Analgesia including opioids Flashcards
Physiology of pain
- Nociceptive impulses are triggered by the stimulation of peripheral nociceptors that respond to chemical, mechanical or thermal damage by releasing chemical mediators
- Mediators that initiate nociception: Histamine, bradykinin, serotonin
- Mediators that sensitize the nociceptors: Prostaglandins, leukotrienes, substance P, neurokinin A
- Aδ fibres are small, myelinated nerve fibres that conduct sharp pain rapidly
- C fibres are unmyelinated nerve fibres that conduct dull pain slowly
- These nerve fibres enter the dorsal horn of the spinal cord via the dorsal root ganglion and terminate at rexed laminae I, II & V. Lamina II = susbtantia gelatinosa
- Further ascending transmission occurs via the lateral spinothalamic tract (where the nerves cross over) to the thalamus
- Finally the signal is transmitted by sensory relay to the sensory cortex at the somatosensory areas I (post central gyrus) & II (Sylvian fissure)
Descending pathways and larger Aβ nerve fibres (which conduct touch) stimulate inhibitory interneurones within the substantia gelatinosa and inhibit C fibre nociceptive inputs, which forms the basis of the gate control theory of pain
Opioids - general properties
Opioids are natural or synthetic compounds which bind to opioid receptors to produce the characteristic effects of opiates
There are four main classes of opioids according to their structure:
* Phenanthrenes - Morphine, codeine, buprenorphine
* Piperidines - Fentanyl, alfentanil, remifentanil
* Diphenylheptanes - Methadone
* Benzomorphans - Pentazocine
* Tramadol is a phenylpiperidine derivative of codeine and does not fit into the above classification
Opioids are weak bases. Most opioids have a pKa above physiological pH, and therefore will be mostly ionized in the body. Alfentanil and remifentanil have a pKa below physiological pH, which therefore explains their rapid onset of action
What is the mechanism of action of opioids at their receptor?
Opioid receptors are G-protein coupled receptors. They are ‘serpentine’ - span the membrane seven times. They are linked to inhibitory G proteins (Gi). When activated this results in inhibition of adenylyl cyclase, reduced production of cAMP, closure of voltage-sensitive Ca2+ channels and efflux of K+ ions causing membrane hyperpolarization. The result is suppression of nociceptive neurotransmitter release (substance P, glutamate)
There are four types of opioid receptors:
* μ (MOP/mu) - Widespread thoughout the CNS, peripheral sensory neurones, GI tract etc. They produce potent analgesia, and are the most common targets for opioids used in clinical practice. They also produce many of the common side effects such as respiratory depression (by reducing chemoreceptor sensitivity to CO2), constipation, nausea & vomiting, and pruritis
* κ (KOP/kappa) - Widespread in CNS, peripheral sensory neurones. They also produce potent analgesia, but use may be limited as they have antagonistic effects at the μ-receptor. They also produce side effects of dysphoria, hallucinations and dissociation - but not respiratory depression
* δ (DOP/delta) - Mostly located within CNS. Produces analgesia but may have antagonistic effects at the μ-receptor. Produces respiratory depression. Could have a role in mood regulation
* NOP - Located within the CNS. Produces hyperalgesia at low doses, but does have analgesic effect at higher doses
What are some examples of partial opioid receptor agonists?
Partial opioid agonists may provide some analgesia in opioid-naive patients, although have a ceiling effect so that they are typically adequate for use in severe pain. They cause less respiratory depression, constipation and urinary symptoms, and have less addiction potential. They may precipitate withdrawal in patients already dependent on full opioid receptor agonists
- Buprenorphine - Available as sublingual tablets and transdermal patches. Produces analgesia at low concentrations due to partial agonist effect at μ (MOP) receptor, but at higher doses has an anti-analgesic effect due to effects at NOP receptor. Metabolized by CYP3A4
- Pentazocine - Produces analgesia with little respiratory depression, however use is limited by nausea & vomiting, hallucinations and dysphoria
- Nalbuphine
Fentanyl
Chemical - Synthetic phenylpiperidine derivative
* Weak base with a pKa of 8.4
Presentation - Clear, colourless sollution containing 50mcg/ml fentanyl. Also available as 72hrs patches, sublingual tablets and lozenges. Can be given via intrathecal or epidural administration
Action - Highly selective μ-opioid receptor agonist
Dose / duration / route
* Titrated to effect
* Acts rapidly in 2-5 minutes, effects last ~30-60 minutes. Higher doses may have a prolonged duration of effect ~4-6 hours
Effects
* CVS - Bradycardia of vagal origin, otherwise unaffected. Obtunds the CVS response to laryngoscopy and intubation
* Resp - Potent respiratory depression, reduces ventilatory response to hypoxia and hypercarbia
* CNS - Potent analgesia (50-100x more potent than morphine), miosis
* Other - Reduced gastrointestinal motility, increased bile duct pressure due to spasm of sphincter of Oddi, increased tone of urinary tract
Toxcity / side effects
* Chest wall rigidity
* Nausea & vomiting
Absorption - Abosrbed orally, bioavailability ~33% due to first pass metabolism
Distribution
* High lipid solubility allows fentanyl to readily cross the BBB and accounts for rapid onset and of action. Rapid offset is due to redistribution, despite having a similar / longer clearance and longer half life than morphine. At higher doses, tissues are saturated and duration of action becomes significantly prolonged
* Protein binding ~85%
* Weak base with a pKa of 8.4 - relatively ionized at physiological pH, therefore slower onset than alfentanil and remifentanil
Metabolism - Hepatic metabolism by CYP3A4 to produce norfentanyl, an inactive metabolite
Excretion - Inactive metabolites excreted in the urine
Alfentanil
- Synthetic phenylpiperidine derivative
- μ-opioid receptor agonist
- Clear, colourless solution containing 500mcg/ml
- Weak base with a pKa of 6.5, so ~89% unionized at physiological pH - explaining rapid onset of action
- Peak onset within 90 seconds of IV dose, duration of effects ~5-10 minutes
- Less lipid soluble and lower volume of distribution than fentanyl
- Hepatic metabolism by CYP3A4 to produce noralfentanil, an inactive metabolite. Urinary excretion of metabolites
What determines the difference in speed of onset between fentanyl and alfentanil?
Alfentanil is a weak base with a pKa of around 6. Therefore at physiological pH around 90% of the drug is in an unionized state and can easily pass across the cell membrane. Alfentanil also has a smaller volume of distribution which produces a greater concentration gradient
Fentanyl is a weak base with a pKa of around 8. Therefore at physiological pH only around 11% of the drug is in an unionized state, which limits its ability to cross the cell membrane. However, fentanyl is still highly lipid soluble and therefore has a relatively quick onset compared to other opioids such as morphine. This also allows fentanyl to be used in transdermal patches
Remifentanil
- Synthetic phenylpiperidine derivative of fentanyl
- White lyophilized powder which requires reconstitution before use - usually diluted in 0.9% NaCl to produce a solution with a concentration of 50mcg/ml. Reconstituted solution is stable for 24hrs at room temperature
- Pure μ- opioid receptor agonist
- Associated with bradycardia and reduces MAP
- Onset within 1-2 minutes, offset ~5-10 minutes after discontinuation regardless of duration of infusion
- Longer acting opioid may be required to provide post-operative analgesia if required
- Weak base with a pKa of 7.1, so ~68% unionized at physiological pH - explaining rapid onset of action
- Rapidly metabolized by non-specific plasma and tissue esterases to an inactive carboxylic acid derivative, which is excreted in the urine. Therefore clearance is context-insensitive, and represents metabolism (clearance of fentanyl and alfentanil represents distribution instead)
- Not affected by renal or hepatic impairment
Morphine
Chemical - A naturally occuring phenanthrene derivative
* Weak base with pKa of 8
Presentation - Available in tablet form, syrup, suppositories and as a clear, colourless solution for injection
Action - Potent μ-receptor agonist, weak κ-receptor agonist
Dose / duration / route
* PO dose: 5 - 20mg 4-hourly
* Equivalent IM / SC dose is half the oral dose
* IV dose: 0.05 - 0.1mg/kg 4-hourly. Equivalent dose is a third of the oral dose. IV dose onset ~10-15 minutes, duration 2-4 hours
Effects
* CVS - Bradycardia at high doses. Drop in systemic vascular resistance may be caused by histamine release
* Resp - Respiratory depression, reduced ventilatory response to hypoxia and hypercapnia
* CNS - Potent analgesia. Drowsiness, anxiolysis, euphoria. Miosis
* Other - Reduced GI motility, nausea & vomiting, constipation. Increases tone of ureters and bladder detrusor - may cause urinary retention
* Histamine release > diaphoresis, pruritis
* Increased secretion of ADH > fluid retention, hyponatraemia
Absorption - Morphine is well absorbed in the small bowel, but oral bioavailability is ~30% due to extensive first pass metabolism
Distribution
* Volume of distribution: 3-5L/kg
* 20-40% protein bound
* Morphine has a much lower lipid solubility than other opioids such as fentanyl (~580x less lipid soluble!) This explains its slower onset and offset of action due to delayed time to cross the BBB - therefore plasma concentration does not correlate with degree of analgesia as significant amount of the drug may still be present within the CNS
Metabolism - Glucuronidation within the liver
* Morphine-3-glucuronide (~70%) - may be pro-convulsant
* Morphine-6-glucuronide (~10%) - active, several times more potent than morphine
Excretion - Metabolites are excreted in urine, and may accumulate in renal failure
Diamorphine
Diamorphine is a prodrug with no affinity for opioid receptors
* Relatively more lipid soluble than morphine, and considered to be ~2x more potent
* Produces the greatest degree of euphoria, and therefore is a drug of abuse
* IV dose: 2.5-10mg
* Intrathecal dose: 0.1-0.4mg
* Epidural dose: 1-3mg
* Diamorphine is preferred for intrathecal use over morphine because of its relatively high lipid solubility, which means that it readily diffuses into local tissues. Morphine will stay in the CSF for longer and theoretically is more likely to spread cranially and cause side effects such as respiratory depression
* Weak base with pKa of 7.6
* Metabolism occurs rapidly in the liver, plasma and CNS by deacetylation to 6-monoacetylmorphine and morphine - which are active metabolites acting as potent μ-receptor agonists. 6-monoacetylmorphine is then further metabolized to morphine, which undergoes glucuronidation in the liver to morphine-3-glucuronide and morphine-6-glucuronide
* Urinary excretion of metabolites
Codeine
- A naturally occurring phenanthrene alkaloid which is a methylated morphine derivative (3-methylmorphine)
- PO / IM dose: 15-60mg 4-hourly. IV route is avoided due to hypotension (likely due to histamine release)
- Significant antitussive effect. Causes respiratory depression and constipation
- Codeine itself is a weak selective μ- opioid receptor agonist. However it is thought that most of its analgesic action is due to the result of its metabolism to morphine
- Restricted use in under 12s due to reports of morphine toxicity
Pharmacokinetics:
Absorption - 50% oral bioavailability
Metabolism:
* Major pathway = conjugation to codeine-6-glucuronide
* CYP2D6 (~10%) - metabolized to morphine. There is significant variability in this enzyme, ~8% of Western Europeans are deficient of this enzyme and will therefore have limited analgesic benefit. Fast metabolizers will produce greater amounts of morphine with increased side effects
* CYP3A4 - norcodeine
Urinary excretion of metabolites, ~15% excreted unchanged
Tramadol
- Synthetic phenylpiperidine analogue of codeine. It is a racemic mixture of enantiomers
- Weak, non-selective agonist at μ-, κ- and δ- opioid receptors. It also inhibits the re-uptake of noradrenaline and serotonin, and stimulates serotonin release - which also provides an analgesic effect via descending inhibitory pathways
- PO, IM or IV dose: 50-100mg 4-6 hourly
- Causes less respiratory depression and constipation
- Should not be used in combination with monoamine oxidase inhibitors due to risk of serotonin syndrome
- High oral bioavailability of 70%
- Hepatic metabolism via the cytochrome P450 isozyme CYP2B6, CYP2D6, and CYP3A4 - O-desmethyltramadol is an active metabolite with high potency and a long duration of action
Oxycodone
- Alternative to morphine - better tolerated in some patients
- Acts as agonist at μ- opioid receptors, also has low affinity for κ- and δ- opioid receptors
- Oxycodone is roughly 2x more potent than morphine
- Hepatic metabolism by CYP3A4 to noroxycodone and CYP2D6 to oxymorphone, and various other conjugated glucuronides. Noroxycodone is weakly active, however oxymorphone is a potent metabolite
- Safer than morphine in renal failure - however dose reduction still needed
Pethidine
- Synthetic phenylpiperidine derivative
- Agonist at μ- and κ- opioid receptors
- Available as tablets or solution for injection. PO dose: 50-150mg. IM dose 25-150mg. IV dose 25-100mg
- Highly lipid soluble and significant amounts can cross the placenta
- Metabolized in the liver to the inactive pethidinic acid and to norpethidine - which has half the analgesic activity of norpethidine, accumulates in renal failure and is associated with seizures. Norpethidine is less lipid soluble and accumulates in the foetus - with clearance of both pethidine and norpethidine prolonged due to reduced foetal clearance
- May cause serotonin syndrome if administered with monoamine oxidase inhibitors
Buprenorphine
- Partial agonist at μ- and κ-receptors
- Slow rate of dissociation from receptors may explain long duration of action
- Available as sublingual tablets and various strength of transdermal patches
- Antagonizes the effects of morphine and other opioid agonists and may cause withdrawal syndrome
What is the mechanism of action of NSAIDs?
How does this result in their common side effects?
What is their general pharmacokinetic profile?
NSAIDs are cyclo-oxygenase (COX) inhibitors, which block the conversion of arachidonic acid to PGH₂, a prostaglandin precursor . Their analgesic effect is the result of reduced production of prostaglandins
- COX-1: Responsible for the production of prostaglandins that control renal blood flow and form the protective gastric mucosal barrier. Also mediates the synthesis of thromboxane A₂ which is produced by platelets and promotes haemostasis by vasoconstriction and platelet aggregation
- COX-2: Produced in response to tissue damage and facilitates the inflammatory response. Also mediates production of prostacyclin (PGI₂) which promotes vasodilatation and inhibits platelet aggregation
Effects:
* Anti-inflammatory - decreased PGE₂ and PGF₂ₐ synthesis
* Antipyretic - decreased PGE₂ synthesis
* Gastric irritation / peptic ulceration - reduced prostaglandin levels impairs the normal protective mechanisms of mucous production and bicarbonate secretion
* Renal impairment - Prostaglandins normally cause vasodilation of the afferent arteriole of nephrons, therefore reduced levels result in reduced blood flow to the nephron
* Impaired platelet function - Reduced production of thromboxane A₂ impairs platelet aggregation and prevents vasoconstriction as a reponse to vascular injury
* Pro-thrombotic effect (MI, stroke)
* Drug interactions - Caution with anticoagulants such as heparin and warfarin. NSAIDs are highly protein bound and may displace warfarin, increasing its effects due to increased concentration of free drug
* Hepatotoxicity
* Bronchospasm - Blocking the COX pathway results in more arachodonic acid being shunted
NSAIDs are generally rapidly absorbed with a high oral bioavailability, are highly protein bound with a low volume of distribution, metabolized in the liver and excreted in an inactive form in the urine and bile
