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Neuropathic pain From A to Z Ayman Abd Al-Maksoud Yousef, MD Assistant professor of Anesthesiology and Pain Relief, Faculty of Medicine, Tanta University

Objectives  

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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 broad categories:

1-Pain owing to tissue disease or damage (nociceptive pain), 2-Pain caused by somato-sensory system disease or damage (neuropathic pain), 3-Coexistence of nociceptive and neuropathic pain (mixed pain).


- IASP has been defined NP as Pain initiated or caused by a primary lesion or dysfunction of the nervous system - Nerve dysfunction can be represented by sensory, motor or autonomic dysfunction. - Dysfunction is a vague , blurs the distinction between NP and other types of pain such as nocicptive inflammatory pain that have a component of neurological dysfunction such as peripheral or central sensitization.

-Many studies have provided evidence of a critical role for immune and inflammatory mediators in the generation of neuropathic pain after tissue injury.

-These immune-inflammatory interactions seem essential for the production of neuropathic 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 sensory phenomena. 3-Precence, in variable degree, of other neurological signs, including motor or autonomic signs manifesting as 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 noxious stimuli. 4-Thermally evoked pain: Cold hyperalgesia: Pain arise from normally nonpainful cold object (20C) Heat hyperalgesia: Pain arise from normally nonpainful 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.


-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 is increased on damaged neurons. - Furthermore, products such as nerve growth factor, trigger expression of channels and receptors ( sodium channels) on uninjured fibres. - These peripheral changes at primary afferent neurons leads to peripheral sensitisation.

Channelpothies -Alternation in the expression of voltage gated and ligand gated channels in the cell bodies and terminal 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 the post-synaptic membrane and greater excitation.

- Coupling between the sympathetic and sensory nervous system: Neuropathic pain is somewhat dependant on activity in the sympathetic nervous system. This is often referred to as (sympathetically maintained 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 from Aβ and Aδ -fibres can be interpreted as nociceptive in origin. Non-nociceptive neurons, (star in yellow neuron) that causes input from mechanoreceptive Aβ and Aδ -fibres to be perceived as pain. Inhibitory interneurons and descending modulatory control systems (green neurons) are dysfunctional after nerve lesions, leading to disinhibition or facilitation of spinal cord dorsal horn neurons.

- Chemokines activate spinal cord glial cells (grey cell) throught chemokines receptors. - Activated microglia further enhance excitability in WDR neurons by releasing cytokines and growth factors and increasing glutamate concentrations.

Spinal cord hyper-excitability

At the synapse level, sensitized primary afferent sensory fibers decrease the threshold for activation of nociceptor neurons which become hyper-excitable and transmit frequent action potentials.

Central sensitization A sustained hyper-excitability of the dorsal horn neurones is associated with greater perception of pain in the higher center a process termed central sensitization.



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

Ephaptic activity

In addition to ectopic activity, direct nerve injury can cause a different form of neuropathic pain activity that is 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, stimulated peripheral afferent sensory fibers and adjacent unstimulated fibers results in an expansion of the area of pain perception.

Diagnosis - Screening tools and questionnaires asking about burning pain, paraesthesias, pain attacks, mechanical and thermal hypersensitivity, and numbness are nondiagnostic.

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McGill Pain Questionnaire (MPQ) were unable to discriminate between pain mechanism. (inflammatory, nociceptive, neuropathic) Neuropathic pain scale (NPS) attempted to discriminate between four diagnostic categories of neuropathic pain using single descriptor.

Leeds assessment of neuropathic symptoms

and signs (LANSS) It is a 7 item pain scale consisted of group sensory

description and sensory examination and a simple scoring system.

If score <12, then neuropathic mechanisms are unlikely to contribute the patient pain. If score >12, then neuropathic mechanisms are likely to contribute the patient pain. It provides qualitative and not quantative assessment of neuropathic pain.

Treatment - The successful treatment of neuropathic pain relies on its early identification, an understanding of the underlying mechanisms and the use of alternative therapeutic approaches.

Types of treatment A- 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 sleep 3-Physical therapy


Pharmacological method

Understanding the relation between symptoms and cellular and molecular mechanisms, provides powerful strategies to change rational drug therapy into mechanism-related

therapy, which include: 1- Reduction of abnormal excitability. 2-Enhancing Inhibition to enhance cellular inhibitory mechanisms.

1- Reduction of abnormal excitability A-Voltage gated ion channels

1- Sodium channel blockers such as locsamide. 2- Calcium channel substrates such as gabapentin and pregablin. 3- Low-voltage-activated T-channels blocker such as ethosuximide .

B-Ligand gated ion channels

Nicotinic receptor agonists (epibatidine) Selective alpha 4 beta 2 nicotinic receptor agonists have demonstrated anti-nociceptive action via descending monamanergic and muscarinic pathways.

2-Enhancing Inhibition Enhance cellular inhibitory mechanisms

1- Cannabinoids pathways. There are two major cannabinoid receptors, CB1 and CB2. The efficacy of cannabinoids towards pain modulation is mediated mainly through CB1 receptors located in both peripheral and CNS. Selective activation of the peripheral cannabinoid CB1 receptors appears to maintain significant pain relief

2-Monoamine pathway: Enhancing monoamine pathway in CNS reinforcing descending inhibitory pain circuitry, which include: 1- SSRI (mirtazepine) 2- SNRI ( paroxetine, fluoxetine) 3- NRI (reboxetine)

Immune therapy

1-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 pathways contributing to neuropathic pain. - Neutrophins represent an important family of regulatory proteins essential for sensory nerve development, survival, and regulation of neuronal excitability. - Several neurotrophins have been identified in chronic 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 Therapy

An engineered gene transcription factor (SB-509) to improve microvascular re-growth and promote peripheral nerve regeneration was used to attenuate neuropathic pain. Deletion of N-channel gene N-type channel are unique to neurons and critical for pain transmission, thus deletion of its gene reduces the severity of neuropathic pain.

Interventional therapy Interventional management is considered in patients who do not respond or who only partially respond to treatment. Interventional therapy could be invasive or non-invasive technique.

Transcutaneous electrical stimulation is used as noninvasive interventional therapy and, although the evidence level is low, the benefit to risk ratio is favorable.

Invasive interventions:

1- Spinal cord stimulation is efficacious in patients with complex regional pain syndrome and failed back surgery syndrome. 2- Motor cortex stimulation is efficacious in patients with central post-stroke pain. 3- Epidural blocks is recommended for patients with postherpetic neuralgia, radiculopathy, and failed back surgery syndrome.

4- Sympathetic nerve blocks are recommended for patients with postherpetic neuralgia and complex regional pain syndrome. 5- Intrathecal injection of opioids, and local anaesthetics is recommended in patients with postherpetic neuralgia, painful diabetic neuropathy, spinal cord injury, failed back surgery syndrome, and complex regional pain syndrome

Treatment in the elderly Drugs should be titrated with caution in older patients as result of reduced metabolism or clearance . - Starting doses need to be low and the doses should be adjusted to liver and renal function. - Topical drugs have a lower risk of side-effects than do systemically acting drugs and might provide a useful benefit to risk ratio. In general, close monitoring of side-effects is needed in elderly patients. -

CONCLUSION Neuropathic pain therapy remains a challenging area of unmet medical need, Despite the increases in our knowledge of its etiology and cellular mechanisms.

- Many details are still lacking , particularly with respect to the time related changes underlying pain progression and the complexity of overlapping mechanisms .


Mechanism-based approaches have lightened the areas for intervention including reduction of peripheral and central hyperexcitablity through a number of molecular targets.

- So, advances in basic and clinical studies, together with further differentiation of the mechanisms on the genesis and maintenance of pain, will certainly results in better and more precise definition which lead ultimately to more specific diagnosis and therapy.


Neuropathic pain