Pain and Opioids Flashcards
(57 cards)
1
Q
What are the Effects of Pain: Parasympathetic Responses?
A
- Lowered B.P
- Lowered Pulse
- Nausea & vomiting
- Weakness
- Pallor
- Loss of consciousness
2
Q
What are the Effects of Pain: Sympathetic Responses?
A
- Pallor
- Increased B.P
- Increased Pulse
- Increased Respiration
- Skeletal muscle tension
- Diaphoresis (excessive sweating)
3
Q
What are the results of untreated pain?
A
- Depression, anxiety, decreased socialisation
- Sleep disturbances
- Impaired movements
- Increased healthcare use and costs
4
Q
What are nociceptors?
A
Specialised nerve endings that respond to painful stimuli
5
Q
What does mechanical stress or damage to the tissues do to mechanosensitive nociceptors?
A
Excite them
6
Q
Chemosensitive nociceptors are exited by what?
A
Various chemical substances released during the inflammatory response
7
Q
Chemical irritation of nerve endings may produce what?
A
A severe pain response without true tissue destruction
8
Q
What is role of the ascending pathway?
A
- Come from periphery up to CNS
- Pain signal is activated
9
Q
What is the role of the descending pathway?
A
- From CNS to periphery
- Pain signal is inhibited
10
Q
What are the sequence of events in pain formation?
A
- Tissue damage occurs
- Synthesis of inflammatory and pain mediators is initiated
- Inflammatory mediators (including prostanoids) are released from damaged tissues
- These mediators activate their receptors on nociceptor nerves
- Pain signal is created and propagated
11
Q
What are neuromodulators?
A
- Inhibitory pain mediators
- Endorphins and dynorphins - morphine-like substances
- Located in brain, spinal cord & GIT
- Produce analgesia when attached with opiate receptors in the brain
- Activate μ receptors (endogenous opiates)
- Endorphins and dynorphins - morphine-like substances
12
Q
What is hyperalgesia?
A
Increased pain response
13
Q
What is allodynia?
A
Pain response to stimuli that normally do not cause it
14
Q
What do NSAIDs do?
A
Block the synthesis of prostanoids
15
Q
What is the MOA of NSAIDs?
A
- Inhibit COX
- Inhibition of COX-1 causes
- impaired gastric cytoprotection
- anti-platelet effects
- Inhibition of COX-2 causes
- anti-inflamatory action
- decreases prostaglandin in tissue, decreases inflammation
- analgesic action
- decreases prostaglandin in tissue, decreases nociception
- anti-inflamatory action
- Inhibition of COX-1 causes
16
Q
What are the three major actions of NSAIDs?
A
- Analgesic
- Antipyretic
- Anti-inflammatory
17
Q
Describe Prostanoids
A
- Unsaturated fatty acids (20 carbons)
- precursor of eicosanoids is present in phospholipids of cell membrane
- arachidonic acid
- liberated by Phospholipase A2 (PLA2) - rate limiting step
- precursor of eicosanoids is present in phospholipids of cell membrane
18
Q
Describe COX-1
A
- Present in constant quantities in all tissues
- all the time
19
Q
Describe COX-2
A
- Inducible to about 50-100 fold during inflammation
20
Q
What are the physiological roles of prostaglandins?
A
- Inflammatory processes
- vasodilators (synergise with histamine, bradykinin)
- indirectly contribute to increased permeability
- Sensitise nerves to bradykinin (increase pain)
- Fever ‘induction’
- Platelet aggregation
- Renal Function (renal blood flow regulation)
- Gastric mucosal integrity (mucosal protection)
21
Q
What is the role of Paracetamol?
A
Anti-pyretic
22
Q
What are the characteristics of prostaglandin receptors?
A
- Prostaglandin receptors are specified by the class and subtype
- e.g. EP2 is the E Prostaglandin receptor subtype 2
- G-protein coupled receptors
- Depending on the cell type in which the receptor is expressed and the receptor type/subtype, varying signal transduction cascades can result in activation of stimulatory or inhibitory G-proteins
23
Q
What is the MOA of prostaglandins?
A
- Prostaglandins don’t cause pain by themselves but they increase pain-producing effects of other mediators
- any receptor that increases cAMP in nerve cell would increase pain signal
24
Q
Major NSAIDs Adverse Effects: Describe GI intolerance and ulceration
A
- Nausea
- Mild dyspepsia
- Heartburn
- Ulceration
25
Major NSAIDs Adverse Effects: Describe Bronchospasms
* Synthesis of prostaglandins starts from arachidonic acid, through action of COX-I and COX-II gets into precursor prostaglandin and then different thromboxanes and prostaglandins are synthesised
* Alternate pathway - synthesise leukotrienes (potent vasoconstrictors)
* if you block COX pathway, this pathway becomes predominant
26
Major NSAIDs Adverse Effects: Describe Renal Failure
* Two blood vessels control how much blood is let in and out
* By inhibiting PG production, NSAIDs cause afferent arteriole vasoconstriction and reduce GFR
27
Major NSAIDs Adverse Effects: Describe Prolongation of Bleeding Time
* Prevent formation of Thromboxane A2
* Accounts for tendency of NSAID to increase bleeding time
* Can make patient more susceptible to haemorrhage
28
How do you decrease the incidence of GI complications from NSAIDs?
* Paracetamol should be used as an alternative analgesic or to allow lower doses of NSAID use
* NSAID with lower relative risk of GI complications should be used e.g. diclofenac
* Lowest effective dose for the shortest period of time should be used in high risk patients that must have a NSAID
* Proton pump inhibitors (PPIs): suppresses acid production
* H2-receptor antagonists: suppresses histamine-induced acid increase
* Muscosal cytoprotective (e.g. misoprostol)
29
Describe how Misoprostol works for NSAIDs long term therapy?
* Drug to protect against GI problems
* prostaglandin E1 analogue
* sometimes co-administered with NSAID therapy to prevent NSAID-induced ulcers
30
Describe the toxicity of Paracetamol and what is its maximum daily dose?
* Phase I metabolism
* if NAPQ1 accumulates, this causes toxic reactions with proteins and nucleic acids
* damages liver - irreversible
* Max. daily dose = 4g
* Glutathione = natural paracetamol detoxifier
* N-acetylcysteine = drug used to speed-up paracetamol detoxification
31
Describe the pathophysiology of Osteoarthritis (OA)
* Progressive loss of cartilage in the joints
* Inflammation does NOT play a predominant role
32
What are drug therapy options for OA and drug classes used?
* Paracetamol
* Topical pain relievers
* Corticosteroids
* Hyaluronic acid
* Opioids (last resort)
* NSAIDs
33
Describe Topical Treatments for OA
* Heat and ice
* Lidocaine patches
* Topical NSAIDs (not long term)
* Capsaicin
* a skin cream made from hot peppers that relieves pain
34
Describe Hyaluronic Acid Therapy for OA
* Used by injection into the joints in patients with severe disease
* Must be used sparingly
* Used to replace lost fluid in the joint spaces and keep the joint working to cushion the bones in the joint
35
Describe the characteristics of Ascending Pathway
* Pain signal carried from periphery to CNS
* Morphine acts on μ receptors
* create conditions in which adenylyl cyclase attached to the receptor, has inhibitory Gi subunits (cAMP levels decrease as a result)
36
What do opiods do to the ascending pathway?
* Blocked by opioids, pain suppressed
37
Describe the characteristics of Descending Pathway
* Pain signal carried from CNS to periphery
* Opiods prevent reuptake of NA and therefore increase the level of NA at the synapse
* This pathway is activated by NA and pain is suppressed
38
Describe the Characteristics of Opioids
* Opioids inactivate pain signal through increase in NA in descending pathway
* Opioids block ascending pathways by depolarisation and neurotransmitter release inhibition
* A group of G-protein coupled receptors
* Act on natural opioid receptors in cerebrum and medulla of the CNS
39
What are the Three Opioid Receptor Types
μ, K, δ
40
What are the actions of μ receptors?
* Most highly concentrated in brain, responsible for most of the analgesic effect of opioids
* Analgesia
* Sedation
* Respiratory Depression
* Hypothermia
* Reinforcing effects
* Euphoria
* Pupil constriction
* Decreased GI motility
* Nausea and vomiting
* Urinary retention
41
What are the natural ligands of μ receptors?
beta-endorphin, endomorphins
42
What are the actions of k receptors?
* Contribute to analgesia at the spinal level
* Produce few unwanted effects (don't contribute to dependence)
* Analgesia
* Sedation
* Dysphoria
* Diuresis
43
What are the natural ligands of k receptor?
Dynorphins
44
What are the actions of δ receptors?
* More potent in the periphery but may also contribute to analgesia
* Respiratory depression
* Reinforcing effects
* Nausea and vomiting
45
What are the natural ligands of δ receptors?
Enkephalins
46
What are the roles of endogenous opioids?
* Modulation of
* pain
* response to stress
* respiration
* emotional response
* For each of these, the effect of opioids is to decrease response, but they also increase pleasure ('runners high')
47
What is the analgesic ladder?
* Non-opioid analgesics such as NSAIDs and/or paracetamol
* Weak opioids (e.g. codeine)
* Strong opioids (e.g. morphine)
48
What is the opioid classification?
1. Original opiate - opium (from poppy seeds)
2. Morphine, codeine - natural derivatives of opium
3. Chemical derivatives e.g. heroin
4. Synthetic opiates which resemble the morphine (e.g. methadone)
* Could be agonists, antagonists and partial agonists
49
What are the characteristics of opioid μ receptor?
* Gi
* Inhibits adenylate cyclase leading to reduced levels of cAMP
* Reduces cellular excitability (K+ channels open)
* Found at presynaptic sites (reducing neurotransmitter release via Ca2+ channel blocking)
50
What are the direct effects of opioids?
* Analgesia
* Reduced emotional distress
* Sedation
* Eurphoria
* Nausea and vomiting
* Respiratory depression
* Reduced GI motility
* Pupil constriction
* Decreased body temperature
* Dry mouth
* All of these effects are consequences of nerve transmission inhibition
51
What are the Acute Adverse Effects of Opioids?
* Respiratory depression (overdose, lung nerves)
* Sedation (overdose, CNS effect)
* Nausea/vomiting (GI nerves blocking)
52
What are the Chronic Adverse Effects of Opioids?
* Constipation (GI nerves blocking)
* μ opioid receptor agonists inhibit gut motility
* Endocrine effects (hormonal changes)
* Osteoporosis (hormonal changes)
53
What is tolerance?
* Decreased effects with prolonged exposure to the drug (or increased dose required to achieve given effect)
* leads to increased pain - may need to increase dose
* affected by dose, frequency, regularity
* doesn't indicate addiction
* normal if taken for a long perioid of time
54
What are the Mechanisms of Tolerance development?
* Tolerance is due to adaptations that reduce or oppose the opioid effect
* Changes include:
* decreased number of receptors
* decreased production of endogenous ligand
* compensatory changes in signalling cascades e.g.
* increased expression of adenylate cyclase
* increased expression of calcium channels
55
What is the withdrawal and addiction process?
* Adaptations to opioid drugs can also result in a withdrawal syndrome on cessation of use
* Occurs because the adaptations don't immediately reverse:
* when no drug is present, the adaptations produce effects opposite to those of the opioid drug
* Withdrawal occurs in people who are and aren't addicted
* In patients treated for pain, the manifestation of withdrawal is pain of greater intensity than prior to opioid use
56
Describe Important Drug Interactions with Opioids
* Other sedatives
* high risk of respiratory depression (in combination with alcohol or other CNS depressants, have additive effects that could be lethal)
* Impairment of cognitive, psychomotor function
* Commonly observed with benzodiazepines and barbiturates
* Drugs that lower blood pressure
* Hypotensive effect of opioids is not strong at normal doses but can become significant in combination with other BP lowering drugs
57
Describe Osteoporosis effects with Opioids
* Elevated risk of fractures in elderly taking opioids
* Decrease in bone mineral density in people taking opioids chronically
* Two main mechanisms:
* Secondary to endocrine disruption
* Inhibitory effect on osteoblasts (involved in bone formation)
