Pain and Opioids Flashcards
What are the Effects of Pain: Parasympathetic Responses?
- Lowered B.P
- Lowered Pulse
- Nausea & vomiting
- Weakness
- Pallor
- Loss of consciousness
What are the Effects of Pain: Sympathetic Responses?
- Pallor
- Increased B.P
- Increased Pulse
- Increased Respiration
- Skeletal muscle tension
- Diaphoresis (excessive sweating)
What are the results of untreated pain?
- Depression, anxiety, decreased socialisation
- Sleep disturbances
- Impaired movements
- Increased healthcare use and costs
What are nociceptors?
Specialised nerve endings that respond to painful stimuli
What does mechanical stress or damage to the tissues do to mechanosensitive nociceptors?
Excite them
Chemosensitive nociceptors are exited by what?
Various chemical substances released during the inflammatory response
Chemical irritation of nerve endings may produce what?
A severe pain response without true tissue destruction
What is role of the ascending pathway?
- Come from periphery up to CNS
- Pain signal is activated
What is the role of the descending pathway?
- From CNS to periphery
- Pain signal is inhibited
What are the sequence of events in pain formation?
- 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
What are neuromodulators?
- 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
What is hyperalgesia?
Increased pain response
What is allodynia?
Pain response to stimuli that normally do not cause it
What do NSAIDs do?
Block the synthesis of prostanoids
What is the MOA of NSAIDs?
- 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
What are the three major actions of NSAIDs?
- Analgesic
- Antipyretic
- Anti-inflammatory
Describe Prostanoids
- 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
Describe COX-1
- Present in constant quantities in all tissues
- all the time
Describe COX-2
- Inducible to about 50-100 fold during inflammation
What are the physiological roles of prostaglandins?
- 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)
What is the role of Paracetamol?
Anti-pyretic
What are the characteristics of prostaglandin receptors?
- 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
What is the MOA of prostaglandins?
- 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
Major NSAIDs Adverse Effects: Describe GI intolerance and ulceration
- Nausea
- Mild dyspepsia
- Heartburn
- Ulceration
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
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
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
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)
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
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
Describe the pathophysiology of Osteoarthritis (OA)
- Progressive loss of cartilage in the joints
- Inflammation does NOT play a predominant role
What are drug therapy options for OA and drug classes used?
- Paracetamol
- Topical pain relievers
- Corticosteroids
- Hyaluronic acid
- Opioids (last resort)
- NSAIDs
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
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
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)
What do opiods do to the ascending pathway?
- Blocked by opioids, pain suppressed
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
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
What are the Three Opioid Receptor Types
μ, K, δ
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
What are the natural ligands of μ receptors?
beta-endorphin, endomorphins
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
What are the natural ligands of k receptor?
Dynorphins
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
What are the natural ligands of δ receptors?
Enkephalins
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’)
What is the analgesic ladder?
- Non-opioid analgesics such as NSAIDs and/or paracetamol
- Weak opioids (e.g. codeine)
- Strong opioids (e.g. morphine)
What is the opioid classification?
- Original opiate - opium (from poppy seeds)
- Morphine, codeine - natural derivatives of opium
- Chemical derivatives e.g. heroin
- Synthetic opiates which resemble the morphine (e.g. methadone)
- Could be agonists, antagonists and partial agonists
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)
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
What are the Acute Adverse Effects of Opioids?
- Respiratory depression (overdose, lung nerves)
- Sedation (overdose, CNS effect)
- Nausea/vomiting (GI nerves blocking)
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)
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
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
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
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
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)
