OPIOIDS

1. Opioids produce analgesia by binding to specific opioid receptors (µ, κ and δ) that are located in the brain and spinal cord regions involved in transmission and modulation of pain.
2. These receptors are all GPCR.
   • The main cellular effect of opioids is to
     1. Close voltage gated Ca2+ channels in pre-synaptic nerve terminals, therefore reducing transmitter release. Reduced Ca2+ entry leads to reduced glutamate, reduced amino acid levels as well as NA, serotonin and ACh from nociceptive terminals.
     2. Open K+ channels, therefore causing hyperpolarization and inhibiting post-synaptic neurons.

Table of opioid receptors and their effects (important)

1. In terms of pain modulation, opioids are thought to act on both ascending and descending pathways.
   • Ascending: may act directly on inflamed tissues, on the dorsal horn and in the thalamus.
   • Descending: act my activating inhibitory nerves and therefore inhibiting pain transmission. May act on the periaqueductal gray and medulla in order to enhance inhibition to the dorsal horn.
2. Tolerance and dependence are features of opioid drugs
   • Frequently administered doses lead to an increase in the dose necessary to produce a similar effect: this is tolerance.
   • Dependence is defined as a withdrawal syndrome that is seen when drug is ceased/antagonist is applied.
   • The withdrawal/dependence mechanism may be due to the following:
     1. Upregulation of cAMP system.
     2. Receptor recycling, where the failure to induce endocytosis of the µ receptor is an important concept in dependence (Maintenance of normal receptor sensitivity requires reactivation by recycling)
   • Note that importantly, tolerance to convulsions, miosis or constipation will not occur.
3. Organ system effects
   • CNS
     1. Analgesia
     2. Euphoria
     3. Sedation
        • Sedation usually manifests as drowsiness and clouding of mentation.
        • Additive effect with other anxiolytics/sedatives (e.g. BZD). Care should be taken when used.
        • Elderly patients are more susceptible to opioid sedation.
        • Sedation is thought to be more marked with morphine than with fentanyl/pethidine.
   • CVS
     1. May cause bradycardia
     2. Hypotension may result if the CVS system is already under stress. This is probably due to vasodilation secondary to histamine release. Therefore, take care in the hypovolemic patient.
     3. Remember that opioids will increase PaCO2 à cerebral vasodilation à RICP.
   • Respiratory
     1. Significant respiratory depression is seen, mainly by depressing the medullary sensitivity to CO2. There is a rise in PaCO2.
     2. This respiratory depression is poorly tolerated in those with limited reserve, namely severe COPD, Cor Pulmonale, severe asthmatics and RICP.
     3. Cough suppression may occur – lead to airway obstruction/atelectasis.
   • Other system effects
     1. GIT – constipation
     2. Biliary – causes biliary smooth muscle contraction: may make biliary colic worse
     3. Skin – pruritus, flushing
     4. Nausea, vomiting and miosis are also seen.

• Pain
  1. Useful in biliary and renal colic
  2. May be useful in labour
• Acute pulmonary oedema
  1. Reduces pre-load and afterload.
  2. Reduces the subjective sensation of dyspnea
• Anaesthetic
  1. Fentanyl may be used as induction agent (either alone, or in conjunction with BZD). Especially useful in patients with unstable haemodynamics.
• Other indications are:
  1. Cough
  2. Anti-diarrhoeal
  3. Pethidine may be used to break rigors

1. Caution in the elderly (increased sensitivity)
2. Renal/hepatic disease (morphine and its metabolites may accumulate)
3. Limited respiratory reserve
4. Limited cardiovascular reserve
5. Head injured patients
6. Pregnancy – crosses the placenta and may precipitate withdrawal states in the baby.
7. Caution with using naloxone + full agonist – may precipitate withdrawal.

1. Sedative hypnotics
   • Added CNS and respiratory
2. Anti-psychotics
   • Additive anti-muscarinic and alpha-blocking effects, leading to tachycardia, hypotension and increased sedation
3. Concurrent use of MAO-I is a relative contraindication
   • Hyper-pyrexial coma, hypertension

1. Extension of their organ system effects
   • CNS – sedation
   • Respiratory – respiratory depression
   • CVS – bradycardia/hypotension
   • Certain opioids may precipitate seizures
   • Tolerance, dependence and addiction