Opioid Analgesics Flashcards
What are the best defined peptides?
- opioid peptides e.g. β-endorphin, met/leo-enkephalin and dynorphin
- substance P
What is substance P?
mediator of slow EPSPs in nociceptive CNS sensory pathways
What are the 3 major families of endogenous opioid peptides and their precursors?
- β-endorphin from pre-proopiomelanocortin (POMC)
- enkephalins from pre-proenkephalin
- dynorphins from pre-prodynorphin
What can influence the perception of pain?
attitude, mood and physical exercise
What parts of the brain process and interpret pain signals?
thalamus and cortex
What does the limbic system influence?
the emotional response of pain, often generating feelings of discomfort, anxiety, or distress
How does opioid analgesia work?
it plays on endogenous mechanisms to inhibit the propagation of pain signals, alter the emotional perception of pain and elevate the pain threshold
What are opioid analgesics used for?
- acute pain e.g. post-surgical pain
- chronic pain management, particularly for cancer-related pain or palliative care
What are the 3 main sites of opioid receptors regulating pain?
- peripheral nociceptive terminals
- spinal cord (dorsal horn)
- brain (PAG, thalamus and cortex)
What are the 3 major opioid GPCRs and what are they responsible for?
- mu – analgesic effects and side effects like euphoria, respiratory depression, and physical dependence
- delta – modulates pain and mood, and has a role in analgesia (less than mu receptor); may also influence antidepressant effects
- kappa – modulates pain, but activation can also produce dysphoria and hallucinations; plays a role in the body’s response to stress and controls some anti-inflammatory effects
How do opioids inhibit neurotransmitter release?
- inhibiting calcium entry
- enhancing potassium efflux
- inhibiting AC which converts ATP to cAMP
How does opioid analgesia cause euphoria?
they bind to Mu receptors in the VTA and nucleus accumbens and inhibit the release of GABA, which leads to an increase in dopamine levels in reward circuits
What is dopamine a precursor of?
noradrenaline
When is dopamine inhibitory?
via GPCR activation of potassium channels
How is dopamine activity increased and decreased respectively?
- increased by CNS stimulants and anti-parkinson drugs
- decreased by antipsychotics
What is D2?
the main dopamine subtype in basal ganglia neurons widely distributed at the supraspinal level
Give examples of dopaminergic pathways
- nigrostriatal (motor control)
- mesolimbic (emotional and drug-induced reward systems)
- tuberoinfundibular tracts (pathway from hypothalamus to pituitary glands that controls secretions)
What are clinical uses of opioid agonists?
- analgesia e.g. codeine, morphine, pethidine
- anaesthetic adjuvant e.g. fentanyl
- cough suppressant/antitussive e.g. codeine
- anti-diarrhoeal e.g. diphenoxylate, loperamide
Describe morphine as an opioid agonist (strength, which receptors, analgesic affinity and liability for abuse)
- strong agonist
- highest affinity for Mu receptor (some affinity for Delta and Kappa)
- high maximum analgesic affinity
- high liability for addiction/abuse
Describe methadone and fentanyl as opioid agonists (strength, which receptors)
- strong agonists
- highest affinity for Mu receptor (no affinity for Delta and Kappa)
What is fentanyl used as?
an anaesthetic adjuvant
Describe codeine as an opioid agonist (strength, which receptors, analgesic affinity and liability for abuse)
- moderate agonist
- weak affinity for Mu and Delta receptors
- low maximum analgesic affinity
- moderate liability for addiction/abuse
What happens to 10% of codeine?
it is converted to morphine/dihydromorphine
Why do 10% of the population show reduced analgesic effects to codeine?
lack of demethylating enzyme
What is tramadol?
a weak Mu agonist and a weak inhibitor of 5-HT (serotonin) and noradrenaline reuptake
Describe buprenorphine as an opioid agonist (strength, which receptors, analgesic affinity and liability for abuse)
- mixed agonist-antagonist
- strong Mu partial agonist and Kappa antagonist
- high analgesic affinity
- moderate liability for addiction/abuse
Describe nalbuphine as an opioid agonist (strength, which receptors, analgesic affinity and liability for abuse)
- mixed agonist-antagonist
- weak Mu antagonist and Kappa agonist
- high analgesic affinity
- moderate to low liability for addiction/abuse
What are opioid antagonists used for?
to counteract opioid overdose
Give examples of opioid antagonists and their route of administration
- naloxone – short-acting, usually intravenous administration
- nalmefene – long-acting usually intravenous administration
Why are opioid antagonists used with caution in patients with opiate dependency?
they can precipitate potentially fatal withdrawal syndrome
What does neuropathic pain usually require?
higher opioid doses than nociceptive pain
How should opioid analgesics be used?
started at a low dose and carefully titrated until an adequate level of analgesia is obtained, or until persistent and unacceptable side effects warrant a reevaluation of therapy
When can respiratory depression be lethal?
- overdose
- respiratory disease
- hepatic dysfunction
- combination with other CNS depressants
- young children
How can opioids cause respiratory depression?
they act on the nucleus tractus solitarius and nucleus ambiguus which reduces responses to CO2 (and H+) and suppresses voluntary breathing
Where does respiratory depression occur?
largely in opioid-naïve patients
What are common adverse effects of opioids?
- nausea/vomiting – due to actions on the chemoreceptor trigger zone in the area postrema of the medulla
- drowsiness
- constipation – due to reduced GI motility
What are less common adverse effects of opioids?
- miosis (pinpoint pupils) – due to actions in the oculomotor nucleus
- urinary retention – due to increased bladder sphincter tone
- postural hypotension and bradycardia – due to actions in cardio-regulatory nuclei in the medulla
- immunosuppressant effect with long term use
What does hisatamine release triggered by morphine cause?
causes itching, bronchoconstriction and hypotension due to vasodilation
What are possible withdrawal symptoms of opioids?
anxiety, irritability, chills, hot flushes, joint pain, lacrimation, rhinorrhoea, nausea, abdominal cramps and diarrhoea
What are the strong opioid agonists?
morphine, methadone and fentanyl
What are the moderate opioid agonists?
codeine and tramadol
What are the mixed opioid agonists and antagonists?
buprenorphine and nalbuphine
