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PAIN and Neuropathy

Pain =
--a feeling of distress, suffering, or agony,
--an unpleasant sensation that can range from mild, localized discomfort to agony
--has physical and emotional components
--emotions have strong effects on physical perception
--algophobia = an irrational dread of pain
--depression etc strongly associated with inadequately treated pain
--also "pain" = painful uterine contraction occurring in childbirth.
--from the Latin "poena" meaning a fine, a penalty
--acute or nociceptive pain vs neuropathic pain
--nociceptive and neuropathic pain are caused by different neuro–physiological processes, and therefore tend to respond to different treatment modalities

--nociceptors and temperature receptors are free nerve endings
--nociceptors: 2 types: mechano-thermal (type Adelta axon) and polymodal (type C axon)
--mechano-thermal nociceptors (distinct from thermoreceptors)
--polymodal nociceptor: heat, tissue damage, chemicals: bradykinin, histamine, insect venom
--FREE NERVE ENDINGS are in skin & mucus memb, periosteium, joint sfcs, arterial walls, and falx and tentorium of the cranial cavity.
--visceral nociceptors: cramping, bloating, tissue irritation or damage-->sympathetic
--physiological: pressure, stretch, tension, blood pressure, gas, heat, etc-->parasympathetic
--"perception of sensation is a CNS phenomenon" ex1: funny bone hit causes pain in little finger, ex2: phantom limb pain/perception (Brons)

--free nerve ending receptors transmit at slower conduction velocities (less or unmyelinated)
--type Adelta axon ("fast pain") is 5-30m/sex conduction
--C axon ("slow pain, dull ache") is slow (.5-2m/sec)
--pain receptors are slow adapting
--continued stimulation --> gradual reduction of maintained activity, usu due to inactivation of Ca or Na channels or activation of Ca sensitive K channels
--slow conducting nerves not as sensitive to stimuli
--slow conductors are smaller nerves with no myeline
--slow conductors not as sensitive to hypoxia, and when reperfused are the first nerves to "wake up" with tingling

--first order neurons BRANCH out along dorsolateral fasciculus (Lissauer's tract) and enter the dorsal horn at several adjacent spinal cord levels. This circuitry causes painful stim from local area to elicit whole limb responses from a large popluation of spinal cord neurons
--second order neurons in dorsal horn receive input from both A delta and C axons
--Neurotransmitters: substance P, CGRP, glutamate and NO
--axons mostly decussate and ascend the anterolateral-spinothalamic (ALS) system
--dorsal roots are classified III for those carrying A-delta axons (alerting "fast" pain) and IV for C axons (slow pain).
--Rexed's lamina are the layers of dorsal horn neurons separated by modality, substantia gelatinosa in rexed lamina II modulates pain and temperature
--paleospinothalamic pathway projects qualitative aspects of pain to reticular formation, hypothalamus, medial thalamus & periaqueductal grey (neospinothalamic-->lateral thalamus)
--medial thalamic neurons project to cingulate gyrus and insula (responsible for affective qualities of pain)
--different medial thalamic nuclei generate different responses, alerting response or dull, persistent pain
--in the reticular formation, the raphe nuclei receive sensory esp pain input

--an unpleasant sensation associated with actual or potential tissue damage
--caused by stimulation of specialized nerve endings
--purpose is chiefly protective; it acts as a warning that tissues are being damaged and induces the sufferer to remove or withdraw from the source
--mediated by specific nerve fibers to the brain where its conscious appreciation may be modified
--may be localized or generalized
--serves a protective biological function by acting as a warning of on–going tissue damage
--symptom of a disease process experienced in or around the injured or diseased tissue
--Associated psychological symptoms are minimal and are usually limited to mild anxiety
--nociceptive in nature
--can be somatic or visceral in nature
--occurs secondary to chemical, mechanical and thermal stimulation of A–delta and C–polymodal pain receptors.
--A–delta and C–fibers which are located in skin, bone, connective tissue, muscle and viscera. --biologically useful: localize noxious chemical, thermal and mechanical stimuli
--somatic pain tends to be well localized, constant pain that is described as sharp, aching, throbbing, or gnawing
--Visceral pain tends to be vague in distribution, paroxysmal in nature and is usually described as deep, aching, squeezing and colicky in nature.
--Examples: post–operative pain, pain associated with trauma, and the chronic pain of arthritis.
--usually responds to opioids and non–steroidal anti–inflammatories (NSAIDS).

--chronic, non–malignant
--peripheral or central nervous systems malfunctions and becomes the cause of the pain
--serves no protective biological function
--not self–limiting, can persist for years and even decades after the initial injury
--inadequately treated-->>chronic anxiety, fear, depression, sleeplessness and social impairment
--"burning", "electric", "tingling", and "shooting"
--can be continuous or paroxysmal
--hallmarks of neuropathic pain are chronic allodynia and hyperalgesia
--allodynia = pain resulting from a stimulus that ordinarily does not elicit a painful response (eg. light touch)
--hyperalgesia = increased sensitivity to a normally painful stimuli
--primary hyperalgesia, caused by sensitization of C–fibers (slow pain), occurs immediately within the area of the injury.
--secondary hyperalgesia, caused by sensitization of dorsal horn neurons, occurs in the undamaged area surrounding the injury.
--Examples: monoradiculopathies, trigeminal neuralgia, postherpetic neuralgia, phantom limb pain, complex regional pain syndromes and the various peripheral neuropathies. Neuropathic pain tends to be only partially responsive to opioid therapy.

--peripheral nerve injury-->anatomical and neuro–chemical changes in the CNS
--changes can persist long after the injury has healed
-->>SENSITIZATION OF NEURONS IN THE DORSAL HORN characterized by a) increased spontaneous activity of the dorsal horn neurons, b) decreased threshold and an increased responsivity to afferent input, and c) cell death in the spinal dorsal horn.
--C-fiber nociceptors (slow pain) can develop new adrenergic receptors and sensitivity
--sympathetically maintained pain
--significant alterations have been shown in the dorsal horn ipsilateral to the injury
--increased mRNA for specific neurotransmitters (e.g. substance P)
--differential temporal expression of mRNA and receptors
--decreased levels of opiod binding sites
--appearance of immediate early gene products (e.g. c–fos),26,27 of which the significance is that peripheral nerve injury is causing changes in the cell's synthesis of products, and alterations in the relative levels of neuropeptides/neuromodulators (e.g. increased galanin and VIP and reductions in sP and CGRP).4
--thermal or tactile hyperalgesia may involve nitric oxide, arachidonic acid & metabolites
--Cyclooxygenase inhibition appears to suppress tactile allodynia
--Blockade of activation of protein kinase C has been shown to prevent behavioral neuropathic manifestations
--injured axon may release factors which may be transported in a retrograde or orthograde fashion to initiate changes important to the development of a pain state
--Thermal hyperalgesia has been prevented in the Bennett model of nerve injury by blocking axonal transport bidirectionally with colchicine.
--WIND UP AND LONG TERM POTENTIATION: Repetitive noxious stimulation of unmyelinated C–fibers can result in prolonged discharge of dorsal horn cells. This phenomenon which is termed "wind–up", is a progressive increase in the number of action potentials elicited per stimulus that occurs in dorsal horn neurons. Repetitive episodes of "wind–up" may precipitate long–term potentiation (LTP), which involves a long lasting increase in the efficacy of synaptic transmission. Where "wind–up" is thought to last only minutes, LTP by definition, lasts at least one hour and maybe even months. Both "wind–up" and LTP are believed to be part of the sensitization process involved in many chronic pain states.
--expansion of receptive fields may also occur following tissue injury
--excessive nociceptive input to the dorsal horn can have excitotoxic consequences resulting in the DEATH OF INHIBITORY INTERNEURONS-->>spinal hyper–excitability
--ALLODYNIA and HYPERALGESIA w/ neuropathic CAUSES: 1) the development of spontaneous activity of afferent input 2) the sprouting of large primary efferents (eg. A–beta fibers from lamina 3 into lamina 1 and 2), 3) sprouting of sympathetic efferents into neuromas and dorsal root and ganglion cells, 4) elimination of intrinsic modulatory systems and 5) up regulation of receptors in the dorsal horn which mediate excitatory processes.
--[[NORMAL, non-injured A beta fibers (large myelinated afferents) penetrate the dorsal horn, travel ventrally, and terminate in lamina III and deeper. C fibers (small unmyelinated afferents) penetrate directly and generally terminate no deeper than lamina II.]]
--formation of ectopic neuronal pacemakers can occur at various sites along the nerve.
-- = Increased densities of abnormal or dysfunctional sodium channels, demonstrate different depolarization characteristics, may explain the rationale of treatment with lidocaine, mexiletine, phenytoin, carbamazepine, and tricyclic antidepressants each of which blocks sodium channels.
--ectopic pacemakers can occur in the proximal stump (eg. neuroma), in the cell bodies of the dorsal root ganglion, and in focal areas of demylenation along the axon.
--NEUROMAS are composed of abnormal sprouting axons and have a significant degree of sympathetic innervation
--neuroma in dorsal horn: prominent sprouting of large afferents dorsally from lamina III into laminae I and II-->>gain access to spinal regions involved in transmitting high intensity, noxious signals, instead of merely encoding low threshold information.
--Neuromas accumulate sodium channels at their distal ends increasing sensitivity, can acquire adrenergic sensitivity (pain following injection of norepi into neuroma) and can acquire sensitivity to catecholamines, prostanoids and cytokines.
--Novel ion channels or receptors, not found in normal nerves, appear to be expressed in the regenerating terminal/axon.
2) EPHAPSES = Abnormal electrical connections between adjacent demyelinated axons
--"Ephaptic cross talk" between A and C fibers develops in the dorsal root ganglion.
--injured nerves may contain ephapses between sensory and sympathetic fibers
--cross–connections may play a role in the pathogenesis of sympathetically mediated pain
3) NEUROGENIC INFLAMMATION = cascade of events following neural injury
--nociceptors release substance P (pro-inflam)
--sympathethic postganglionic neurons release prostaglandins (PGE2) 3)
--prior two activate nearby receptors-->spreading activation
--thus some neuropathic pain patients to topical nonsteroidal anti–inflammatory drugs, lidocaine, and capsaicin
4) NERVI NERVORUM can be damaged by compression/injury/inflam of the CT sheath around peripheral nerves
--In cancer patients, pain associated with tumor compression of neural structures is clinically indistinguishable from non–malignant neuropathic pain.
--NSAIDs and corticosteroids effective sometimes, perhaps due to decreased edema so less pressure on nerve
--extremely difficult to tell tumor-inflam pain from nervi nervorum etc pain

--Early recognition and aggressive management of neuropathic pain are key
--many use multiple treatment modalities incl: systemic medication, physical modalities (eg. physical rehabilitation), psychological modalities (eg. behavior modification, relaxation training), invasive procedures (eg. trigger–point injections, epidural steroids, sympathetic blocks), spinal cord stimulators, intrathecal morphine pump systems and various surgical techniques (eg. dorsal root entry zone lesions, cordotomy and sympathectomy)
--caution is warranted regarding the use of neuroablative techniques (may produce deaffrentation and exacerbate the underlying neuropathic mechanisms)
--responds poorly to NSAIDS and opioid analgesics
--tricyclic antidepressants (TCA's) such as amitriptyline (Elavil)
--anticonvulsants (phenytoin, valproate, or carbamazepine)
--systemic local anesthetics
--topical therapy with substance P depletors (capsaicin (Xostrix) the only medication approved by the FDA for treatment of postherpetic neuralgia)
--autonomic drugs
--opiates (oxycontin, percoset)
--narcotics (vicadin, liver probs)
--NMDA receptor antagonists
--surgery (to decompress nerves)
--TENS (transcutaneous electrical nerve stimulation) Electrodes placed over the painful area deliver a mild electrical impulse to nearby nerve pathways, thereby easing pain.
--dorsal root zone (DREZ) surgery (a treatment of last resort)
--desensitization: the painful area is stimulated with whatever is causing the pain

--B-complex vitamins, IM
--whole foods diet with adequate protein, carbohydrates, and fats
--diet includes includes yeast, liver, wheat germ, and foods that are high in B vitamins
--Acupuncture is very effective, esp for postherpetic neuralgia, releases endogenous opiates
--homeopathics also can be very effective
--black cohosh (Cimicifuga racemosa) appears to have anti-inflammatory properties

--paroxysmal pain in a nerve or along the course of one or more nerves
--pain of a severe, throbbing, or stabbing character in the course or distribution of a nerve
--usually sharp, spasmlike pain that may recur at intervals
--pain usually felt in the part of the body that is supplied by the irritated
--causes: systemic disease, inflammation, infection, and compression or irritation of a nerve
--Neuralgia is a symptom of an underlying disorder; its diagnosis depends on finding the cause of the condition creating the pain.
--usually the pain subsides within 5 years, sometimes faster with the right treatment

--1) trigeminal nerve (see tic douloureux) (most common type of neuralgia), causes a brief, searing pain along trigeminal n. (sensation to face).
--2) sciatic nerve
--3) postherpetic neuralgia = intense debilitating pain felt at the site of a previous attack of shingles. Minimize by aggressively treating rash, to minimize neuralgia. (shingles caused by the herpes zoster virus). Has been treated by destroying nerves at spinal column.
--4) brachial, supraorbital, etc.
--5) anaemic, diabetic, gouty, malarial, syphilitic, etc.
--causes: tooth decay, eye strain, or shingles (an infection caused by the herpes zoster virus), poor diet, nose infections, or exposure to damp and cold
--6) Migraine neuralgia = A variant of migraine pain, also called cluster headache, in which severe attacks of pain affect the eye and forehead on one side of the face. Lasts between 30 minutes and an hour and occurs at the same time on successive days. Cause is not known.
--7) glossopharyngeal neuralgia is an intense pain felt at the back of the tongue, in the throat, and in the ear-all areas served by the glossopharyngeal nerve. The pain may occur spontaneously, or it can be triggered by talking, eating, or swallowing (especially cold foods such as ice cream). Its cause is not known.
--8) Occipital neuralgia is caused by a pinched occipital nerve, paired, back of neck, feeling to skin over half of back of the head. Nerve injury via arthritis or injury, causesnumbness, pain, or tingling over half the base of the skull.

--a chronic condition causing pain, stiffness, tenderness of the muscles, tendons, joints
--to see what condition your condition is in
--characterized by restless sleep, awakening feeling tired, fatigue, anxiety, depression, and disturbances in bowel function
--formerly known as fibrositis.
--cause unknown
--no tissue inflammation--> no body damage or deformity
--no tissue inflam, UNLIKE rheumatoid arthritis, systemic lupus, and polymyositis
--no damage to internal body organs



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