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Applied Pathophysiology > Neuropathic Pain > Flashcards

Neuropathic Pain Flashcards

1
Q

What produces a sensation?

A

vision, hearing, fine touch etc:
Stimulus –> receptor activation –> afferent transmission –> sensation

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2
Q

What is pain?

A

is not a sensation…. but is a PERCEPTION.
‐unpleasant sensory and emotional experience associated with actual, potential
or imagined tissue damage.

“Pain” is SUBJECTIVE! The same stimulus may or may not be deemed “painful” (depending on the person, or even for the same person) ex: a needle

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3
Q

Pain can be felt in the absence of activation of _______?

A

nociceptors (ex: phantom limb pain)

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4
Q

“Nociceptor”:

A

‐sensory receptor that when activated, pain would normally be perceived.

‐is not a modality specific term. (there are mechanoreceptors,
chemoreceptors and temperature receptors that are nociceptors)

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5
Q

What are the Dimensions of Pain?

A
  1. Sensory‐discriminative
    * intensity, location, duration of pain
    * provides info about a noxious stimulus present
  2. Affective-motivational
    * unpleasantness & urge to escape the unpleasantness
    * imp. motivational system (“I won’t do that again!”)
  3. Cognitive-evaluative
    * appraisal, cultural valves, distration
    * response to pain may vary widely b/t individuals & cultures
    ex: soccer player vs hockey player - (probably not different physiology)
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6
Q

What is a Nociceptor?

A

“Nociceptor” is a generic term for sensory receptors (i.e. not modality specific) that if activated, the stimulus would typically be perceived as painful.

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7
Q

What are Nociceptors activated by?

A

Nociceptors are activated by noxious stimuli and project to the spinal cord (or from the face to the trigeminal nucleus) by unmyelinated (type C) or SMALL DIAMETER myelinated (type A-delta) sensory axons

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8
Q

What are the types of nociceptors?

A

Thermal nociceptors

Mechanical nociceptors

Chemical nociceptors (incl. cooking spices - capsaicin for ex)

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9
Q

What is Nociception mediated by?

A

is mediated by small diameter myelinated
or unmyelinated sensory fibres.

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10
Q

What is the signal pathway for pain & temp?

A
  1. C fibers (unmyelinated) & A-delta (small diameter myelinated) sensory afferent fibers enter the spinal cord via the dorsal roots
  2. Afferents synapse on ipsilateral spinal neurons in the dorsal horn gray matter (Substantia gelatinosa)
  3. These “2nd order” neurons cross (as they ascend 1-2 segments) to form the contralateral spinothalamic tract
  4. Ascending axons of 2nd order spinothalamic neurons ascend in the CONTRALATERAL ventrolateral (=”anterolateral”) white matter as the spinothalamic tract
  5. Spinothalamic tract projects to the thalamus
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11
Q

What is the Systemic System?

A

left body –> right brain

1a. left body
afferent to cord (cell body in DRG)

1b. terminate on ascending spinothalamic tract neurons

  1. contralateral spinothalamic tract(s)
    *the decussation of ascending spinothalamic fibres occurs over ~2 spinal segments
  2. thalamus to cortex (3rd order neurons)
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12
Q

What occurs in the Parietal Lobe?

A

Sensory Processing
i) somatosensory cortex (= primary sensory cortex = postcentral gyrus)
* immediately behind the central sulcus (front of the parietal lobe)
* location of “sensory homunculus”

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13
Q

What is determined by the central processes?

A

the threshold, intensity & modality of the “pain” perceived

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14
Q

What are ex’s of things not explained by only the “classic pain pathway” (ie the spinothalamic system)?

A
  • Referred Pain
  • Trigeminal neuralgia
  • Fibromyalgia
  • Complex Regional Pain Syndromes
  • Phantom Limb Pain
  • Analgesia produced by acupuncture
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15
Q

Referred Pain:

A

pain perceived as coming from a site other than its actual origin

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16
Q

Trigeminal neuralgia:

A

sudden onset, no noxious stimulus, excruciating pain

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17
Q

Fibromyalgia:

A

no explanation for widespread muscular pain

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18
Q

Complex Regional Pain Syndromes:

A

ex: nerve damage results in autonomic fibres activating nociceptive fibres –> pain (“causalgia”)

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19
Q

Phantom Limb Pain:

A

brain perceives pain originating from a limb that was amputated long ago (doesn’t have the nociceptors but still feel pain)

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20
Q

Analgesia produced by acupuncture:

A

produces effective analgesia, but mech not likely mediated by classic pain pathway

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21
Q

What are the immediate effects of pain?

A

1) local burn
2) action potentials in sensory fibres (1st awareness of pain)
3) reddening, weal (swelling)

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22
Q

What happens soon after pain?

A

4) active COMPOUNDS RELEASED FROM SENSORY NERVES cause release of histamine & other substances –> Neurogenic pain/inflammation

5) “flare”: further reddening & hyperalgesia (intense pain)

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23
Q

Chemical mediators can sensitize and sometimes activate nociceptors…

A

Injury or tissue damage releases substance P and CGRP (calcitonin gene related peptide). Substance P acts on mast cells in the vicinity of sensory endings to bradykinin and prostaglandins. which activate or sensitize nociceptors. Activation of nociceptors leads to the release of evoke degranulation and the release of histamine, which directly excites nociceptors. Substance P produces plasma
extravasation and CGRP produces dilation of peripheral blood vessels; the resultant edema causes additional liberation of bradykinin

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24
Q

The release of some of the compounds (substance P & CGRP) is triggered by what?

A

the terminals of sensory fibres themselves!

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25
Q

What are the long-term effects of pain?

A

6) Secondary hyperalgesia (increase pain perception) due to receptor sensitization & changes in CNS transmission –> Central synaptic plasticity/re-organization
7) Pain sensation lingers beyond tissue damage –> Prolonged pain changes the system!

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26
Q

Nociceptive Pain =

A

Acute Pain

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27
Q

Nociceptive pain is caused by…

A

some nociceptive stimuli activating nociceptors –> Pain perception

In addition to the pain:
–> increased sympathetic activity
–> fear & anxiety
–> shallow breathing

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28
Q

Over time… (minutes to days) there is the possibility of peripheral & central sensitization and plasticity leading to a state of….

A

Chronic Pain

hat may (e.g. arthritis) or may not (e.g. neuropathic pain syndromes) be associated with an ongoing nociceptive stimulus (due to the pain system itself)

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29
Q

What is Gate Control?

A

Activity in Non-nociceptive Afferents
inhibit ascending spinothalamic tract neurons and decrease transmission activates inhibitory interneurons that through the nociceptive pathway.

*The level of activity of this inhibitory interneuron “gates” the transmission through the spinothalamic tract.

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30
Q

Gate Control:

A

Activity in large diameter sensory fibres (e.g. proprioceptive, fine touch) reduces transmission through the second order (ascending) neuron of the ventral spinothalamic tract (=anterolateral system)

31
Q

What does Gate Control provide?

A
  • Provides physiological basis for pain relief from:
  • acupuncture
  • TENS (transcutaneous electrical nerve stimulation)
  • clinical massage therapy
  • Mom’s are pretty smart
  • a barrage of large diameter afferent activity will decrease transmission through nociceptive pathways
32
Q

What are the consequences of dysfunctional gate control?

A

because the inhibitory “gating” interneuron is not
activated, the second order (ascending) spinothalamic tract neuron becomes more active activated
–> more pain

33
Q

What is a possible mech of dysfunctional gate control?

A

Allodynia:
- perception of pain from what would normally be a non-nociceptive stimulus
-Can be caused by the loss or disruption of large diameter fibres.
(There are other mechanisms that also can –> allodynia.)

34
Q

What is convergence?

A

–> Referred Pain
* Nociceptive afferents from viscera enter the spinal cord at the same spinal
* CONVERGENCE onto common neurons –> perception of pain in a location other

Whether it comes from skin or arm it’ll synapse to the same spot
- Somatic Nociceptive Afferent ex: left arm/T1
- Nociceptive Afferent from Viscera ex: from heart

*Brain interprets this signal as “sore arm”, despite the origin being the heart

35
Q

Referred Visceral Pain

A
  • diff organs mostly map to diff areas

but

there is overlap (ex: heart & esophagus)

36
Q

When is pain perceived?

A

Pain is perceived when the inhibitory modulatory control of the pain system is < the activation (e.g. by nociceptive afferents).
- system is always in balance (but if damaged then it is off balance & you perceive pain)

37
Q

Where are the multiple sites of modulation of the pain system?

A
  • sensory modulation: (i.e. gate control processing in spinal cord)
  • descending modulation:
  • serotonergic
  • noradrenergic
  • dopamineric
  • endogenous opioid antinociception system
  • endogenous cannabinoid antinociception system
38
Q

There are MULTIPLE monoaminergic systems that
regulate spinal pain transmission in the cord & pain processing in the brain:

A
  • Dopaminergic
  • Noradrenergic
  • Serotonergic
39
Q

What is Periaqueductal gray matter?

A

imp. midbrain relay

  • activates relay sites in Pons & Rostral Ventromedial medulla
  • the descending projections alter sensory processing at the spinal (& trigeminal) levels

*-multiple sites mean large capability of integration of a variety of inputs affecting sensory/nociceptive processing

40
Q

What is imp. about Antidepressants?

A

Since monoamines are involved in both mood & pain modulation, drugs altering monoaminergic activity can be effective therapeutics for both depression & pain
*-this does not mean that pain reduced by an “antidepressant” was caused by depression!

41
Q

What is the Endogenous Opioid System?

A
  • stimulation around the cerebral aqueduct produces long lasting pain reduction
  • endogenous opioids released onto descending pathways in spinal cord (& other places)
  • CNS has multiple opioid receptor types
42
Q

What do opioids do?

A

recruitment of descending opioid systems can inhibit transmitter release from nociceptive afferents & –> “analgesic” effect

43
Q

What is the Endogenous Cannabinoid System (ECS)?

A

stimulation of the periaqueductal gray matter also causes release of endogenous cannabinoids
‐e.g.’s anandamide (AEA), 2 arachidonylglycerol (2‐AG)

bind to cannabinoid receptors (Cb1, Cb2) (G‐protein coupled)
‐receptors upregulated in chronic pain states

cannabinoids –> attenuation of neurogenic inflammation
(↓ inflammatory activity of microglia & astrocytes)

oral mixture of active compounds available (e.g. for neuropathic pain)
(marijuana delivers MULTIPLE bioactive compounds)
- can lower BP (via vasodil)
- slow heart rate
- lower intraocular pressure
- stimulate appetite
- anti-inflammatory
- reduces pain
- anti-nausea

44
Q

Activation of the endogenous modulatory systems can reduce Pain:

A
  1. Use the Gate Control
  2. Activate the endogenous DESCENDING pain modulating system
45
Q

Damage or dysfunction of the spinothalamic/pain system can produce:

A

negative &/or positive symptoms:

(-):
- analgesia
- loss of temp appreciation
- may be relayed as “numbness” despite preserved large diameter sensory modalities

(+):
- paresthesias
- spontaneous pain
- increased sensation of pain (ex: allodynia)

46
Q

Neuropathic Pain =

A

Pain of neural origin
‐may be produced by dysfunction of peripheral or central pain circuitry
‐not due to prolonged external noxious stimulus (therefore, persistant pain)

47
Q

Peripheral neuropathic pain:

A
  • often produced by prolonged release of inflammatory compounds from peripheral nerves (ie neurogenic inflammation)
48
Q

Central neuropathic pain:

A
  • can follow lesions of the CNS (ex after stroke) = “thalamic pain syndrome”
49
Q

What are properties of neuropathic pain?

A
  • pain out of proportion to tissue injury (ex: burning, tingling), & any signs of nerve injury detected during neurologic exam
  • may be triggered by surgery, amputaion, diabetes, drugs, herpes, HIV/AIDS, MS, spinal injury, stroke, tumor, arthritis etc.
  • some neuropathic pain responds to opioids (not all)
  • gabapentin & pregabalin are centrally acting agents used to treat neuropathic pain
50
Q

Allodynia

A
  • non-nociceptive stimuli perceived as painful
  • can be produced by diff mech’s
    ex: dysfunction gate control, sprouting/enhanced activation in the dorsal horn, other central changes ?
51
Q

Phantom Limb Pain

A
  • pain perceived as arising from an amputated limb (sometimes amputated years ago)
  • no nociceptor activation, so due to altered central processing
52
Q

Central Pain Syndrome

A
  • post CNS injury, ex: stroke, SCI, MS
  • potential mech’s include:
    – hyperexcitability in remaining ascending STT neurons, disinhibition within the thalamus
53
Q

What is Complex Regional Pain Syndrome (CRPS)?

A
  • main syndrome is pain in arm or leg often describes as burning, sharp stabbing or stinging (regional)
  • gentle touch may  severe pain (=Allodynia)
  • may follow trauma (even mild), surgery, or medical conditions (e.g. post M.I.)
  • involved extremity is often warm, edematous, tender and motion is painful
  • Symptoms vary in severity and durations (weeks, months, years)
  • CRPS can be severe and is often difficult to treat (early treatment is important)
54
Q

CRPS pain…

A

continues after the original injury has healed.
* may get worse with time, may spread to other limbs

55
Q

What is involved in CRPS?

A

The Sympathetic Division of the Autonomic system is involved.
* temperature differences in the limb on opposite sides (blood flow)
abnormal sweating
* abnormal sweating
* swelling of the painful region, and beyond (can spread)

56
Q

What is the treatment for CRPS?

A
  • NSAIDS, Opioids
  • physiotherapy
  • neuropathic pain drugs (pregabalin, gabapentin)
57
Q

CRPS 1

also called Reflex Sympathetic Dystrophy (RSD)

A

‐pain WITHOUT nerve damage (driven by sympathetic system)

58
Q

CRPS 2

AKA Causalgia

A

‐pain after nerve injury
‐activity in sympathetic fibres –> activation of pain fibres at site of injury

Injury may start the cycle, but pathological changes in
the CNS keep it going.

Patients may benefit from a
reduction of sympathetic
activity in the area (drugs, ganglion lesions, nerve block).

59
Q

What is imp. about CRPS?

A

Symptoms can spread to other parts of the body.

‐likely due to BILATERAL activation of the sympathetic division of ANS

With an aging pop. & increased #’s of joint replacements, the incidence of CRPS will likely increase

60
Q

What are the Diffuse Pain Syndromes?

A
  • Myofascial Pain Syndrome
  • Fibromyalgia
61
Q

Myofascial Pain Syndrome:

A
  • chronic pain originating from muscular “trigger points” possibly due to muscle fibres with particularly high tension
  • increased risk by repetitive movements, high levels of stress/anxiety
  • may (?) develop into fibromyalgia in some people
62
Q

What are the treatments of Myofascial Pain Syndrome?

A
  • OTC analgesics, physiotherapy, massage therapy, acupuncture,
    antidepressant med’s (e.g. amitriptyline)
63
Q

Fibromyalgia (former name fibromyositis):

A
  • ‘widespread’ pain, fatigue, sleep problems often associated with emotional distress
  • disorder of pain processing –> lowered pain threshold (& allodynia)
64
Q

What is the Fibromyaliga treatment?

A
  • OTC analgesics, antidepressant med’s, ‘antilepileptic’ drugs (e.g. Gabapentin,
    pregabalin), physical therapy/exercise
65
Q

Pain treatment strategy:

A

INCREASE INHIBITION or DECREASE EXCITATION of neurons in the pain system!

66
Q

What is the pharmacology for pain treatment strategy?

A
  • Narcotics/opioids
  • Cannabinoids
  • Antiepileptics
  • Antidepressants
  • Analgesics
  • Topical analgesics
67
Q

Narcotics/opioids:

A

ex: Morphine, codeine, oxycodone
- agonists of endogenous opioid system
- decreases release of neurotransmitter of synapses in the pain system
–> antinociceptive effects

68
Q

Cannabinoids:

A

ex: Medical Marijuana
- agonists of endogenous cannabinoid system
–> antinociceptive effects

69
Q

Antiepileptics:

A

pregabalin; gabapentin
- increase concentration of GABA (–> increased inhibition)
- also inhibits Vdep Ca2+ channels (ex: at presynaptic terminals)
- therefore they DECREASE neural excitability (hence utility as antieleptics)

70
Q

Antidepressants:

A

amitriptyline:
- NA & Serotonin reuptake blocker
- increase efficacy of nociceptive modulatory system
- is a tri-cyclic antidepressant

sertraline:
- SSRI
- increases efficacy of serotonergic system (–> nociceptive modulation)
- antidepressant

71
Q

Analgesics:

A

e.g. NSAIDS
- analgesics, & also anti-inflammatory (–> reduced peripheral activation of nociceptors)

72
Q

Topical analgesics:

A

lidocaine
- applied topically
- blocks Vdep Na+ channels needed for APs
- “nerve block” of peripheral axons (unmyelimated nociceptive are afferents most sensitive)

capsacian ointment
- applied topically
- is the chemical in chili peppers that –> “spicy-ness”
- acts on TRP (Transient Receptor Potential) receptors
- anti-nociceptive when applied topically

73
Q

What is the Activate Endogenous Anti‐nociception Systems?

A

Use the “Gate Theory”:
TENS (Transcutaneous Electrical Nerve Stimulation); Acupuncture; Massage
‐ activate large diameter, non‐nociceptive afferents
–> increased inhibition of ascending spinothalamic tract neurons

Exercise, Meditation:
–> activation endogenous opioid system (e.g. endorphins etc)

74
Q

What is the most effective treatment for Neuropathic Pain?

A
  • the most effective treatments for Neuropathic Pain may be diff for diff patients (there are many diff potential mech’s underlying it)
  • although a combined approach may help, the treatment(s) often often REDUCES the pain, rather than eliminating it

Applied Pathophysiology (34 decks)

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