Neuropathic painFrom A to Z

Ayman Abd Al-Maksoud Yousef, MDAssistant professor of Anesthesiology and Pain Relief,

Faculty of Medicine, Tanta University

Objectives Define neuropathic pain. Understand the underlying pathogenesis om

molecular basis. Define diagnostic tools and their utility. Mechanism related therapy and the importance

of other treatment options.

- Chronic pain falls into three broadcategories:

1-Pain owing to tissue disease or damage(nociceptive pain),

2-Pain caused by somato-sensory system disease ordamage (neuropathic pain),

3-Coexistence of nociceptive and neuropathic pain(mixed pain).

Definition- IASP has been defined NP as Pain initiated or caused

by a primary lesion or dysfunction of the nervoussystem

- Nerve dysfunction can be represented by sensory,motor or autonomic dysfunction.

- Dysfunction is a vague , blurs the distinctionbetween NP and other types of pain such asnocicptive inflammatory pain that have acomponent of neurological dysfunction such asperipheral or central sensitization.

-Many studies have provided evidence of acritical role for immune and inflammatorymediators in the generation of neuropathicpain after tissue injury.

-These immune-inflammatory interactionsseem essential for the production ofneuropathic pain .

- Characteristics of NP:1- Pain and sensory symptoms that persist beyond the

healing period.2-Presence, in variable degree, of neurological sensory

signs manifesting as negative and positive sensoryphenomena.

3-Precence, in variable degree, of other neurologicalsigns, including motor or autonomic signs manifestingas negative and positive phenomena.

- The positive sensory signs are:1-Paraesthesias: abnormal skin crawling

sensation or tingling.2-Spontaneous pains: those that arise without

detectable stimulation.3-Evoked pains: those that arise with detectable

stimulation.

Types of evoked pain could be:1-Allodynia: pain in response to a non-nociceptive

stimulus.2-Hyperalgesia: an increased pain sensitivity to a

nociceptive stimulus.3-Summation: progressive worsening of pain evoked

by slow repetitive stimulation with mildly noxiousstimuli.

4-Thermally evoked pain:Cold hyperalgesia: Pain arise from normally non-

painful cold object (20C)Heat hyperalgesia: Pain arise from normally non-

painful hot object (40C) .

- The negative sensory signs can include:1- A deficit in the perception of mechanical or

vibratory stimuli, which indicates damage to large diameter afferent fibres or to the dorsal column tract, and

2- A loss of noxious and thermal perception,which indicates damage to small diameter afferent fibers or to central pain processing pathways such as the spino-thalamic tract.

Etiology-Trauma: phantom limb, spinal cord injury.-Ischemic injury: central pain, painful diabetic

neuropathy.-Inflammation: post-herpetic neuralgia, HIV.-Cancer: invasion/ compression of neural

structures.-Drugs: alkaloids derivatives.-Compression: sciatica-Unknown: trigeminal neuralgia

Path-physiology- A variety of pain–related phenomena, both central and

peripheral, have been associated with nerve injury.- It is inappropriate to attempt to generate a unifying

theory for path-physiology for all neuropathic pain states.

- The nociceptive C-fibres (red) terminate at spino-thalamic neurons in upper laminae.

- Non-nociceptive myelinated A-fibres project to deeper laminae. (blue)- The second-order neuron is a WDR type—it receives direct synaptic

input from nociceptive and also multisynaptic input from myelinated A-fibres.

- Interaction with microglia (grey) facilitates synaptic transmission.- GABAergic interneurons (green) normally exert inhibitory synaptic

input on the WDR neuron. - Descending modulatory systems synapse at the WDR neuron (green).

Nerve Severance- Complete or partial nerve transaction, compression,

infiltration, infectious, inflammatory or ischemic etiologies always starts the process of neuropathy.

- After nerve lesion, expression of sodium channels isincreased on damaged neurons.

- Furthermore, products such as nerve growth factor, triggerexpression of channels and receptors ( sodium channels)on uninjured fibres.

- These peripheral changes at primary afferent neurons leadsto peripheral sensitisation.

Channelpothies-Alternation in the expression of voltage gated and

ligand gated channels in the cell bodies andterminal neuroma of peripheral nerve injury .

Ectopic Activity - There is a large increase in the level of spontaneous firing

in the afferent neurons linked to injury site.

Wind up - Prolonged opening of the ion channels enables

greater influx of calcium and sodium across thepost-synaptic membrane and greater excitation.

- Coupling between the sympathetic andsensory nervous system:Neuropathic pain is somewhat dependant onactivity in the sympathetic nervous system.This is often referred to as (sympatheticallymaintained pain)

Spinal cord-anatomical re-organization:C-fibers normally innervate lamina I, II and responsible for nociceptive

signaling, while Aß-fibres innervate lamina III and IV.

If Aß-fibres sprout into lamina II, then low threshold non-noxious inputs fromAβ and Aδ -fibres can be interpreted as nociceptive in origin.

Non-nociceptive neurons, (star in yellow neuron) that causes input frommechanoreceptive Aβ and Aδ -fibres to be perceived as pain.

Inhibitory interneurons and descending modulatory control systems (greenneurons) are dysfunctional after nerve lesions, leading to disinhibition orfacilitation of spinal cord dorsal horn neurons.

- Chemokines activate spinal cord glial cells (grey cell)throught chemokines receptors.

- Activated microglia further enhance excitability inWDR neurons by releasing cytokines and growthfactors and increasing glutamate concentrations.

Spinal cord hyper-excitabilityAt the synapse level, sensitized primary afferent sensoryfibers decrease the threshold for activation of nociceptorneurons which become hyper-excitable and transmitfrequent action potentials.

Central sensitizationA sustained hyper-excitability of the dorsal hornneurones is associated with greater perception ofpain in the higher center a process termed centralsensitization.

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HyperalgesiaSo, individual manifests increased pain sensitivity to a nociceptive stimulus.

Ephaptic activityIn addition to ectopic activity, direct nerve injury cancause a different form of neuropathic pain activity thatis the ephaptic activity

Cross talk-Transmission of action potentials along adjacent,

undamaged unstimulated sensory fibers, or cross talk.

Receptive field expansion:Cross-talk between damaged, stimulatedperipheral afferent sensory fibers and adjacentunstimulated fibers results in an expansion of thearea of pain perception.

Diagnosis

- Screening tools and questionnaires askingabout burning pain, paraesthesias, painattacks, mechanical and thermalhypersensitivity, and numbness are non-diagnostic.

McGill Pain Questionnaire (MPQ) wereunable to discriminate between painmechanism. (inflammatory, nociceptive,neuropathic)

Neuropathic pain scale (NPS) attempted todiscriminate between four diagnosticcategories of neuropathic pain using singledescriptor.

Leeds assessment of neuropathic symptomsand signs (LANSS)It is a 7 item pain scale consisted of group sensory

description and sensory examination and a simplescoring system.

If score <12, then neuropathic mechanisms areunlikely to contribute the patient pain.

If score >12, then neuropathic mechanisms are likelyto contribute the patient pain.

It provides qualitative and not quantative assessmentof neuropathic pain.

Treatment- The successful treatment of neuropathic

pain relies on its early identification, anunderstanding of the underlyingmechanisms and the use of alternativetherapeutic approaches.

Types of treatmentA- Non-pharmacological therapy. B- Pharmacological therapy.C- Immunological therapy.D- Genetic therapy.E- Interventional therapy.

Non-pharmacological methods include:1-Stress reduction.2-Good hygiene sleep3-Physical therapy

Pharmacological method - Understanding the relation between symptomsand cellular and molecular mechanisms,provides powerful strategies to change rationaldrug therapy into mechanism-relatedtherapy, which include:

1- Reduction of abnormal excitability.2-Enhancing Inhibition to enhance cellular

inhibitory mechanisms.

1- Reduction of abnormal excitabilityA-Voltage gated ion channels

1- Sodium channel blockers such as locsamide.2- Calcium channel substrates such as gabapentin andpregablin.

3- Low-voltage-activated T-channels blocker such asethosuximide .

B-Ligand gated ion channelsNicotinic receptor agonists (epibatidine)Selective alpha 4 beta 2 nicotinic receptor agonistshave demonstrated anti-nociceptive action viadescending monamanergic and muscarinic pathways.

2-Enhancing InhibitionEnhance cellular inhibitory mechanisms1- Cannabinoids pathways.There are two major cannabinoid receptors, CB1

and CB2.The efficacy of cannabinoids towards pain

modulation is mediated mainly through CB1receptors located in both peripheral and CNS.

Selective activation of the peripheral cannabinoidCB1 receptors appears to maintain significant painrelief

2-Monoamine pathway:Enhancing monoamine pathway in CNSreinforcing descending inhibitory pain circuitry,which include:

1- SSRI (mirtazepine)2- SNRI ( paroxetine, fluoxetine)3- NRI (reboxetine)

Immune therapy1-Neuro-immune modulation:Glial cell stabilizers:

They reduce glial cell activity, attenuate evoked pain; include(minocycline and L-carnitine)

Glial cell receptor modulation:A number of purogenic receptors (P2X7 & P2X4) are

upergulated in microglial cells after peripheral nerve injury.Deletion of the P2X7 receptor gene produced a complete

absence of mechanical and thermal allodynia.Chemokines receptor neutralizing antibodies:Blockade of CX3CR1 by a receptor neutralizing antibody

induces anti-allodynic effects.Deletion of CCR2 gene blocks glial cell recruitment and

attenuate neuropathic pain.

2-Restoring the neural phenotype- A variety of phenotypic changes have been

identified in cellular elements of the pain pathwayscontributing to neuropathic pain.

- Neutrophins represent an important family ofregulatory proteins essential for sensory nervedevelopment, survival, and regulation of neuronalexcitability.

- Several neurotrophins have been identified inchronic pain models including nerve growth factor(NGF), Brain derived neurotrophic factor (BDNF),and neurotrophin 3, 4 and 5.

- NGF antagonists (ALE0540)and (PD90780), have shown efficacy in chronic pain models.

- Humanized anti-NGF monoclonal antibodies (m Ab) RN624 (Rinat) and AMG403(Amgen) have been reported to be efficacious in reducing pain in patients with PHN, and low back pain.

Gene TherapyAn engineered gene transcription factor (SB-509) to

improve microvascular re-growth and promoteperipheral nerve regeneration was used toattenuate neuropathic pain.

Deletion of N-channel geneN-type channel are unique to neurons and critical for

pain transmission, thus deletion of its gene reducesthe severity of neuropathic pain.

Interventional therapyInterventional management is considered in patients

who do not respond or who only partially respondto treatment.

Interventional therapy could be invasive or non-invasivetechnique.

Transcutaneous electrical stimulation is used as non-invasive interventional therapy and, although theevidence level is low, the benefit to risk ratio isfavorable.

Invasive interventions:1- Spinal cord stimulation is efficacious in

patients with complex regional pain syndromeand failed back surgery syndrome.

2- Motor cortex stimulation is efficacious inpatients with central post-stroke pain.

3- Epidural blocks is recommended for patientswith postherpetic neuralgia, radiculopathy, andfailed back surgery syndrome.

4- Sympathetic nerve blocks are recommendedfor patients with postherpetic neuralgia andcomplex regional pain syndrome.

5- Intrathecal injection of opioids, and localanaesthetics is recommended in patients withpostherpetic neuralgia, painful diabeticneuropathy, spinal cord injury, failed backsurgery syndrome, and complex regional painsyndrome

Treatment in the elderly- Drugs should be titrated with caution in older

patients as result of reduced metabolism orclearance .

- Starting doses need to be low and the doses shouldbe adjusted to liver and renal function.

- Topical drugs have a lower risk of side-effects thando systemically acting drugs and might provide auseful benefit to risk ratio. In general, closemonitoring of side-effects is needed in elderlypatients.

CONCLUSIONNeuropathic pain therapy remains achallenging area of unmet medical need,Despite the increases in our knowledge ofits etiology and cellular mechanisms.

- Many details are still lacking , particularlywith respect to the time related changesunderlying pain progression and thecomplexity of overlapping mechanisms .

- Mechanism-based approaches havelightened the areas for interventionincluding reduction of peripheral andcentral hyperexcitablity through anumber of molecular targets.

- So, advances in basic and clinical studies,together with further differentiation of themechanisms on the genesis andmaintenance of pain, will certainly resultsin better and more precise definitionwhich lead ultimately to more specificdiagnosis and therapy.

THANK YOUayman.yousef@rocketmail.com