HUF 2-64&65 Pain: drug overview Flashcards
Pain
- Actual or potential tissue damage => unpleasant sensory and emotional experience
- Psychical adjunct of imperative protective reflex
- Stimulus
=> Signal generation and transduction
=> Signal transmission
=> Signal modulation
=> Pain perception - Physiologic pain: acute, protective (withdrawal reflex)
- Pathologic pain: chronic, diseases (RA, DM neuropathy)
=> Neuropathic pain (nerve damage / altered expression of receptors or channels at nerve endings)
Physiologic pain (nociceptive pain)
- Somatic (skin surface, ms, joints, tendons)
- Visceral (internal organs)
- External stimuli
- Nociceptors located on peripheral endings of 1° sensory neurons (pain fibres)
- Postoperative pain
Peripheral signal transduction and sensitisation of pain
- Neuronal depolarisation => AP
- Direct result of stimuli activating nociceptors
- ↑ Nociceptor sensitivity (lower activation threshold)
OR ↑ Na+/Ca2+ influx, ↑ Ca2+ release
(phosphorylation by protein kinase)
=> Signal enhanced (freq, duration)
=> Peripheral sensitisation (SP, BK, PG, Histamine)
Signal conduction of pain
- Thinly myelinated Aδ
- Unmyelinated C
- AP propagaion: VGNC opening => depolarisation
Signal transmission of pain
- Various laminae of dorsal horn
- Both pre- and post-synaptic sides contain receptors, ion channels and transporters => alter transmission
- Aβ: non-nociceptive, sensitive to rubbing, light pressure
- Lamina II: substantia gelatinosa - inteneurons that receive inputs from Aδ, C and Aβ fibres
Central sensitisation of pain
- ↑ receptor/channel expression and phosphorylation
=> ↑ neuronal response to stimuli
=> Easier to generate AP (↓ threshold)
=> Short term OR long term (altered gene expression) sensitisation
e.g. Role of PG
Signal relay control at spinal cord of pain
Gate control theory
- Nociceptive signals travel via Aδ and C fibres to SG
- Non-nociceptive signals travel via Aβ to SG
- Interneurons in SG are inhibitory
* Absence of Aβ
=> Aδ and C transmit inhibitory signals to SG
=> Suppress SG activity
=> Smaller inhibitory outputs for further projection
=> ↑ Pain perception
* Greater stimulation on SG by Aβ
=> Greater inhibitory outputs for further projection
=> Negate small stimulatory signal that causes pain perception
Signal modulation of pain
- Descending inhibition
- Periaqueductal gray (targets of opioids)
- Locus ceruleus (NA)
- Nu raphe magnus (5-HT)
2 Descriptions of pathologic painL allodynia, hyperalgesia
Allodynia: pain elicited by stimulus that normally should not cause pain
Hyperalgesia: ↑ pain response produced by stimulus that normally causes lighter pain
Treatment choices according to characteristics of pain
- Pain etiology severity, duration, mechanism, treatment effectiveness
- WHO Pain Relief Ladder for Cancer Pain
1. Better pain control: higher steps => descend to lower steps afterwards
2. Pain not controlled: lower steps => move upward - Adjuvants: steroids, anxiolytics, antidepressants, antiepileptics, Na+ channel blockers, Ca2+ channel blockers, NMDA receptor blocker
- Opioids, non-opioids
Paracetamol
- Weak (~50%) COX1 and COX2 inhibitory activity
- Much stronger analgesic than anti-inflammatory effect
- Comparable efficacy to aspirin in treating tension headache; slower onset
Opioid analgesics and related drugs
- Narcotic analgesics = opioid analgesics
- Opiate: structurally related compounds to morphine
- Opioid: any compound with properties of opiate
- Endogenous opioids enkephalin, endorphin, dynorphin
- Opioid antagonists: Naloxone, Naltrexone
- Opioid receptor subtypes: μ, δ, κ, ORL1
Opioid receptors: structural characteristcs
- G1 coupled
- From homodimers or heterodimers e.g. μ-δ
- Receptor selectivity dependent on positioning of extracellular loops (favour some agonists over others0
- Receptor internalisation and subsequent tolerance for μ and δ receptors differentially induced depending on agonist and binding duration
Functional effects of opioid receptors
μ
- Analgesia: supraspinal, spinal, peripheral
- Respiratory depression
- Pupil constriction
- Reduced GI motility
- Euphoria
- NO dysphoria and hallucination
- Sedation
- Physical dependence
δ
- Spinal analgesia
- Respiratory depression
- Reduced GI motility
κ
- Analgesia: spinal, peripheral
- Dysphoria and hallucination
- Sedation
Points to note on functional effects of opioid receptors
- Analgesic effects may be diminished (tolerance)
=> May display hyperalgesia after prolonged use - Supraspinal effects
- Analgesia and reduced affective component of pain (limbic system; related to euphoria) - ↓ Sensitivity of respiratory centres and respiratory rhythm generator
=> Highly fatal in acute opioid poisoning - Miosis: diagnostic of opioid poisoing; resistant to opioid tolerance
- Opioid withdrawal symptoms: runny nose, restlessness aggression, shivering, irritability, diarrhoea
Proposed mechanisms of consequences of chronic opioid use
- Flawed internalisation-recycling process
=> Fewer new, sensitive receptors on call membrane
+ Impaired receptor-2nd messenger signalling
=> Tolerance
=> Hyperalgesia (↑ pain transmission) - Persisting AC activity even after drug removal
- ↑ AC expression
=> ↑ cAMP
=> ↑ excitatory NT release; Changes in signalling, synaptic structures and channel expression (e.g. NMDA)
=> Withdrawal symptoms; Hyperalgesia (↑ pain transmission)
Principal sites of opioid analgesic actions
Brain: inhibit GABAergic interneuronal activity in PAG, LC and NRM (↓ Ca2+ influx)
=> Less Cl- influx to postsynpatic descending neurons
=> Descending neurons are under less inhibition
=> Stronger signal to suppress pain (↑ 5-HT, NE, opioid)
Spinal cord:
1. ↓ Ca2+ influx
=> inhibit presynaptic NT release (e.g. GLU)
2. ↑ K+ efflux and ↓ response of postsynaptic neuron to excitatory NT
=> inhibit postsynaptic neuronal activities
Morphine
- Juice of opium poppy seed pod
- Strong μ agonist; δ, κ agonist
- Analgesic: IV, IM, SC, oral (less potent)
PK
1. Not as lipophilic as fentanyl or methadone
=> Fewer % drug permeates BBB
2. Glucuronidation
- 10% becomes morphine-6-glucuronide (more potent, longer t1/2 = 6-8 h)
- More is metabolised to morphine-3-glucuronide
=> Neuro-excitatory effect
Codeine
- Poppy seed pod
- Methyl-morphine
- Weaker μ agonist than morphine; less potent
- Low risk of dependence
- Analgesic (moral orally active than morphine)
- Antitussive (dose of no analgesic effect) - Codeine + Paracetamol
PK
- Converted to morphine by CYP2D6
- Potential risks in 2D6*2x2 individuals
- Less prone to first-pass metabolism than morphine
- t1/2 = 2-4h (similar to morphine)
Buprenorphine
- Very weak partial μ agonist, high affinity; κ antagonist
- Analgesic in naive persons (more potent than morphine at lower doses)
- Withdrawal symptoms in chronic opioid users (dissociation of stronger opioids; symptoms less severe than methadone)
- Analgesic; opioid dependence treatment (IV, sublingual, transdermal)
- Combined with naloxone => minimise abuse
PK
- Metabolised by CYP3A4
- Long t1/2 = 12h (high receptor affinity)
- Highly lipid-soluble
- Respiratory depression not easily reversed by naloxone
Pethidine
- Strong μ agonist (weaker and less potent than morphine)
- Analgesic (short term)
PK
- t1/2 = 2-4h
- Highly lipophilic
- First-pass metabolism (converted by CYP2D6/3A4 to norpethidine with longer t1/2 = 15-20h)
=> Delirium (confusion), seizures if pethidine is used for >48h
- Antimuscarinic => delirium (confusion)
- Blocks 5-HT reuptake
∴ DDI with MAOI, SSRI => Serotonin syndrome (delirium, hyperthermia, convulsions, death)
Fentanyl
- Strong μ agonist
- More potent than morphine
- Analgesic, general anaesthetic (IV, parenteral, transdermal)
- High potential for abuse and risk of overdose and death with transdermal patches
- Transdermal patch: slow inset ~12h later, prolonged duration
- NOT induce histamine release => less hypotensive effect
PK
- Short t1/2 = 1-2h; fast onset and offset
- Highly lipid-soluble
- Metabolised by CYP3A4 to inactive metabolites
Methadone
- Strong μ agonist (no significant depression and less euphoric)
- Analgesia; management of opioid dependence
- Orally active; buccal mucosa
- Tolerance; withdrawal slightly more severe and prolonged than buprenorphine
PK
- Orally active
- Long t1/2 = 40h
- Converted to inactive metabolites mainly by CYP2D6 (rifampicin) and 3A4 (phenytoin, rifampicin)
=> May precipitate withdrawal symptoms after enzyme induction
- QT prolongation
- Block NMDA receptor and monoamine reuptake
=> Used for neuropathic pain and hyperalgesia (opioid rotation)
Pentazocine
- Weak partial μ agonist / weak μ antagonist, full κ agonist
- Withdrawal symptoms in chronic opioid users
- (Rarely) analgesic: κ agonism; combined with naloxone to minimise abuse
- Dysphoria at high doses
- Does NOT reverse morphine-induced respiratory depression
- Tachycardia, HT
- Buprenorphien and Pentazocine at high doses may displace other μ agonists
=> Precipitate withdrawal symptoms
Tramadol
- Weak μ agonist; low potency
- Analgesic (effect equiv. to Morphine or Pethidine in mild-to-moderate pain)
PK
- t1/2 = 6h
- CYP3A4, 2D6 => active demethylated Tramadol - μ agonist
- Seizure
- Inhibit monoamine reuptake
=> Analgesic effect; DDI with MAOI and SSRI
Heroin and Etorphine
Heroin (diamorphin)
- Very potent μ, δ and κ agonist
- Converted to Morphine and 6-acetylmorphine
- Very rapid onset - penetrate BBB easily
Etorphine
- Very potent μ, δ and κ agonist
- No legitimate use in humans
- Immobilise large animals
Opioid antagonists: Naloxone, Naltrexone
- High affinity at μ receptor; block δ and κ
Naloxone
- Short t1/2 = 1-2h
- IV, IM, intranasal spray
- Antidote for acute opioid poisoning (need continual monitoring to prevent relapse)
Naltrexone
- Long t1/2 = 10h
- Given orally
- Maintenance treatment for opioid dependence
