Opioids
Willem van Eeden
Department of Pharmacology
University of Pretoria
[Link]@[Link]
Opioids
• Term “opiate” - drugs obtained from Opium Poppy
extracts (Papaver somniferum)
• Primary use of opioids is to relieve intense pain and anxiety
• Opioids bind to opioid receptors to produce effects that
mimic the action of endogenous peptide
neurotransmitters
Pain
• Unpleasant sensation that can be either acute or chronic
• Complex neurochemical processes in the peripheral and
central nervous systems
• Pain is subjective and clinicians must rely on the patient ’s
perception and description of pain
• Severe and chronic pain treated with opioids
Opioid receptors
• Present in central and peripheral nervous systems and GIT
• Opioid receptors are activated by
• Endogenous peptides (endorphins, enkephalins and
dynorphins)
• Synthetic (morphine and codeine)
• Three types of opioid receptors
• μ (mu) receptor
• δ (delta) receptor
• κ (kappa) receptor
Opioids- mechanism of action
• Presynaptic neuron
• Activation of opioid receptor decreases calcium influx
in response to incoming action potential
• Decreases release of excitatory neurotransmitters
(glutamate)
• Postsynaptic neuron
• Activation of the opioid receptor increases potassium
efflux
• Decreases the response of the postsynaptic neuron to
excitatory neurotransmitters
Distribution of opioid receptors
Distribution Receptor stimulation
Brainstem Respiration, cough, nausea and vomiting, blood pressure,
pupillary diameter and stomach secretions
Thalamus Deep pain that is emotionally influenced
Spinal cord Receipt and integration of incoming sensory information =
attenuation of painful afferent stimuli
Hypothalamus Neuroendocrine secretion
Limbic system Receptors located in the amygdala and influence
emotional behaviour
Periphery Inhibit release of excitatory and pro-inflammatory
substances (substance P) from nerve endings
Immune cells Opioid-binding sites found on immune cells but role of
receptors unknown
Opioids - common side effects
• μ (mu) receptors
• Analgesic effects (supraspinal, spinal and peripheral)
• Side effects – Respiratory depression, euphoria,
sedation, dependence and reduced GIT motility
• δ (delta) receptors
• Peripheral analgesia
• Side effects – respiratory depression and reduced
GIT motility
• κ (kappa) receptors
• Spinal analgesia
• Side effects – Sedation, dysphoria and miosis
Opioid receptor activity
• Full agonists
• Binds to receptors and imitates endogenous opioids
• Highest risk of abuse
• Partial agonists
• Binds to receptors but activates them less than a full
agonist would
• Antagonists
• Binds with high affinity to receptors but fail to activate
the receptor mediated response
Effects of opioids
• Analgesia
• Analgesia without loss of consciousness
• Provide symptomatic relief without alleviation of the
cause of pain (alters pain perception)
• Respiratory depression
• Depress rate of respiration
• Decrease in sensitivity of respiratory center
neurons to carbon dioxide
Effects of opioids
• Euphoria
• Powerful sense of contentment and well-being
• Reduces anxiety and agitation that is associated with
pain
• Suppression of cough reflex
• Experienced with all opioids
• Codeine widely used in cough preparations
• Depression of cough reflex area in the brainstem
Effects of Opioids
• Miosis
• Pupillary constriction (pinpoint pupils) = used to
diagnose overdose
• Nausea and vomiting
• Occurs in up to 40% of patients
• Directly stimulates chemoreceptor trigger zone
(medulla)
Effects of Opioids
• Gastrointestinal tract
• Constipation
• Increase smooth muscle tone and decrease motility
• Histamine release
• Mast cell degranulation
• Flushing, skin irritation, vasodilation and
bronchoconstriction
Morphine analogues
Pure agonists Partial agonists Antagonists
Codeine Nalorphine Naloxone
Morphine Levallorphine Naltrexone
Oxycodone
Diamorphine
Synthetic derivatives
unrelated to morphine
Pure agonists Partial agonists
Methadone Pentazocine
Pethidine Buprenorphene
Fentanyl Cyclazocine
Atypical opioids
Partial agonist
Reuptake inhibitor
Tramadol
Tapentanol
Morphine
• Pharmacokinetics
• Administered orally, intramuscularly, subcutaneously or
intravenously (titrate dose according to patient ’s needs)
• Absorption from GIT slow and erratic
• Significant first pass metabolism
• Morphine is conjugated in the liver to morphine-6-
glucuronide
• Excreted primarily in urine and partially in bile
Morphine
Drug interactions
• Phenothiazines, monoamine oxidase inhibitors
(MAOIs), tricyclic anti-depressants and
antihistamines
• CNS depressant actions of morphine are enhanced
Codeine
• Prodrug converted to morphine resulting in analgesia
• Used mainly for mild pain (headache, back pain
• Good absorption with oral administration
• Less potent than morphine with same abuse potential
• Low level of euphoria (can be addictive)
• Combined with other analgesics (paracetamol)
Codeine
Indications
• Usually combined with other non-opioid drugs for
relief of acute mild/moderate dental pain
• Added to cough syrups as an antitussive (suppresses
cough reflex)
Codeine
Adverse effects
• Respiratory depression but to a lesser degree
compared to morphine
• Dizziness, nausea, vomiting, constipation and
sedation
Drug-drug interactions
• Selective serotonin reuptake inhibitors (CYP2D6
inhibitors) = increase plasma levels of codeine
• Increase in CNS depression effects when taken with
alcohol
Naloxone and Naltexone
• Used to reverse drug overdose
Mechanism of action
• Competes with endogenous and exogenous opioids at
opioid receptors
• Binds with high affinity to opioid receptors but exerts no
receptor-mediated response
• No analgesic effect, antitussive activity or respiratory
depression
Naloxone and Naltexone
Pharmacokinetics
• Rapidly metabolised (effects lasts 2 – 4 hours)
• Naloxone reverses respiratory depression and coma
within 30 seconds of administration
• Naltrexone blocks the effect of injected heroin for up
to 48 hours
Pethidine
• Chemically unlike morphine although pharmacological
actions are similar
• Used for pain relief, post-operative pain and for labour
pain
• Contraindications
• Patients with renal and hepatic insufficiency
Pethidine
• Side effects
• Restlessness, euphoria
• Anti-muscarinic effects (dry mouth, blurred vision)
• Drug-drug interactions
• Monoamine oxidase inhibitors (MAOIs) and selective
serotonin reuptake inhibitors (SSRIs) - serotonin
syndrome
Fentanyl
• Rapid onset and shorter acting
• Administered intravenously for analgesic and sedative
effects or skin patches for chronic pain
• Indicated for severe chronic pain when continuous
analgesia is required
• Anaesthesia - lipid soluble and crosses blood brain barrier
rapidly
Methadone
• Pure agonist and long acting
• Well absorbed when taken orally
• Plasma half like > 24 hours
• Analgesic activity equivalent to that of morphine
Buprenorphine
• Partial agonist and long acting
• Produces opiate effects (i.e. euphoria, analgesia and
sedation) to a lesser degree
• Used for severe to chronic musculoskeletal joint and
lower back pain
• Initial stages of addiction therapy
• Combined with naloxone for maintenance
Tramadol
Mechanism of action
• Atypical opioid
• Acts on opioid receptor
• Inhibits reuptake of serotonin and noradrenaline
Side effects
• Nausea, headache, constipation and seizures
Tramadol
Drug interactions
• Do not use with alcohol, carbamazepine and
serotonergic agents
Contraindications
• Patients suffering from respiratory depression
Tolerance
• Repeated dosing of exogenous opioids desensitizes
receptors
• Shortened duration or reduced analgesic effect of
administered opioids increased dose required
Dependence
• After withdrawal of opioids, endogenous opioids are
not sufficient to stimulate the insensitive receptors
• Results in withdrawal state that is associated with
autonomic, motor and psychological responses
• Physical or psychological effects
• Dose should be tapered off when opioids used for a
long period
Acute opioid intoxication
Signs of acute opioid intoxication (overdose)
• Constricted pupils
• Depressed respiration
• Decreased blood pressure due to hypoxia
• Results in coma or death
Acute opioid intoxication
Treatment of acute opioid intoxication
• Restoration of adequate ventilation
• Opioid receptor antagonist = IV Naloxone
• Displaces agonists from binding sites and reduces
physiological response to opioid therapy
• Continued monitoring and re-administration of drug if
necessary
Special considerations
• Rapidly enters all body tissues
• Avoided in pregnancy – fetal respiratory depression
• Elderly patients more sensitive to analgesic effects
• Decreased metabolism or impaired renal function
• Lower dosage required
Special considerations
• Patients with bronchial asthma or liver failure
• Tolerance and physical dependence
• Acute opioid intoxication
• Drug-drug interactions
• CNS depressants, tricyclic antidepressants, MAOIs, local
anaesthetics and oral anticoagulants
Take home question
1. Name two drugs that are opioid receptor antagonists.
2. Describe the mechanism of action of tramadol.
3. Give an example of an opioid drug that is a:
◦ pure agonist
◦ partial agonist
