Pain Flashcards
1
Q
Nociception Definition
A
-the physiological processes in response to a noxious stimulus
2
Q
Allodynia Definition
A
-pain in response to a normally innocuous stimulus
3
Q
Hyperalgesia Definition
A
-enhanced pain to a normally painful stimulus
4
Q
What are 3 forms of pain?
A
- nociceptive
- inflammatory
- neuropathic
5
Q
Draw the pain pathway
A
-opioids pain lecture
6
Q
Referred Pain
A
- pain from an area or organ that wasn’t initially damaged
- neighbouring sensory nerves sense the increased firing–> causes pain in areas adjacent to the joint
7
Q
Opiate
A
-drugs derived from opium (morphine and codeine)
8
Q
Opioid
A
- agents with opiate like actions
- synthetic drugs
- proteins that mimic opiate actions (endorphins)
9
Q
Narcotic
A
- sleep inducing (pharmacological)
- drugs producing dependence (legal)
10
Q
What are 3 properties of fentanyl?
A
- highly selective mu opioid R agonist
- long acting transdermal patch (peak effect=35 hr)
- less nausea than morphine
11
Q
What are 4 properties of Oxycodone?
A
- semi-synthetic selective mu opioid R agonist
- usually given with NSAID
- sustained release oral formation (oxycontin, peak=3hrs)
- drug of abuse (pill crushed and injected), crush proof tablet (oxecta)
12
Q
What are the 4 opioid R subtypes and their actions?
A
- mu
- delta
- kappa
- ->inhibit neuronal depolarization
- NOP–>neuronal depolarization
13
Q
What are the endogenous ligands for each opioid R subtype?
A
- mu-endomorphin
- delta-enkephalin
- kappa-dynorphin
- NOP-nociceptin
14
Q
What are the exogenous ligands for each opioid R subtype?
A
- mu-morphine, codeine, heroin, fentanyl
- delta-diprenorphine
- kappa-etorphine
- NOP-orphanin FQ
15
Q
What are the opioid antagonists for each opioid R subtype?
A
mu-CTOP, DAMGO
- delta-naltrindole
- kappa-nor-BNI
- NOP-nocistatin
- naloxone is a non specific antagonist
16
Q
What are the 4 sites of action of opioids
A
- periphery
- lamina II of dorsal horn (explain)
- supraspinal
- mesolimbic system
17
Q
What causes up regulation of mu opioid Rs?
A
-acute inflammation
+MOR made in DRG
+axonal transportation of MORs +MOR in periphery & dorsal horn
+opioid analgesia
18
Q
What are the 3 negative side effects of opioids?
A
- severe constipation, somnolescence, cardio respiratory depression
- tolerance
- dependence
19
Q
Explain opioid tolerance and its treatment
A
-increasing doses required to achieve therapeutic level
-minimized by start low and go slow
-occurs 2-3 weeks after frequent opioid use
Treatment
-rotation to another opioid
-recouple to a non opioid adjunct (e.g ketamine, cannabis)
20
Q
Explain the mechanism of tolerance (GPCRKs)
A
- arrestin binds and R is desensitized at surface
- arrestin bound Rs are internalized and recycled to cell surface OR degraded in lysosome
21
Q
Explain physical dependence (physical abstinence syndrome)
A
Mild-lacrimation, sweating, yawning
severe-pain
22
Q
Explain psychological dependence
A
- compulsive drug seeking behaviour
- occurs with drugs with mood enhancing properties
- activates dopaminergic circuits
23
Q
What is the treatment for dependence?
A
- cessation of drug intake
- naltrexone (opioid antagonist)
- methadone (mu agonist, good oral availability, selective, long lasting/slow withdrawal)
24
Q
Explain paradoxical opioid induced hyperalgesia
A
- prolonged opioid use leads to an increase in pain
- sensitization of peripheral nociceptors
- sensitization of dorsal horn neurones
- altered descending control mechanisms
- glutamate R involvement–> coadminister glutamate antagonist
25
Polypharmacy with opioids
- mu opioid Rs dimerize with CB1, opioid and cannabinoid have synergistic effect
- opioid and low dose amphetamine (offset sedation)
- opioid and antidepressant (useful for neuropathic pain)
26
Future of opioid analgesia: peripherally restricted opioids
- can target pain at the source
- reduce sensitization of nociceptors
- do not pass the BBB, less likely to cause addiction and centrally mediated side effects
27
Future of opioid analgesia: Improve opioid R levels
- inhibit beta arrestin activity-reduced R internalization
- inhibit R degradation (protease inhibitors)
- promote R recycling
28
Describe prostaglandins
- involved in causing inflammation and pain
- produced by oxygenation of arachidonic acid in cell membranes
- oxygenation occurs via COX1 and COX2
29
Describe COX1
- CONSTITUTIVELY EXPRESSED
- found throughout the body
- levels are relatively constant
- involved in cell homeostasis
30
Describe COX2
- INDUCIBLE
- found in inflamed tissue
- present only transiently during inflammation or pain
- short half life
- promote inflammation and pain
31
Draw the COX pathway
see NSAID lecture
32
What are the physiological effects of prostaglandins on smooth muscle (2)?
- vascular vasodilation
| - GI contraction
33
What are the physiological effects of prostaglandins on platelets (1)?
-aggregation, clotting responses
34
What are the physiological effects of prostaglandins on kidneys (2)?
- increases renin release
| - increases glomerular filtration rate
35
What are the physiological effects of prostaglandins on nervous system (2)?
- peripheral sensitization
| - central sensitization
36
What are 4 types of NSAIDs?
- acetlylsalicyclic acid (ASA) (anti platelet aggregation, shorter half life, less potent)
- ibuprofen
- naproxen
- diclofenac
* also non selective
37
What are negative side effects of NSAIDs?
-prolonged use leads to GI damage and renal failure
38
Explain the COX2 Hypothesis
- COX2 inhibitors (Coxibs) would reduce inflammation induced prostaglandin production
- preserve protective effects of COX1 pathway
39
Why did the Coxib VIOXX fail?
- it was too good at inhibiting COX2
| - eg PGI2 is produced predominantly by COX2, causes vasodilation, platelet inhibition, protective of cardiomyocytes
40
What are the recommendations for COX2 NSAID use?
- patients at low risk of thrombotic events
- prescribe lowest dose required to control symptoms (and maintain as long as possible)
- add aspirin and a proton pump inhibitor to patients with increased risk of thrombotic events (aspirin for anti thrombotic effects, proton pump to prevent GI ulcerations)
41
NSAID and opioid combinations
- not possible to keep escalating NSAID dose, use in combo w/ opioid
- FDA requires combination effect>individual components and NSAID>placebo
42
What are the benefits of NSAID and opioid combinations (2)?
- less propensity for opioid abuse
| - highly effective analgesia while minimizing side effects of individual components
43
Topical NSAIDs are primarily used for ? Benefits?
-arthritis pain
Benefits:
-target pain in the periphery, minimize centrally meditated side effects
-analgesia easily applied to superficial joints
44
What are four topical NSAIDs approved by FDA?
1. pennsaid
2. solarez
3. voltaren
4. flector
- contain diclofenac in differing concentrations
- applied as either gel or patch
- can produce local irritation due to vehicle
45
What is the proposed mechanism of action of acetaminophen (5 steps)?
1. deacetylated in the liver
2. converted into endocannabinoid in the brain
3. endocannabinoid can reduce pain at CB1 R
4. endocannabinoid reinforces descending serotinergic pathway
5. spinal release of 5HT inhibits pain transmission
46
What are the benefits of acetaminophen (2)?
- lacks side effects of ASA
| - few drug interactions
47
What are the adverse effects of acetaminophen (3)?
- very few therefore safe up to 6g/day
- overdose causes kidney necrosis and hepatotoxicity
- hepatotoxicity may be potentiated in chronic alcoholics
48
What are the 3 types of cannabinoids?
- phytocannabinoids-derived from cannabis plant
- synthetocannabinoids-man made
- endocannabinoids-present naturally in the body (anandamide)
49
What are the 2 cannabinoid Rs?
- CB1, GPCR, located on peripheral and central nerves
| - CB2, assoc. w/ immunocytes
50
What is cannabis?
- flowering plant
- 3 species (sativa, indica, ruderalis)
- oils secreted by trichomes of female plants
51
What are the 3 sites of cannabinoid actions?
1. peripheral nervous system-pain info no longer gets from the joint to the brain
2. doral horn of the spinal cord
3. supraspinal regions
52
Describe cannabinoid actions at the spinal cord?
- activation of CB1R on presynaptic terminal
- inhibition of Ca flux
- increased conductance of K ion channels, the neutron will hyper polarize making it more difficult to fire
- decreased excitatory neurotransmitter release
53
Draw the pathway for endocannabinoid degradation
-adjuncts pain lecture
54
Prescription Cannabinoids-dronabinol
-synthetic THC
-oral capsule
approved for chemotherapy induced nausea, vomiting, anorexia associated with HIV AIDS
55
Prescription Cannabinoids-Nabilone
-synthetic THC
-oral capsule
approved for chemotherapy induced nausea, vomiting, anorexia associated with HIV AIDS
56
Prescription Cannabinoids-Nabiximols
- oralmucosal spray
- approved in canada for ms associated neuropathic pain, spasticity, advanced cancer pain
- side effects-dry mouth, feelings of getting a little high
57
Prescription Cannabinoids-herbal cannabis
- various levels of CBs, terpenes, flavinoids
- no formal approval
- has to be heated to form chemical conversion
58
Transient Receptor Potential Channels (TRPs)
- named after the role of these channels in drosophila phototransduction
- 6 families
- molecular sensors of taste, temp and pain
59
AMG517
-excellent TRPV1 antagonist candidate for treatment of inflammatory pain
oral bioavailability
-caused systemic TRPV1 blockade
-concentration dependent hypothermia
60
Draw how capsaicin works on TRPV1
-adjuncts pain
61
TRPM8
- melastatin TRP family
- non selective cation channel
- expressed on 15% of small diameter sensory neurones
- expression increases in models of neuropathic pain
