Action: Steriospecific opiate receptor binding in

Receptor Agonist Antagonist Behaviour Analgesia Respiration Pupil Dependance Other
Mu Morphine
Enkephalin  Beta-Endorphin
Euphoria Supra spinal Spinal Depression Miosis Morphine Decrease GIT motility
Vagal bradycardia
Delta d Enkephalin
Naloxone   Supra spinal Spinal Less Resp
    Modulate mu receptors
Kappa k cyclazocin dynorphin Naloxone Sedation Spinal Depression Miosis cyclazocine Decrease ADH release


  Morphine Pethidine Fentanyl Sufentanil Alfentanil Remifentanil 
A bsorption
intra muscular


Only available in parentral formulations
D istribution
t 1/2 alpha
t 1/2 beta
t 1/2 Ke0

2 min
3 hours

4 min
3 hours

13 min
3.6 hours
4-5 min

18 min
2.7 hours

12 min
1.6 hours
0.6-1.2 min

8 min
1.0-1.5 min
Onset time 15-30 min 10-20 min 1-2 min 1-3 min 30 seconds 30 seconds
Peak effect 45-90 min ~ 20 min 3-4 min 5-6 min 1-2 min 1 minute
Duration 4-5 hrs 2-4 hrs 30 min 30 min 15 min 5-10 min
oil/H 2 O 1.4 39 860 1,778 13.4 17.9
Vd L/Kg 3.2 4.4 4 1.7 0.86 0.3-0.4
prot bind 35 % 65 % 80 % 92 % 92 % 92%
pKa 7.9 8.7 8.4 8 6.5 7.07
% ionised @ 7.4 75 95 90 80 10  
M etabolism Conjugation
Hepatic & Renal
Demethylation Demethylation Demethylation

Hydrolysis by non specific esterases not related to pseudo - cholinesterase

Metabolites M-6-glucuronide (opioid activity)
(minimal opioid activity)
Normeperidine Inactive metabolites
E xcretion Renal + biliary Renal + biliary Renal + biliary Renal + biliary Renal + biliary Renal + biliary
  M6G accumulates with renal dysfunction normeperidine accumulates with renal dysfunction       Pharmaco - kinetics are unchanged by end organ disease
Clearance ml/Kg/min 14 7-16 13 13 6.4 50
Factors affecting pharmocokinetics and pharmacodynamics
Dose     Redistrubution.
Enterohepatic circulation
Redistrubution with increasing "context - sensitive half-time"   Static
"context- sensitive half-time" of
5-8 minutes

Ionised drug attaches to the receptor - promoted during respiratory acidosis

Protein binding

Binding is to alpha 1 acid glycoprotein, which as an acute phase reactant increases in times of stress
Other drugs - Propanolol, Lignocaine and Imipramine - can displace opioids


Decrease dosage recommended in:
< 20 days - An immature blood brain barrier with associated low clearance and hepatic function
Elderly - Lower volume of distribution, lower clearance and increased CNS sensitivity

Hepatic function

pharmacodynamic interaction.  Titrate dose carefully to effect, with increased time between boluses

Renal function

Excretion of M6G and normeperidine is decreased leading to clinical effects

C hemisty

Phenanthrene nucleus

Equipotent ivi D ose 10 mg 100 mg 100 mg 15 mg 750 mg 10 mg
ivi /Kg 0.1-0.2 mg 1-2 mg 1-2 mg 0.1-0.2 mg 10-20 mg 0.05-2 mg/kg/min
Epidural 1-5 mg         No!
CSF 0.1-1 mg 1mg/Kg       No!
E ffects

Central nervous system Depression

Analgesia = = = = = =
Sedation +++ ++ + ++ + ++
Antitussive = = = = = =
Apnoea = = = = = =
Decrease CMRO 2 = = = = = +
Deacrease BP +++
++ ++ + + +++

Central nervous system Excitation

Euphoria ++ +++ ++ +++ ++ +
Miosis = = = = = =
Vomiting +++ ++ ++ ++ ++ ++
ADH release ++ + + + + +
Convulsions ++ +++ (normeperidine) + + + +
Muscle rigidity +++ + + + +++ +++
  1. Initial decrease in respiratory rate (and minute ventilation) with an increase in the rib cage contribution to tidal volume.
  2. An increase in PaCO2 due to a decreased minute ventilation
  3. Compensatory increase in tidal volume to try and increase minute ventilation.
  4. A decrease in the inspiratory duty (inspiratory time/total cycle time).
  5. Apnea - Voluntary control is retained initially

Bronchoconstriction via histamine release


Vagally mediated bradycardia possible.
Histamine release (not opioid receptor mediated) decreases SVR causing a decrease in systolic and diastolic blood pressure


Delayed gastric emptying and decreased lower oesophageal sphincter tone, not reveresed by metoclopramide. Dry mouth. Spasm of the sphincter or oddi

GUT Urinary retention
GNL Puritis (especially the tip of the nose), Flushing, Warm sensation.
Endocrine Can abolishes or modify the hormonal stress response to pain and surgery
F ormulation M. Sulphate
P. HCl
F. Base
S. Base
A. Base

R. HCl  Lyophilised powder
with 15mg glycine

Trade name Morphine Demerol Meperidine Sublimaze Sufenta Rapifen


/ml 10 / 15 mg 25 / 50 mg 50 mg 10 mg 500 mg

Reconstitute with water or 5% dextrose to
25 or 50 mg/ml

      Transdermal Duragesic 25/50/100 mg/hr    
I ndications
  Severe Pain
Myocardial Infarction. Terminal pain  Surgery
Severe Pain
Biliary and renal colic
Acute and chronic pain

Monitored Anaesthesia Care for acute pain of short duration.
local or regional analgesia
placement of intravascular cannulae,

loading 0.5 mg/kg 1-2 mg/kg 1-3 mg/kg 0.1-0.3 mg/kg 10-25 mg/kg 0.5 mg/kg over
30+ seconds
maintenance 0.5-2 mg per unit dose PCA repeated 4 hourly.   0.01-0.03 mg/Kg/min 0.002-0.006 mg/Kg/min 0.25-1 mg/Kg/min 0.05-0.1 mg/Kg/min
  Potential build up of metabolites Best effect acheived if associated with an axiolytic-
example - midazolam 2 to 6 mg
Pain relief
Pre-emptive analgesia
Pain relief
Pre-emptive analgesia
Intra surgical pain management for cases requiring intense analgesia for a sharply circumscribed period of time.
  Neurolept anaesthesia Co-Induction Co-Induction &
  Opioids alone do not cause anaesthesia and must be associated with an hypnotic (propofol > 80mg/Kg/min or >0.3 MAC of Volatile agent) for anaesthesia.
loading     5-15 mg/kg 1-2 mg/kg 50-150 mg/kg 1 mg/kg over
30+ seconds
Maintenance     0.03-0.1 mg/Kg/min 0.005-0.3 mg/Kg/min 0.5-3 mg/Kg/min 0.05-2
Bolus Dose Titrate to the individual with top up doses every 1 to 4 hours Strategies to deal with post operative pain must be in place prior to emergence from anaesthesia.  Immediate post operative pain is most notable when using remifentanil.
C ontra - indications Monitoring and equipment for the maintenance of haemodynamics + respiration
D rug interactions Most CNS medications potentiate the magnitude and duration of all the opioid effects
  • Tricyclics, phenothiazines, alcohol, barbiturates, benzodiazepines
MAO inhibition.
  • Marked potentiation of opioid effects with the development of a malignant hypermetabolic syndrome type picture.
  • Excitation, convulsions, increasing T o , resp depression with inc PaCO 2 , hypotension, coma, death

"Context-sensitive half-time"

Of the main pharmacokinetic variables, half-life is the easiest to comprehend. However it gives little information about the bahaviour of a drug in a single compartment, and cannot predict the behaviour of drugs with two or three compartment models.  A more useful descriptor, "context-sensitive half-time" is where the "context" refers to the duration of infusion and the "half-time" is the time required for the drug concentration in the central compartment to decline by half after infusion is stoped.  The concept can be extended from a 50% decrease to an 80% decrease, which is more closely related to the offset of action.

The differance between single injection and prolonged infusion arises when distribution from the central to the peripheral comparments is responsible for a considerable part of the offset of action of a drug

Other opioid agonists


Mode of action:

  1. Weak mu opioid receptor agonist
  2. Inhibition of noradrenaline uptake
  3. Release of serotonin


Dose: Moderate post-operative pain

  1. 50-100mg orally every 4 hours
  2. 50-100mg intravenously titrated to effect



  1. solution of 50mg/ml for intravenous and intramuscular usage (racemic mixture)
  2. capsule or tablet of 50mg


Moderate post operative pain control, especially in patients who have a problem taking opioids or non-steroidal anti-inflammatory drugs


  1. NOT for intra surgical pain management as there is increased intra-operative awarness.
  2. Avoid in patients taking mono-amine oxidase inhibitors
  3. Caution in epileptics
  4. Not recommended for children

Neuraxial opioids

  1. Opioid receptors are present in the substantia gelatinosa in the dorsal horn of the spinal cord.
  2. Certain initial theories surrounding their use have unfortunatly often been accepted as dogma.

Centoneuraxis opioids enhance pain relief, decreasing overall patient mortality

Post-operative mortality is a rare occurrence in healthy patients undergoing short, minor surgical procedures. It is unreasonable to expect a reduction in mortality and so should not be used as a rationale for centroneuraxis opioids in this patient population. Post-operative mortality in high risk patients undergoing major surgery is reduced by the usage of centroneuraxis opioids, in the post-operative period. The exact mechanism underlying this phenomenon is still unknown, we do know that post-operative pain contributes to the "stress response" which is a plethora of hormonal changes following surgery. The sympathetic nervous system is activated in this "stress response" increasing circulating catecholamine concentrations. Catecholamines stimulate the cardiovascular system and enhance platelet activation, which may play an important role in the incidence, timing and severity of myocardial ischaemia in patients with coronary artery disease. Epidural opioids are superior in decreasing the circulating catecholamine concentrations, and the resultant hypercoagulable state in the post-operative period. Exactly which group of patients will definitely benefit from centroneuraxis opioids, the level and duration of pain relief necessary and whether or not the addition of local anaesthetics contributes to a further decreases in the "stress response", or in fact if it is the reduction in the hormonal "stress response", that is crucial to the improved outcome, has all still to be decided

Centroneuraxis opioids minimise opioid dose decreasing all opioid side effects

Dose sparing effectMorphine is the only opioid which shows a dose sparing effect by epidural and intrathecal placement. 1/4 of the parentral dose (0.1-0.2mg/kg) is effective epidurally (0.02-0.05mg/kg) and 1/100 of the parentral dose is effective intrathecally (0.001-0.005mg/kg). Although meperidine (pethidine) has both local anaesthetic and opioid properties 7/10 of the parentral dose (1-2mg/kg) is needed epidurally (.7-1mg/kg) and in an equivalent dose intrathecally (1mg/kg). No other opioids display any dose sparing effect. Fentanyl, butorphanol and alfentanil all require 100% of the parentral dose when given epidurally or intrathecally. Sufentanil actually requires a larger intrathecal and epidural than parentral dose. The theoretical explanations of this phenomenon are:Dural permeability was thought to increase with increasing lipid solubility. Drugs have to pass through lipid and water barriers to traverse the dura and arachnoid membranes, eventually the advantage of increasing lipid solubility is lost by slow transfer through hydrophilic regions. This theory fails to explain why there is no advantage to intrathecal administration which bypasses the dural membrane.Non-specific binding analogous to the blood gas partition coefficient of inhalational agents. Lipid soluble opioids diffuse extensively into epidural fat and the spinal cord white matter, leaving relatively little drug to reach the spinal opioid receptors in the grey matter.Synergy between supraspinal and spinal opioid action is the most elegant theory. All opioids are rapidly absorbed into the circulation after epidural injection and have access to supraspinal sites of action. Morphine acts at all opioid receptors resulting in a synergy between the supraspinal and the spinal effects. Fentanyl and sufentanil have increasing specificity for the m receptor subtypes and may lack a synergistic interaction between supraspinal and spinal action.

Decreased opioid side effects

Morphine centroneuraxis blockade decreases sedation, but increases pruritis, which is associated with herpes reactivation, urinary retention and nausea compared to systemic administration. Fentanyl and sufentanil require centroneuraxis dosages identical or greater than parentral doses, the plasma drug concentration are similar and so the incidence and severity of side effects are comparable. Treatment of these side effects with continuous infusion of naloxone at 2-5mg/kg/hour does not appear to reduce the analgesia of centroneuraxis morphine, as it would for parentral morphine. Oral administration of the long-acting antagonist naltrexone 3-6mg may diminish analgesia. The partial agonists nalbuphine (5-10mg ivi) and butorphanol (1-2mg ivi) effectively reverses the side effects without affecting the analgesia. Purely symptomatic treatment with droperidol (0.5-1mg ivi) for the nausea and diphenhyramine.(12.5-25mg ivi) for the pruritis is also effective.

Centroneuraxis opioids reduces the risk of respiratory depression

Dermatomal level of analgesia ascends slowly after epidural morphine injection, reaching the cervical levels 6-8 hours after injection. This corresponds to the time for circulation of morphine in the cerebrospinal fluid and accounts for the delayed respiratory depression seen when high morphine concentrations are achieved in the cerebrospinal fluid bathing the respiratory centres in the brainstem. As anaesthetics we expect and indeed observe rapid, extensive dermatomal spread after lumbar intrathecal injection of isobaric bupivacaine but anticipated a restricted spread of fentanyl which is not much more lipid soluble than bupivacaine. The odd observation is not the rapid cephalad spread of fentanyl, but the slow cephalad spread of morphine. This rapid cephalad spread of lipid soluble opioids may explain the rapid onset of severe respiratory depression following centroneuraxis administration. The relatively large doses of lipid soluble opioids that must be employed in centroneuraxis blockade, may result in delayed respiratory depression following systemic absorption. We must not use a decrease in respiratory depression as a rationale for using centroneuraxis opioids.Morphine is the opioid of choice for epidural usage. A single injection yields 12 to 24 hours of analgesia, which covers the patient for the most painful post operative period. Continuous infusion of 0.2-0.6mg/hour can prolong analgesia provided there is a high awareness of pump malfunction or misprogramming and catheter migration into a blood vessels, which would result in loss of analgesia. Patient controlled analgesia with epidural morphine can also be successfully utilised.Morphine is the opioid of choice for intrathecal usage following the withdrawal of spinal catheters, it is the only drug that can provide 12 to 24 hours of pain relief following a single intrathecal injection.Pethidine can be used to good effect intrathecally providing 8-12 hours of pain relief following a single intrathecal injection.



Action: Antagonist at all opioid receptors, highest affinity for mu receptors.




Narcan (naloxone HCl) 0.4mg/ml diluted to 10 mls = 40mg/ml

Narcan neonatal 0.02 mg/ml = 20mg/ml (1/2 ml per kg)