OPIOIDS

Action: Steriospecific opiate receptor binding in

• CNS tissues concerned with pain perception, integration and the response to pain
  • Limbic system - Amygdaloid nucleus and hypothalamus
  • Medial and lateral thalamus including the area postrema with its chemo-emetic trigger zoneNucleus of the solitary tract with its cough centre
• Peripheral tissues
  • Substantia gelatinosa. in the dorsal horn of the spinal cord (Rexed's lamina I and IIa)
  • GIT

• All three subtypes of opioid receptors interact to produce synergistic analgesia
  • Inhibition of adenylyl cyclase causing inositol mobilisation of intracellular Ca ²⁺ .
    1. Utilisation of Gi and Go proteins with all receptorsGq proteins involved in kappa mediated analgesia.
    2. Ryanodine receptor activity may be regulated via the delta receptor.
    3. Different agonists may have different effects on G-proetin coupling.
  • Cell membrane Ca ²⁺ channel modulation.
    1. Mu and delta receptors inhibit L-type Ca ²⁺ channels.
    2. Kappa receptors modulate neuroendocrine nerve terminal Ca ²⁺ currents.
  • Regulation of inwardly rectifying K ⁺ channels.

Agonists

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

Tramadol

Mode of action:

1. Weak mu opioid receptor agonist
   • Metabolised by CYP2D6 to ortho-desmethyltramadol, which is a reasonable mu opioid receptor agonist
2. Inhibition of noradrenaline uptake
3. Release of serotonin

Biokinetics

• Rapidly absorbed with an initial bioavailability of  68% after a single dose
• Appears in plasma in 15-45 minutes with a peak concentration at 2-4 hours
• High tissue affinity with a volume of distribution 200-300 litres
• 20% protein binding
• Liver metabolism by CYP2D6 to ortho-desmethyltramadol with subsequent sulphation or glucuronidation
• 90% excretion via the kidneys. Decrease dosage in renal dysfunction
• 10% excretion via the liver.  Decrease dosage in heptic dysfunction
• Elimination half life of 5 hours

Dose: Moderate post-operative pain

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

Effects

• Analgesia is achieved by a combination of indirect postsynaptic alpha 2 - adrenoceptors activation and opioid activity
• Respiratory depression is clinically less and with a different pattern than with the specific opioid agonists
• Minor reports of dizziness, nausea, sedation and dry mouth

Formulation:

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

Indication:

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

Contra-indications

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.

OPIOID ANTAGONISTS

Naloxone:

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

Dose:

• 1.5 - 3 mg/Kg boluses in adult.
• 10 mg/Kg in neonate
• Duration 30-45 minutes

Effect:

• Alone has no clinical effect. Very large doses cause mild drowsiness.
• Reverses resp depression, sedation, puritis, urinary retention and bradycardia assoc with opioid administration. There is better antagonism of opioid analgesia than opioid respiratory depression.
• Overshoot of reversal causing sudden awarness of pain can lead to hypertension, tachy, hypervent, dysrythmias + pulm oedema, following central catecholamine release.

Formulation:

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)

Indication:

• Reversal of opioid induced resp depression, CVS depression, Sedation, Puritis + urinary retention.
• Reversal of neonatal resp depression following maternal opioids
• Respiratory stimulation in neonates (? enkephalin mediated control of respiration in intrauterine and neonatal life)
• Diagnosis if coma or resp depression of opioid aetiology
• Precipitation of acute withdrawl syndrome in addicts
• In animal studies can attenuate hypotension in septic and hypovolaemic shock states.

Nalorphine;

• mu antagonist causing dysphoria and ataxia

Nalmefene;

• Good oral absorption, high receptor affinity,
• long duration of action (72hours), actual reversal of respiratory depression only 4-6 hours

Naltrexone;

• Long acting mu antagonist, used in the treatment of morphine addiction.t _1/2b 7 hours t _1/2g 96 hours
• Good oral absorption