Pharmacodynamics of opioids

[SH4:p87-p90,p93-p102]

Mechanism of actions

• Opioids act as agonist at stereospecific opioid receptors at presynaptic and postsynaptic sites
  * In CNS (mainly in brainstem and spinal cord) and outside CNS.
  --> Mimic action of endogenous peptides
• Peripheral opioid's antinociceptive actions are
  * Effective against hyperalgesia due to inflammation
  * Act on opioid receptors on primary afferent neurons
  * These receptors are normally activated by endogenous peptide opioid receptor agonists (enkephalins, endorphins, and dynorphins)

NB:

• Ionised state is necessary for strong binding at the anionic opioid receptor site
• Only levorotatory form has agonist activity
  * Naturally occurring morphine is L-isomer

Activation of opioid receptors

Activation of opioid receptors does one of the following:

• Increase inward-flowing K+ channel conductance
• Decrease conductance of voltage-gated Ca2+ channels
• Inhibition of adenylyl cyclase --> Decreased cAMP

The first 2 will result in hyperpolarisation

 

End results are:

• Decrease in transmission of nerve impulses
• Presynaptic inhibition of release of neurotransmitters (including ACh, Dop, NE, substance P)

NB:

• Opioid does NOT affect responsiveness of afferent nerve endings to noxious stimulus or impair (slow down) conduction along peripheral nerves

Activation of central opioid receptors

Activation of CENTRAL opioid receptors (i.e. in CNS)
--> Analgesia

Activation of peripheral opioid receptors

Activation of peripheral opioid receptors is responsible for:

• Decreased GIT motility
• Pruritis
• Urinary retention

NB:

• These symptoms can be reversed by a peripherally-acting opioid antagonist (e.g. methylnaltrexone)

Effects by systems

CNS

Analgesia

• Analgesia is more prominent when an opioid is administered before painful stimulus starts
• More effective for continuous dull pain than for sharp intermittent pain
• Effective for visceral and somatic pain

Euphoria

• In absence of pain, morphine produce dysphoria instead of euphoria

Sedation

• Sedation often precedes the onset of analgesia
  * Should be not taken as an indicator of appropriate analgesia during post-operative morphine titration
• Sedation can also be an early sign of opioid overdose

Nausea and vomiting

Opioids induce N&V by

• Direct stimulation of the chemoreceptor trigger zone (CTZ) in the floor of the 4th ventricle (in area postrema)
• May be because opioid agonists also act as partial dopamine agonists at dopamine receptors in the CTZ
• Evidence
  * Apomorphine very emetic and also most potent agonist (of all opioids) at dopamine receptors
  * Butyrophenones antiemetic

NB:

• Morphine depresses vomiting centre in the medulla
  --> IV causes less N&V than IM administration
  * Because IV administration means morphine reaches the vomiting centre as quickly as it reaches the CTZ
• May also have a vestibular component
  * Recumbent patients are less likely to be sick

CBF and ICP

• Opioids (with normal pCO2) decreases CBF and possibly ICP

However,

• Hypoventilation will increase PaCO2 and thus increases CBF and ICP

EEG

• EEG resembles changes associated with sleep
  * Replacement of rapid alpha waves by slower delta waves
  * No increase in seizure activity

Anaesthetic-sparing

[SH4:p121-p122]

• MAC of a volatile anaesthetic agent is decreased in the presence of an opioid antagonist

 

For example,

• Fentanyl 3 microgram/kg IV can decrease isoflurane or desflurane MAC by about 50%
• Sufentanil plasma concentration of 0.145 ng/mL produces 50% decrease in isoflurane MAC
• Remifentanil produces decrease in MAC range from 50% to 91%

 

However,

There appears to be a ceiling effect
--> Opioid agonists probably cannot provide total amnesia reliably even with high doses

Other effects

• Diminished ability to concentration

CVS

• Main CVS effect = hypotension in some circumstances

Orthostatic hypotension

• In supine and normovolaemic patients, direct myocardial depression or hypotension is unlikely
• Orthostatic hypotension and syncope occur due to impairment of compensatory sympathetic nervous system response

However,

• Frank hypotension may occur, if
  * Opioid-induced bradycardia (due to increased vagal tone, or depressant effect on SA and AV node)
  * Opioid-induced histamine release (wide variability)

NB:

• Sufentanil and fentanyl do not evoke the release of histamine
• Morphine does NOT sensitise the heart to catecholamines or increase risk of dysrrhythmia

Pain response

• May decrease the likelihood of tachycardia and hypertension occurring in response to painful stimulation

Synergism with other drugs

• When given with NO2 or benzodiazepine, CVS depression (decreased SVR, CO, and BP) may occur

Respiratory

Main respiratory effects:

• Respiratory depression
• Cough suppression

Respiratory depression

Dose-dependent and gender-specific depression of ventilation

• Produced by all opioid agonists
• Primarily due to agonist effect at mu2 receptors
  --> Direct depressant effect on brainstem ventilation centres
  --> Decreased sensitivity to pCO2
  --> Increased resting pCO2 and displacement of CO2 response curve to the right
• Also interferes with pontine and medullary ventilatory centres
  --> Prolonged pauses between breaths and periodic breathing
• Effect is rapid and persists for several hours

Symptoms and signs of respiratory depression

• Decreased RR
• Partly compensated by increased in tidal volume

Factors increasing the depressant effect respiration

• Advance age
• Occurrence of natural sleep

Factors decreasing the depressant effect on respiration

• Surgical stimuli

NB:

• Analgesia and ventilation effects occur by similar mechanisms

Cough suppression

• Opioids act on medullary cough centres
  * Different from respiratory effects
• Greatest cough suppression occurs with opioids with bulky substitution at C3
  * e.g. codeine
• Dextromethorphan (a dextrotatory isomer of opioids) also suppress cough
  * Without analgesic effects

Other respiratory effects

• Opioids also cause dose-dependent depression of ciliary activity in the airway
• May also cause increase in airway resistance
  * Direct effect on bronchial smooth muscles
  * Indirect effect due to histamine release

GIT

• Decreases propulsive peristaltic contractions of the small and large intestines
• Increased tone of pyloric sphincter, ileocecal valve, and anal sphincter
• Also spasm of biliary smooth muscle

Three main effects:

• Biliary spasm
• Constipation
• Delayed gastric emptying

NB:

• These effects can be treated with a peripheral-acting opioid antagonist

Biliary spasm

• Opioids can cause spasm of biliary smooth muscle
  --> Increase in intrabiliary pressure
  --> Could be associated with epigastric distress or biliary colic
• Increase in intra-biliary pressure due to opioids
  * Fentanyl > Morphine > Meperidine > Pentazocine
• Incidence of spasm of sphincter of Oddi is about 3% in patients receiving fentanyl
• Can precipitate pancreatitis and give false positive cholangiograms

Treatment of biliary smooth muscle spasm

• Naloxone
  * Relieve pain due to biliary spasm
  * Does NOT relieve MI pain
  * May also antagonise analgesia
• Glucagon (2mg IV)
  * Reverse biliary spasm
  * Does NOT antagonise analgesic effect of opioids
• Nitroglycerin
  * Relieve both pain due to biliary spasm or MI

NB:

• Not reversed by anticholinergic drugs (unlike ureteric tone)

Constipation

• Delayed passage
  --> Increased absorption of water
  --> Constipation
• Very little tolerance develops for this effect

Delayed gastric emptying

• Passage of gastric content into the proximal duodenum is delayed
  * Due to increased tone at gastroduodenal junction

Lower oesophageal sphincter tone

• Opioids relax the lower oesophageal sphincter tone
  * [RDM6:p398]

Genitourinary

Mainly to do with morphine, but may occur with other opioids
* ???? Reference needed

• Morphine can increase tone and peristaltic activity of the ureter
  * Can be reversed by anticholinergic drug (unlike biliary spasm)
• Morphine can increase detrusor muscle tone
  --> Urinary urgency
• Morphine can increase vesicle sphincter tone
  --> Difficult voiding
• Morphine can increase ADH in animals, NOT in human
  * ?? But does increase ADH when used as neuraxial opioid

Musculoskeletal

• Does not alter response to neuromuscular blocking drugs
• Skeletal muscle rigidity common after large rapid IV dose
  * Especially in the thoracic and abdominal muscles
  * May be sufficient to interfere with lung ventilation
• Fentanyl is most commonly associated with generalised hypertonus of skeletal muscles
• Sufentanil could cause closure of the vocal cords
  --> One of the major causes of difficult ventilation after sufentanil induction

Mechanism of generalised hypertonus of skeletal muscles

• Inhibition of striatal release of GABA and increased dopamine production

Skin

• Flushing due to dilation of cutaneous blood vessels
• Especially in face, neck, and upper chest
• In part due to histamine release
• Also cause pruritis

NB:

• Morphine-induced histamine release may account for:
  * Pruritus
  * Conjunctival erythema

Eyes

Miosis

• Due to excitatory action of opioids on autonomic nervous system component of the Edinger-Westphal nucleus of the oculomotor nerve
• Tolerance to miotic effect is not prominent
• Can be antagonised by atropine
• Profound hypoxaemia can still result in mydriasis
• Except for pethidine

Others

• Dry mouth

Side Effects/Toxicity

Tolerance, dependence, and drug abuse

Tolerance
= The development of the need to increase the dose of opioid agonists to achieve the same analgesic effect previously achieved with a lower dose
* [SH4:p100]

Hypotheses on mechanism of tolerance

• Receptor desensitisation, followed by down-regulation of the opioid receptors (decrease in number)
• Up-regulation of cAMP system
• NOT due to enzyme induction (because there is no increase in rate of metabolism of opioid agonists)

NB:

• NMDA receptors may play a role
  --> Prolonged exposure to opioids
  --> Activates NMDA receptors and down-regulates spinal glutamate transporters
  --> Increased synaptic concentration of glutamate and NMDA activation
  --> Opioid tolerance and abnormal pain sensitivity
• Potential for physical dependence is an agonist property
  --> Does not occur with opioid antagonists

Tolerance

• Cross-tolerance develops between all the opioids
• Acquired tolerance takes 2-3 weeks to develop with analgesic dose of morphine

 

Tolerance develops to

• Analgesia
• Euphoria
• Sedation
• Respiratory depression
• Emesis

 

Tolerance does NOT develop to

• Miosis
• Bowel motility (constipation)

Dependence

• Physical dependence on morphine requires about 25 days to develop
  * May be sooner in emotional unstable persons
• Some degree of physical dependence may occur after only 48 hours of continuous medication

Tolerance and physical dependence

• Tolerance can occur without physical dependence
• Physical dependence does NOT occur without tolerance

Withdrawal

• Discontinuation
  --> Typical withdrawal abstinence syndrome
• During withdrawal, tolerance to morphine is quickly lost

Symptoms and signs of withdrawal

• Yawning
• Diaphoresis
• Lacrimation
• Coryza
• Insomnia and restlessness
  * Prominent

Followed by

• Abdominal cramps, N&V, and diarrhoea
  * Peak in 72 hours and decline over the next 7-10 days

Prolonged opioid therapy

Can lead to...

• Increased prolactin
• Decreased LH, FSH, testosterone, oestrogen, and cortisol
• Immunosuppression
  * Altered development, differentiation, and function of immune cells
  * But pain itself can also cause immunosuppression

Overdose

Principle manifestation of opioid overdose is depression of ventilation

• Triad:
  * Miosis
  * Hypoventilation
  * Coma
• Symmetric and miotic pupils
  * But mydriasis may occur if severe hypoxaemia
• Pulmonary oedema commonly occurs
  * Mechanism unknown

 

Treatment

• Opioid antagonists
• Remember it may precipitate acute withdrawal