease causing NP , if applicable Initiate symptom treatment with one or more of the following: • A secondary amine TCA ( nortriptyline , desipramine ) or an SSNRI ( duloxetine , venlafaxine ) • A calcium channel a2-d ligand , either gabapentin or pregabalin • For patients with localized peripheral NP: topical lidocaine used alone or in combination with one of the other first-line therapies • For patients with acute neuropathic pain, neuropathic cancer pain, or episodic exacerbations of severe pain, and when prompt pain relief during titration of a first-line medication to an efficacious dosage is required , opioid analgesics or tramadol may be used alone or in combination with one of the first-line therapies Evaluate patient for non-pharmacologic treatments , and initiate if appropriate

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Step 3 Reassess pain and health-related quality of life frequently If substantial pain relief (e.g., average pain reduced to 63/10) and tolerable side effects, continue treatment If partial pain relief (e.g., average pain remains P4/10) after an adequate trial (see Table 3), add one of the other first-line medications If no or inadequate pain relief (e.g., < 30% reduction) at target dosage after an adequate trial (see Table 3), switch to an alternative first-line medication TCA, tricyclic antidepressant; SSNRI, selective serotonin and norepinephrine reuptake inhibitor .

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Step 4 If trials of first-line medications alone and in combination fail, consider second- and third-line medications or referral to a pain specialist or multidisciplinary pain center

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Source: Journal of Pain and Symptom Management 2003; 25:S4-S11 (DOI:10.1016/S0885-3924(03)00064-2

Current theepeutic targets:

Current theepeutic targets HYPR EXCITABILITY OF NOCICEPTIVE NEURON DRG CENTRAL SENSITIZATION GENE REGULATION MICROGLIAL ACTIVATION REDUCTION OF SEGMENTAL INHIBITION OF GABA,GLYCINE ALTERATION OF INHIBITORY CONTROLE EXCITABILITY DESENSITIZATION INHIBITION OF TRANSMISSION TCA Na .C.B.-LIDOCAINE CAPSAICIN α 2 d agonist GABA,PREGB α 2 d agonist GABA,PREGB ANTIDEPRESSENTS OPIOIDS NEUROSTIMULATION OPIOIDS ????? ?????

IASP ,NeuPSIG guidelines: First-line medications and opioid agonists-- 1997:

IASP , NeuPSIG guidelines: First-line medications and opioid agonists-- 1997 Medication class Drugs Drug dosages (starting dose to maximum dose)* a2-d Ligands Pregabalin Gabapentin 50 mg tid or 75 mg bid to 600 mg/d (200 mg tid or 300 mg bid ) 100–300 mg nocte or 100–300 mg tid to 3,600 mg/d (1,200 mg tid ) Secondary-amine TCA Nortriptyline Desipramine 25 to 150 mg/d 25 to 150 mg/d SSNRI Duloxetine Venlafaxine 30 mg od to 60 mg bid 37.5 mg od or bid to 225 mg/d Topical lidocaine 5% Lidocaine patch Maximum of 3 patches daily for a maximum of 12 to 12–18 hours Opioid agonists** Morphine, oxycodone , methadone, Tramadol Levorphanol See individual prescribing information 50 mg od or bid to 400 mg/d (100 mg qid ); in patients >75 y, 300 mg/d Bid, twice daily; od, once daily; qid, four times daily; TCA, tricyclic antidepressants; tid, three times daily; SSNRI, selective serotonin norepinephrine reuptake inhibitor * See individual prescribing information for further details ** First-line medications only in certain clinical circumstances, ie, acute neuropathic pain, neuropathic cancer pain, episodic exacerbations of severe neuropathic pain, or when titrating one of the first-line medications if prompt painrelief is required

EFNS guidelines: Recommendations for the pharmacological management of commonly studied neuropathic pain conditions---2006:

EFNS guidelines: Recommendations for the pharmacological management of commonly studied neuropathic pain conditions---2006 Diabetic neuropathic pain Postherpetic neuralgia Classical trigeminal neuralgia Central neuropathic pain First-line treatments Pregabalin Gabapentin Duloxetine TCA Venlafaxine ER Pregabalin Gabapentin TCA Lidocaine patches** Carbamazepine Oxcarbazepine Pregabalin Gabapentin TCA Second- or third-line treatments Opioids Tramadol * Capsaicin Opioids Surgery Cannabinoids (MS) Lamotrigine Opioids Tramadol (SCI) ER, extended release; MS, multiple sclerosis; SCI, spinal cord injury; TCA, tricyclic antidepressants Adapted from reference 4. * Tramadol may be considered first-line in patients with acute exacerbations of pain especially for the tramadol/acetaminophen combination ** Lidocaine is recommended in elderly patients

NICE guidelines for pharmacological management of neuropathic pain in adults in non-specialist settings--March 2010.:

NICE guidelines for pharmacological management of neuropathic pain in adults in non-specialist settings--March 2010 . PAINFULL DIABETIC NEUROPATHY OTHER NEUROPATHIC CONDITIONS First-line treatment Duloxetine Amitriptyline if duloxetine is contraindicated Pregabalin or amitriptyline If pain reduction is satisfactory with amitriptyline but side effects are intolerable, consider imipramine or nortriptyline as an alternative Second-line treatment Treat with another drug instead of or in combination with the original drug - if first-line treatment was duloxetine , switch to amitriptyline or pregabalin , or combine with pregabalin - if first-line treatment was amitriptyline , switch to or combine with pregabalin Treat with another drug instead of or in combination with the original drug - if first-line treatment was amitriptyline (or imipramine or nortriptyline ), switch to or combine with pregabalin - if first-line treatment was pregabalin , switch to or combine with amitriptyline (or imipramine or nortriptyline if amitriptyline effective but patient cannot tolerate side effects Third-line treatment Refer to a specialist pain service and/or a condition-specific service. While waiting for referral: - consider tramadol instead of or in combination with second-line treatment - consider topical lidocaine for treatment of localized pain for people who are unable to take oral medication Drug dosages (starting dose to maximum dose): Amitriptyline: 10 mg/d to 75 mg/d; pregabalin: 150 mg/d (divided into 2 doses) to 600 mg/d (divided into 2 doses); duloxetine 60 mg/d to 120 mg/d; tramadol: 50–100 mg not more than every 4 h to 400 mg/d

Treatment selection considerations for first-line medications :

Treatment selection considerations for first-line medications Medication class Therapeutic index Major side effects Precautions Other benefits Secondary amine TCAs Nortriptyline , desipramine (use a tertiary amine TCA only if a secondary amine TCA is not available + Sedation, dry mouth, blurred vision, weight gain, urinary retention Cardiac disease,glaucoma , suicide risk,seizure disorder,concomitant useof tramadol Improvement of depression, improvement of insomnia SSNRIs Duloxetinec ++ Nausea Hepatic dysfunction,renal insufficiency,alcohol abuse, concomitant use of tramadol Improvement of depression Venlafaxine + Nausea Concomitant useof tramadol , cardiac disease, withdrawal syndrome with abrupt discontinuation Improvement of depression Calcium channel a2-d ligands Gabapentin ++ Sedation, dizziness, peripheral edema Renal insufficiency Improvement of sleep disturbance, no clinically significant drug interactions Pregabalin ++ Sedation, dizziness, peripheral edema Renal insufficiency Improvement of sleep disturbance, improvement of anxiety, no clinically significant drug interactions

Treatment selection considerations for SECOND-line medications and for opioid agonists:

Treatment selection considerations for SECOND-line medications and for opioid agonists Medication class Therapeutic index Major side effects Precautions Other benefits Topical lidocaine ++ Local erythema , rash None No systemic side effects Opioid agonistsd Morphine, oxycodone , methadone, levorphanol + Nausea/vomiting, constipation, drowsiness, dizziness History of substance abuse, suicide risk, driving impairment during treatment initiation Rapid onset of analgesic benefit Tramadol + Nausea/vomiting, constipation, drowsiness, dizziness seizures History of substance abuse, suicide risk, driving impairment during treatment initiation, seizure disorder, concomitant use of SSRI, SSNRI, TCA Rapid onset of analgesic benefit TCA, tricyclic antidepressants; SSNRI, selective serotonin and norepinephrine reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor. a Refers to the likelihood of pain relief relative to the likelihood of side effects, with ‘‘++’’ being more favorable. b Cost varies by region but is estimated on the basis of availability and cost of generic formulations, with ‘‘$$’’ being relatively more expensive. c Lack long-term clinical experience and safety data because new to market. d First-line only in certain circumstances; see text.

Prescribing recommendations for first-line medications :

Prescribing recommendations for first-line medications Medication class Starting dosage Titration Maximum dosage Duration of adequate trial Secondary amine TCAs Nortriptyline,desipraminea (use a tertiary amine TCA only f a secondary amine TCA is not available) 25 mg at bedtime Increase by 25 mg daily every 3–7 days as tolerated 150 mg daily; if blood level of active medication and its metabolite is below 100 ng /ml (mg/ml), continue titration with caution 6–8 weeks with at least 2 weeks at Maximum tolerated dosage SSNRIs Duloxetine 30 mg once daily Increase to 60 mg once daily after one week 60 mg twice daily 4 weeks Venlafaxine 37.5 mg once or twice daily Increase by 75 mg each week 225 mg daily 4–6 weeks Calcium channel a2-d ligands Gabapentin 100–300 mg at bedtime or 100–300 mg three times daily Increase by 100–300 mg three times daily every 1–7 days as tolerated 3600 mg daily (1200 mg three times daily); reduce if impaired renal function 3–8 weeks for titration plus 2 weeks at maximum dosage Pregabalin 50 mg tid or 75 mg bid Increase to 300 mg daily after 3–7 days, then by 150 mg/d every 3–7 days as tolerated 600 mg daily (200 mg three times or 300 mg twice daily); reduce if impaired renal function 4 weeks

Prescribing recommendations for SECOND-line medications and for opioid agonists:

Prescribing recommendations for SECOND-line medications and for opioid agonists Medication class Starting dosage Titration Maximum dosage Duration of adequate trial Topical lidocaine 5% lidocaine patch Maximum of 3 patches daily for a maximum of 12 h None needed Maximum of 3 patches daily for a maximum of 12–18 h 3 weeks Opioid agonists Morphine, oxycodone , methadone, levorphanol 10–15 mg morphine every 4 h or as needed ( equianalgesic dosages should be used for other opioid analgesics After 1–2 weeks, convert total daily dosage to long-acting opioid analgesic and continue short-acting medication as needed No maximum dosage with careful titration; consider evaluation by pain specialist at relatively high dosages (e.g., 120–180 mg morphine daily; equianalgesic dosages should be used for other opioid analgesics 4–6 weeks Tramadol 50 mg once or twice daily Increase by 50–100 mg daily in divided doses every 3–7 days as tolerated 400 mg daily (100 mg four times daily); in patients older than 75, 300 mg daily 4 weeks TCA, tricyclic antidepressants; SSNRI, selective serotonin and norepinephrine reuptake inhibitor. a Consider lower starting dosages and slower titration in geriatric patients. b First-line only in certain circumstances; see text. c Consider lower starting dosages and slower titration in geriatric patients; dosages given are for short-acting formulation

Neu.psig recommendations:

Neu.psig recommendations 1– ANTIDEPRESSENTS- TCA/SNRI 2—GABAPENTIN/PREGABALIN 3—TOPICAL LIDOCAINE 4—OPIOIDS/TRAMADOL ( acute neuropathic pain, neuropathic cancer pain, episodic exacerbations of severe neuropathic pain, or when titrating one of the first-line medications if prompt painrelief is required) DWORKEN et al. PAIN 2007

Neu.psig recommendations:

Neu.psig recommendations HOW TO IMPROVE THERAPEUTIC OUTCOME ? USE COMBINATION THERAPY USE NEWER DRUGS ACTING ON NEW TARGETS BETTER DEFINE RESPONDER PROFILES DWORKEN et al. PAIN 2007

DIABETIC NEUROPATHY-MANAGEMENT:

DIABETIC NEUROPATHY-MANAGEMENT

THIRD LINE MEDICATIONS:

THIRD LINE MEDICATIONS Antiepileptic (carbamazepine, lamotrigine, oxcarbazepine, topiramate, valproic acid) Antidepressant (bupropion, citalopram, paroxetine) medications, Mexiletine, Nmethyl- D-aspartate (NMDA) receptor antagonists-Dextromethorphan and memantine Topical capsaicin.(0.075%,8%) Botulinam –BTX-A

LIDOCAINE PATCH 5%:

LIDOCAINE PATCH 5% LIDOCAINE 5% IN PLIABLE PATCH UP TO 3 PATCHES APPLIED ONCE DAILY OVER PAINFULL SITE -12H ON,12H OFF(FDA APPROVED LABEL) -RECENTLY PUBLISHED DATA INDICATE 4 PATCHES(18-24H) SAFE EFFICASY DEMONSTRATED IN 3 RCT ON PHN DRUG INTERACTIONS AND SYSTEMIC SIDE EFEECTS UNLIKELY—MOST COMMON SIDE EFFECT –APPLICATION SITE SENSITIVITY CLINICALLY INSIGNIFICANT SEERUM LIDOCAINE LEVELS MECHANICAL BARRIER DECREASES ALLODYNIA

RESEARCH DRUGS FOR NEUROPATHIC PAIN:

RESEARCH DRUGS FOR NEUROPATHIC PAIN KRN5500 DILMAPIMOD Endomorphin-1 and endomorphin-2 BL-7050 Adenosine Angf

THERAPIES ACTING ON NEW TARGETS FOR NP:

THERAPIES ACTING ON NEW TARGETS FOR NP HYPR EXCITABILITY OF NOCICEPTIVE NEURON DRG CENTRAL SENSITIZATION GENE REGULATION MICROGLIAL ACTIVATION REDUCTION OF SEGMENTAL INHIBITION OF GABA,GLYCINE INHIBITION OF TRANSMISSION ALTERATION OF INHIBITORY CONTROLE EXCITABILITY DESENSITIZATION NEUOTROPHINS GDNF,ANTI NGF Na Channel Blockers POTASSIUM OPENERS TRPV1 agonist/antagonist AMPA antagonists mGalutamate inhibitors Dextrometorphin Quinidine Ca channel blockers Novel α 2 d agonist CCL2 INHIBITORS MAPK INHIBITORS GABA AGONISTS CANNBINOID RECEPTOR AGONISTS 5HT 17 AGONISTS ADENOSNE

TAKE HOME MESSAGE:

TAKE HOME MESSAGE T H A N K Y O U MANY MECHANISMS SO MANY METHODS

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