Sequence of Resulting in Neuropathic Pain

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Therefore prevention of such transition from acute to chronic pain with opioids is the major goal in pain therapy. Also, intracellular gene expression can be prevented most successfully, if opioids are administered before nociceptive stimuli reach the cells [65], and before neuroplastic changes within the cells are being initiated. It is because of such intracellular changes, that acute pain can become chronic if it not sufficiently treated from the start. If however, during the process of initiation of pain a neuropathic component is diagnosed, it is of clinical importance that in addition to an opioid, an unspecific NMDA-antagonist such as ketamine is given in sub-anesthetic doses, to reduce pain. Such considerations are of significance,

Respiratory Spasms
Figure I-38. Transmission of visceral pain to segmental motor neurons, resulting in muscle spasm and the projection of pain to the skin (head zones)

because long-term pain may also result in apoptotic degeneration of interspinal neurons with their attached opioid receptor sites, resulting in a opioid resistance to any exogenous narcotic analgesic (Figure I-42). It is for this reason that up to 35% of all patients with neuropathic pain of peripheral or central origin may be opioid non-responders. The following disorders with associated pain states may show focal/diffuse neuropathic pain (Table I-1).

The phenomena of insufficient pain relief with opioids demands an additional and multimodal therapeutic approach. In such situations additional antiepileptic and/or antidepressive agents should be given. Those agents primarily act at the GABA receptor site with increase in GABA-synthesis, diminution of intracellular Ca2+-ions, and an increase in the release of GABA. In addition to NMDA-antagonists,

Table I-1. Classification of neuropathic pain disorders

- Phantom limb pain,

- Post-herpetic neuralgia,

- Entrapment syndrome,

- Post-traumatic neuralgia,

- Chronic radiculopathy,

- Complex regional pain syndrome (CRPS),

- Central post-stroke pain (CPSP),

- Multiple sclerosis (MS),

- Painful diabetic neuropathy (PDN),

- Ischemic neuropathy,

- Polyarteriitis nodosa,

- Polyneuropathy in long-term alcohol abuse,

- Toxic reaction due to vincristine, taxoids, cisplatin,

- Neuro-borrelliosis

- AIDS neuropathy

- Amyloid, plasmacytoma, morbus Fabry interventional blocks with local anesthetic (sodium-channel blockers), topical therapy with lidocaine or capscaicin are used as adjuncts in neuropathic pain. Certain cases will respond to neuromodulation with TENS (transcutaneous electrical nerve stimulation) or SCS (spinal cord stimulation), while physical and occupational therapy as well as psychobiological treatment, regularly are implemented in the therapeutic armamentarium of neuropathic pain.

Description of Neuropathic Pain Deafferentiation

Symptoms: Burning, shooting, stabbing, paroxysmal, vice-like, electric-shocklike pain, paresthesias

Causes: Injury to peripheral nerves leading to spontaneous and paroxysmal discharges, loss of central inhibitory modulation, interaction of sympathetic to somatic afferent nociceptors

Treatment: Opioids, antidepressants, anticonvulsants, antiarrhythmics, local anesthetics, topical capscaicin or lidocaine

Neuropathic pain is often described as burning, shooting, stabbing, paroxysmal, vice-like, electric-shock-like, or an abnormal sensation such as that of ants crawling on the skin. Neuropathic pain is often associated with sensibility changes such as allodynia and hyperalgesia or paresthesia. Neuropathic pain is caused by aberrant somatosensory processing induced by injury to an element of the nervous system. This may result from compression, destruction, or penetration injury of the nervous tissue or by an intrinsic disease process. Spontaneous paroxysmal discharges, loss of central inhibitory modulation, and sympathetic to somatic afferent nociceptor interaction may all contribute to the genesis of neuropathic pain.

Some common types of neuropathic pain include trigeminal neuralgia, post-herpetic neuralgia, reflex sympathetic dystrophy, lumbosacral plexopathy, phantom limb pain, nerve avulsion after trauma, and diabetic peripheral neuropathy. Damage to thalamic sensory relay neurons (as might occur after a stroke) can also give rise to intense neuropathic pain referred to the body surface.

Unlike nociceptive pain, which tends to decline with the cessation of the noxious stimulus, neuropathic pain persists for prolonged periods. Mechanisms involved in sustaining neuropathic pain are thought to include cellular and molecular changes in the pain pathway. For example, ephaptic stimulation of sensory fibers by adjacent autonomic fibers can lead to a perception of pain in the absence of any noxious stimulus (Table I-2). In addition, changes at the level of the spinal cord and brain, such as hypersensitivity to stimuli and excessive release of neurotransmitters, can lead to molecular changes, changes in gene expression, and changes in the receptive fields of neurons involved in perception of pain.

Neuropathic pain appears to develop by the following mechanisms: activated C fibers release glutamate or substance P, or both, in the dorsal horn of the spinal cord. These neurotransmitters have excitatory effects on second-order neurons, mediated

Sequence of Resulting in Neuropathic Pain Table 1-2. Postulated mechanisms involved in sustaining neuropathic pain


Altered "gating" Molecular changes Gene expression changes Receptive field changes

Spinal Cord

Altered "gating"

Dorsal horn denervation hypersensitivity Molecular changes Gene expression changes Receptive field changes

Altered "gating"

Dorsal horn denervation hypersensitivity Molecular changes Gene expression changes Receptive field changes

by AMPA and NMDA receptors. Glutamate activates AMPA receptors, resulting in an influx of cations (sodium, potassium, calcium) and depolarization of the postsynaptic neuron. These excitatory effects are rapid and short-lived. Repeated stimulation of primary afferent fibers can also lead to membrane depolarization via tachykinin receptors, which may be additive with stimulation of AMPA receptors. In the second-order neuron, membrane depolarization releases the inhibition (by magnesium) of voltage-gated calcium channels coupled to NMDA receptors and releases the inactivation of NMDA receptors, both of which contribute to a rise in cytosolic calcium. Glutamate activates the metabotropic aminocycIopentane-1, 3-decarboxylate (ACPD) receptors coupled to inositol phosphate, which mobilizes microsomal calcium, and this also contributes to the increase in intracellular calcium. Substance P stimulates IP3 (inositol triphosphate) synthesis and activates voltage-dependent channels.

The increased calcium concentration in the cell activates various enzyme cascades (e.g. phospholipase A2 and nitric oxide synthetase, which synthesize prostaglandin and nitric oxide) and induces transcription of immediate-early genes (C-fos, C-jun), all of which impair synaptic efficiency between primary afferent fibers and second-order neurons. The second-order neurons are gradually depolarized, and their responses increasingly amplified. This is referred to as the "wind-up phenomenon". Glutamate-initiated hyperactivity, or wind-up, leads to a vicious cycIe of pain. It is because of this glutamate-related neuronal hyperactivity, which is also the principal cause of epilepsy, that antiepileptic drugs are useful agents in neuropathic pain.

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