B&B 5 Chronic Pain Flashcards Preview

Brain & Behavior > B&B 5 Chronic Pain > Flashcards

Flashcards in B&B 5 Chronic Pain Deck (82):
1

PAIN

What are the 3 types?

►Superficial Pain
– Sharp, Pricking → myelinated Aδ fibres
– Dull, Burning, Soreness (slow & longlasting) → un-myelinated C fibres

►Deep Visceral Pain (muscles, joints, CT) → aching sensation → un-myelinated C fibres

►Referred Pain → un-myelinated C fibres
(eg) Angina ... referred to shoulder

2

PAIN ...
is classified by being divided in 2 categories:

ADAPTIVE
(coupled with noxious stimulus or healing)

... and ...

MALADAPTIVE
(uncoupled from noxious stimulus or healing)

ADAPTIVE
►Nociceptive (acute) pain → acute pain caused by a noxious stimulus
►Inflammatory → increased sensitivity to prevent contact with or movement of injured part until repair is complete

MALADAPTIVE
►Neuropathic → pain occurring in response to damage to the NS (can be peripheral or central)
►Functional → pain occurring in response to abnormal operation of the nervous system

3

Allodynia
...vs...
Hyper-algesia

►Allodynia
– A painful response to a normally benign stimulus

►Hyper-algesia
– an increased response to a normally painful stimulus

4

Neuropathic Pain

(eg) Shingles:
Reactivated virus migrates from DRG along nerves to spinal cord and skin

What happens to 20% of people who get shingles?

Post-Herpetic Neuralgia (PHN)
– Continuation of pain long after the rash and blisters heal
– Occurs from nerve damage caused by the virus
– Pain described as burning, stabbing, or gnawing

NOTE: Shingles & PHN are an example of Neuropathic Maladaptive Pain

5

Functional Pain
→ pain occurring in response to abnormal operation of the nervous system

Example?

Fibromylagia
– Medically unexplained syndrome with no cure or universally-accepted treatment
– Characterized by chronic widespread pain and allodynia.
– Muscle and CT pain (but wide range of symptoms)
– These people have MSK problems, sleep problems, nausea, vision issues ….

6

Two major challenges in pain management are to ...
(1) identify the mechanisms responsible for producing hypersensitivity to pain
(2) to find a means of normalizing sensitivity or preventing hypersensitivity from becoming established

Mechanisms involved in hypersensitivity:
► peripheral sensitization
► central sensitization.

What do we mean by sensitization?

'Sensitization'
– means an increase in the excitability of neurons → neurons are more sensitive to stimuli or sensory inputs

7

Peripheral Sensitization

Peripheral sensitization
– a reduction in threshold, and an increase in responsiveness of the nociceptors.
(eg. change in heat sensitivity after a sunburn)

– occurs due to the action of inflammatory chemicals or mediators released around the site of tissue damage.
(eg) PGE2, kinins, Substance P

RESULT: threshold falls and messages are sent on to the CNS

8

Peripheral Sensitization

What are the two processes possibly involved?

1) Changes to existing nociceptor receptors (post-translational processing)

2) Changes to the proteins being made by the nociceptor (altered transcription).

9

1) Changes to existing nociceptor receptors (post-translational processing)

EXPLAIN ...

● Involve the addition of PO4 groups to receptors / channels
● Alters the properties of the receptor / ion channel
– lower the threshold at which they open
– makes the channel open for longer (so that any stimulus will evoke a greater response)
● these signals act locally to change the properties of proteins right at the terminal

10

2) Changes to the proteins being made by the nociceptor (altered transcription).

EXPLAIN ...

● Signals are transported back to the cell body of the sensory neurons in the DRG, where they either change transcription translation
● The increased protein is shipped back down to the terminal where it contributes to an increased responsiveness of the terminal to peripheral stimuli

– Post-translational processing takes minutes, changes in protein levels a day or so.
– These peripheral mechanisms are likely to result in the early stages of primary hyperalgesia.

11

Central Sensitization

What is it?

An increase in the excitability of neurons within the CNS, so that normal inputs begin to produce abnormal responses.

Contributes to the hyperresponsive conditions of postoperative pain, migraine, neuropathic pain, fibromyalgia, and GI tract pain.

12

NMDA Receptors

What are they?

N-methyl-D-aspartate receptor

– is a glutamate receptor and ion channel protein found in nerve cells

– activated when glutamate and glycine (or D-serine) bind to it

13

Central Sensitization

Acute Phase

The summation of synaptic inputs from activation of nociceptors results in the removal of the Mg2+ block of NMDA receptors increasing the sensitivity to glutamate.

Postsynaptic receptors are phosphorylated.
1) Increases their recruitment to the synaptic membrane
2) Enhances receptor kinetics (channel open longer)
3) Decreases receptor threshold (require lower stimulus
to open)

RESULT: "windup"
– a progressive increase in the discharge of dorsal horn neurons in response to repeated low-frequency activation of nociceptors

14

Central Sensitization

Persistent phase
(gene regulation)

● Upregulation of genes encoding receptors locally

● Upregulation of genes globally (e.g. COX2 is expressed in neurons in many areas of CNS several hours after a localized peripheral tissue injury. This expression is initiated by a circulating factor released by inflammatory cells. This results in increase of PGE2 which facilitates synaptic transmission and excitability)

15

Central Sensitization

Persistent phase
(disinhibition)

Inhibitory interneurons in spinal cord act pre and postsynpatically to focus sensory input so it produces a limited, appropriate and brief response to any input

HOWEVER ... Loss of inhibition can also lead to increased excitability and pain

RESULT: Heightened transmission of pain

16

Central Sensitization

Persistent phase
(structural reorganization)

● After nerve injury the central terminals of C fiber atrophy creating vacant synaptic sites
● Interneurons also die

● "Aß" fibers SPROUT and form novel synapses in lamina II which creates inappropriate functional connections leading to persistent hypersensitivity & phenotypes conversion (i.e. touch leads to pain sensation)

RESULT:
– spinal cord has been restructured
– Phenotype conversion

17

TENS Machine

What is it?

How does it work?

"Transcutaneous electrical stimulation"
– weak electrical current is applied to the skin near the site of pain
– Believed to stimulate the Aβ fibers and reduce the flow of pain information to the brain

Based of off "GATE THEORY"
– states that the transmission of pain from the peripheral nerve through the spinal cord can be modulated by ...
1) other afferent neurons
2) controls emanating from the brain

18

Ketamine

MOA?

NMDA receptor antagonist
– blocks the NMDA receptors to prevent hyper-responsiveness
– used to reduce the early phase of central sensitization
– used in very low doses to prevent windup

19

Pharmacology of Chronic Pain

OVERVIEW of agents

1st-LINE
– TCAs
– anticonvulsants (Gabapentin, Pregabalin)

2nd-LINE
– SNRIs
– topical lidocaine

3rd / 4th LINE
– opioid analgesics
– tramadol
– SSRIs
– IV lidocaine and mexilitine
– topical capsaicin,
– cannabinoids,
– NMDA receptor antagonists

20

TCAs
Secondary amines
...vs...
Tertiary amines

Secondary amines
– Nortriptyline
– Desipramine

Tertiary amines
– Amitriptyline
– Imipramine

NOTE: Secondary amines are better tolerated

21

TCAs

Indications?

• Diabetic neuropathy
• Post-herpetic neuralgia
• Sleep disorder
• anxiety disorder
• depression

22

TCAs

MOA?

• Serotonin & NE reuptake inhibition

• ↑ Endogenous inhibition by ↑ descending pathway transmission

23

TCAs

Dosage?

Onset?

Analgesic dose is lower than antidepressant dose

Analgesic effect almost immediate
(unlike several weeks for antidepressant)

24

TCAs

S/E?

►Anticholinergic effects
– dry mouth
– blurred vision
– constipation
– urinary retention

►CVS effects
– postural hypotension (due to α adrenoceptor bloackage: risk of falls ... avoid in elderly)
– conduction delay & myocardial depression

25

Calcium channel alpha 2-delta ligands

Dug Names?

Gabapentin
– Neurontin®

Pregabalin
– Lyrica®

NOTE: Pregabalin has more linear pharmacokinetics than gabapentin

26

Calcium channel alpha 2-delta ligands

MOA?

Binds to α2δ1 Ca channel → reduce release of glutamate, NE, substance P & CGRP

27

Calcium channel alpha 2-delta ligands

Indications?

Chronic neuropathic pain
• diabetic neuropathy
• post-herpetic neuralgia
• MS
• cancer related neuropathic pain

28

Calcium channel alpha 2-delta ligands

S/E?

Generally well tolerated
Few s/e include:
– dizziness
– somnolence (drowsy)
– confusion
– ataxia

29

trigeminal neuralgia
(tic doloreux)

– chronic pain condition that affects the trigeminal nerve
– even mild stimulation such as brushing teeth or putting on makeup may trigger a jolt of excruciating pain.

30

trigeminal neuralgia
(tic doloreux)

What is the Tx drug of choice?

Carbamazepine
• Anticonvulsant

31

Carbamazepine

MOA?

MOA unclear ... may act by blocking Na channels

32

Carbamazepine

S/E?

• Dizziness
• ataxia
• nausea
• hepatitis
• aplastic anemia
• Stevens-Johnson syndrome

33

Other anti-covulsants include:
• lamotrigine
• valproic acid
• topiramate

MOA?

MOA = unclear; may act by blocking Na channels

(just like Carbamazepine ...)

34

Tramadol
(Ultram®)

MOA?

Synthetic opioid
– weak μ-agonist activity
– SSNRI
– peripheral local anesthetic

35

Tramadol
(Ultram®)


Indications?

• diabetic neuropathy
• post-herpetic neuralgia
• polyneuropathies
• post-amputation pain ... phantom limb pain!

36

Tramadol
(Ultram®)

Advantages
...vs
Disadvantages

Advantages:
• Relative lack of respiratory depression, major organ toxicity, depression of GI motility
• Relatively low abuse potential

Disadvantage
• reduces seizure threshold

"Interesting drug that we will probably see more of ..."

37

Topical capsaicin
(Active ingredient of red hot chilli peppers)

What is it actually effective for?
MOA?
A/E?

Effective in diabetic neuropathy & post-herpetic neuralgia

MOA =
• depletion of substance P in C fibers; nociceptor desensitization
• agonist at the transient receptor potential vanilloid receptor 1, TRPV1.

A/E = local burning sensation & erythema (cessation after 3-4 weeks before analgesic effect)

38

Cannabinoids

How do we use it?

Delta-9-tetrahydrocannabinol: THC
(buccal spray)

Effect in reducing pain and sleep disturbance in central pain of MS

SEs
• dizziness
• fatigue
• nausea
• euphoria
• potential for precipitation of psychosis

NOTE: Causes urine to be positive to cannabinoids test

39

Which drugs are NOT used in treatment of chronic pain?

Hypnotics / Sedatives
►Propofol
►Fiorinal® / Fioricet®
• Combination of
— Butalbital (barb)
— Caffeine
— ASA (Florinal) / Acetaminophen (Floricet)
Used for cluster headaches, NOT chronic pain

Fiorinal® / Floricet® is used for cluster headaches, NOT chronic pain

40

Barbituates

What are they?

• CNS depressants
• can produce a wide spectrum of effects, from mild sedation to total anesthesia.
• large abuse / addictive potential
• habit-forming
• hypnotic/sedative
• now mostly replaced by Benzos for anxiety & insomnia

USAGE:
• general anesthesia
• epilepsy
• acute migraines and cluster headaches

41

General Classification of Headaches

Primary
...vs...
Secondary

►Primary headaches
= headache & associated features are the disorder in itself
– migraine
– tension-type headache
– cluster headache
– paroxysmal headache

►Secondary headaches
= caused by exogenous disorders
– Trauma
– vascular disease
– tumour, infection
– CSF pressure
– drugs
– metabolic disorders
– extra cranial structural

42

Headache

Pathophysiology

• Pain usually occurs when peripheral nociceptors are stimulated in response to injury, visceral distension or other factors

• Pain can also result when pain producing pathways of the peripheral or CNS are damaged or activated in appropriately

43

Which key anatomical structures are involved in primary headache?

• Large intracranial vessels and dura mater

• Peripheral terminals of the trigeminal nerve that innervate these structures

• Caudal portion of trigeminal nucleus, which extends into the dorsal horns of the upper cervical spinal cord and receives
input from the first and second cervical nerve roots (the trigeminocervical complex)

• Pain modulatory systems in the brain that receive input from trigeminal nociceptors

44

Migraine Headaches

"PAIN OF THE BRAIN"

Epidemiology

• Second most common cause of headache
• afflicts about 15% of women and 6% of men

45

Migraine Headaches

What brings it on?

• sensitivity to light, sound or movement; nausea and vomiting often accompany the headache

• Sensitivity to environmental stimulus is especially amplified in females during menstrual cycle

TRIGGERS...
– alcohol
– foods
– weather change
– oversleeping
– exposure to odours
– letdown period of stress

46

Migraine Headaches

How to dx?

Dx:
At least 2 of:
(unilateral pain, throbbing pain, aggravation by movement, moderate or severe intensity)

At least 1 of:
– nausea/vomiting
– photophobia
– phonophobia

47

Migraine Headache can be preceded by an aura.

What are aura Sx?

Aura symptoms:
►Visual → photopsia (perception of light that is purely subjective), scintillations (flash of light), central scotoma, peripheral field loss

►Sensory, cognitive, motor, basilar, retinal, ophthalmoplegia (weakness of eye muscles)

48

Tx of acute migraine:

►Non-pharmacological
– cold
– pressure
– rest (quiet/dark atmosphere)

►Simple analgesics
– acetaminophen
– ASA
– caffeine

►NSAIDs: ibuprofen, naproxen, tolfenamic acid
►Combination analgesics
►Opiodis
►Specific agents
– ergotamine
– dihydroergotamine (DHE)
– triptans

49

Triptans
– revolutionary drugs
– validated migraine as a legit medical disorder
– can be used as nasal sprays in people who have GI issues

MOA?

►Triptans MOA
– ↓afferent transmission
– vasoconstriction
– central modulation

NOTE: — Due to the vasoconstrictive effect, we don’t give it to people with CAD (but that’s usually not a problem because it s a different age group!)

50

What is the our step-wise drug therapy regime for management of headaches?

►Mild attacks
– ASA / NSAIDs

►Moderate attacks
– triptan
– Combo: analgesics / opioid

►Severe attacks
– triptan, opioid for rescue

51

Preventable Measures

►Non-pharmacological:
– relaxation training
– biofeedback
– behavioural therapy

►Pharmacological:
– B-blocker
– TCAs
– CCBs
– serotonergic drugs
– GABA minergic agents
– botulium neurotoxin A

52

I have a headache by the end of the day after studying. This is called:

"Episodic Tension-type Headache"

Nobody would go to the doc for this. What are characteristics?

• Generalized pressure (nonpulsating)
• Mild to moderate intensity
• No aggravation with activity
• No nausea or vomiting
• Photophobia and sonophobia absent

NOTE: these people do NO come to the doc for their headache. If someone seeks help, it's because they most likely suffer from migraines!

53

"Tension-type Headache"

Tx?

EPISODIC:
"mild migraine"

CHRONIC
• central sensitization?
• Tx ...
– acetaminophen
– aspirin
– NSAIDs
– behavioural approaches including relaxation
– Amitriptyline: only proven treatment

54

Patient presents with sudden, first occurance of a headache?

What must we rule out?

Anueyrsm until proven otherwise!

55

Cluster Headaches

Who gets them?

– Mostly males
– Rare form of primary headache with a population frequency of 0.1% (1/1000)

56

Cluster Headaches

PAIN IS TERRIBLE

Describe it ...

What is the timing of it?

● Pain is deep, usually retro-orbital, often excruciating in intensity, nonfluctuating, and explosive in quality

● Core feature of cluster headache is periodicity

● Can have noctunal attacks → fear of going to sleep

● occur in "clusters"

● At least one of the daily attacks of pain recurs at about the same hour each day for the duration of a cluster bout

● The typical cluster headache patient has daily bouts of one to two attacks of relatively short-duration unilateral pain for 8-10 weeks a year usually followed by a pain-free interval that averages 1 year

57

Cluster Headaches

When is it considered "chronic"?

when there is no period of sustained remission

"The cursed of the world have chronic cluster in which they can occur multiple times throughout the day"

58

Migraine

Pathophysiology

Serotonin and other neuropeptides activate BLOOD VESSEL changes such as dilation, distention and inflammation, creating a neurogeneic inflammation that provokes the trigeminal nerve system, stimulating in turn neurons in the brain, to ultimately create a sensation of pain.

59

Cluster Headaches

What are the associated with?

Ipsilateral symptoms of cranial parasympathetic autonomic activation:
– conjunctival injection or lacrimation,
– rhinorrhea or nasal congestion
– cranial sympathetic dysfunction such as ptosis

60

Cluster Headaches

How do we treat ...
– acute attacks?
– for prevention?

Acute attack Tx
– oxygen inhalation
– sumatriptain (intra-nasal / SC) → magic!
– DHE (intra-nasal / SC)

Preventative treatments:
– Verapamil
– prednisone
– topiramate
– methysergide
– lithium
– divalproex
– Surgery considered for refractory pts

61

Paroxysmal headaches

What is it?

– Frequent unilateral, severe, short lasting episodes of headache

– Pain tends to be retro-orbital but may be experienced all over the head and is associated with autonomic phenomena such as lacrimation and nasal congestion

62

Paroxysmal headaches

What are essential features?

Essential features
– unilateral
– very severe pain
– short lasting attacks
– very frequent attacks
– marked autonomic features ipsilateral to pain
– rapid course
– excellent response to indomethacin

63

Paroxysmal headaches

Which headaches are included?

These are "TACs:"
Trigeminal Autonomic Cephalgias
– a type of primary headache that occurs with pain on one side of the head in the trigeminal nerve area and symptoms in autonomic systems on the same side, such as eye watering and redness or drooping eyelids

Includes:
• cluster headache
• ice-pick headache
• cough headache
• coital (sex) headache
• benign exertional headache
• chronic paroxysmal hemicranias

64

Chronic Daily Headache

What is the diagnostic criteria?

Daily or near daily headache for:
>4 hours per day
>15 days per month
>6 months

65

Medication overuse headache

What are characteriestics?

daily or near daily, diffuse bilateral headache

• Early morning wakening with headache
• Mixed mood disorder
• Tolerance to acute meds
• Withdrawal headache
• Refractory to prophylaxis

66

Post-traumatic headache → cervicogenic headache

• Pain begins in the neck and is triggered by head and neck postures
• Local neck tenderness
• Referred pain to the head

67

What is our goal for patients living with chronic pain?

Relieve Suffering.
• Suffering is the patient's experience.
• Multi-disciplinary team is required
• Screen for & treat depression

To reduce the pain, but realistically the pain will always be there. Medications may help take the edge off

68

What screening tool can use for depression?

Beck Depression Inventory

69

Migraines

Take Home Message

• There is no nerve injury here.
• Not a neuropathic pain disorder.
• In this case, neurogenic inflammation causes episodic abnormalities in blood vessels
• This is a physiolgical disorder of the brain.
• Take it seriously and treat these people.

70

How to treat opioid induced coma?

MOA?

Naloxone (Narcan)

MOA:
• Opioids have receptors at various sites in the CNS, brain stem and cortical centres, as well as spinal cord.
• There is NO unique site where they are felt to induce coma and similarly, no unique site where Naloxone is felt to reverse opioid induced coma.

71

►Primary hyperalgesia
...vs...
►Secondary hyperalgesia

►Primary hyperalgesia
• describes pain sensitivity that occurs directly in the damaged tissues

►Secondary hyperalgesia
• describes pain sensitivity that occurs in surrounding undamaged tissues.

72

Which of the following increases pain on suprathreshold stimulation, which is thought to be mediated by wide dynamic range neurons?

● primary hyperalgesia
● secondary hyperalgesia
● allodynia
● dysesthesia
● hyperesthesia

►Secondary hyperalgesia

• describes pain sensitivity that occurs in surrounding undamaged tissues.

73

Cortical spreading depression
(CSD)

What is it?

CSD
• decreased neuronal activity left in the wake of an event
• spreads anteriorly from the occipital cortex
• Initiated by increased extracellular K+ ion concentration and excitatory glutamate
• underlying cause of migraine aura

74

Which direction does CSD spread?

from posterior to anterior

(occipital cortex to frontal)

75

TCAs are used in Chronic Pain Management

What is the MOA?

►Tertiary amines (metabolized into secondary amines)
— amitryiptyline
— imipramine

►Secondary amines
— nortriptyline
— desipramine

MOA: increases endogenous inhibitory descending pathway transmission

76

TCAs

What kind of pain are the they effective for?

Chronic pain associated with ...
— diabetic neuropathy
— postherpetic neuralgia.

77

TCA's

Common S/E?

postural hypotension

dry mouth

78

TCA's

How is the usage for chronic pain different from that of depression?

►Chronic Pain
— lower dose
— analgesic effect is immediate

►Depression
— higher dose
— antidepressant effect takes week

79

Which ONE of the following act as central excitatory neurotransmitters in the dorsal horn?
• Serotonin
• GABA
• Glycine
• Substance P
• Enkephalin

Substance P

80

Pain and temperature fibres that project to medial thalamic areas and then to diffuse cortical areas play a role in ...

Play a role in ...
— localization & intensity of pain
— sharp, pricking pain

Do NOT play a role in ...
— affect and cortical arousal
— dull, aching pain

81

Which of the following classes of agents are NOT used to treat symptomatic (acute) migraine?
►Triptans
►Opioids
►NSAIDs
►Beta- blockers
►Ergot derivatives

►Beta- blockers

Propanolol is used for prevention
(not acute attack!)

82

Activation of neutrophils leads to ⬆︎COX-2 isoenzyme which leads to nociceptor hypersensitivity by increasing the production and secretion of:

prostaglandin E2