Opioids
Common Features
| Property | Effect |
|---|---|
| Uses | Analgesia, sedation, elimination of sympathetic response to laryngoscopy/surgical stress response |
| Resp | ↓ CNS sensitivity to CO2 causing respiratory depression (↓ RR > ↓ VT) - ↑ reliance on hypoxic drive (therefore respiratory depression may be potentiated by high FiO2) |
| CVS | ↓ HR. May ↓ BP due to histamine release (less with synthetic agents). ↑ PVR |
| CNS | Sedation, euphoria. Nausea and vomiting due to CTZ stimulation. Meiosis due to stimulation of the Edinger-Westphal nucleus. ↓ MAC up to 90% |
| Renal | ↑ ADH, ↑ ureteric and sphincter tone |
| MSK | Muscle rigidity, pruritus (especially with intrathecal administration) |
| Metabolic | ↓ ACTH, prolactin, gonadotrophic hormone secretion. ↑ ADH secretion |
| GIT | ↓ Peristalsis and GIT secretions with subsequent constipation |
| Immunological | Impaired: chemotaxis, lymphocyte proliferation, and antibody production |
Comparison of Naturally Occurring Opioids
| Property | Morphine |
|---|---|
| Receptor | MOP, KOP |
| Route of Administration | SC/IM/IV/Intrathecal |
| pKa | 8.0, 23% unionised at physiologic pH. |
| Absorption | Low (relative) lipid solubility - slower onset and SC absorption. PO preparations absorbed in small bowel, bioavailability 30% - high first pass metabolism. |
| Distribution | ~35% protein binding. VD 3.5L.kg-1 |
| Clearance (ml.kg-1.min-1) | 15 |
| Metabolism | Hepatic glucuronidation to 70% inactive morphine-3-glucuronide and 10% active morphine-6-glucuronide, which is 13x as potent as morphine. t1/2β of 160 minutes. |
| Elimination | Renal elimination of active metabolites - accumulation in renal failure |
| Time to Peak Effect (IV) | 10-30 minutes |
| Duration (IV) | 3-4 hours |
| Equianalgesic Dose (IV, to 10mg IV morphine) | 10mg |
Comparison of Semisynthetic Opioids
| Property | Oxycodone | Buprenorphine |
|---|---|---|
| Receptor | MOP, KOP, DOP | Partial MOP agonist, KOP antagonist (antanalgesic effect) |
| Route of Administration | PO/IV | Topical |
| pKa | 8.5, < 10% is unionised at physiologic pH. | |
| Absorption | PO bioavailability 60-80% | Significant 1st pass metabolism |
| Distribution | As lipid soluble as morphine, 45% protein bound, VD 3L.kg-1. More rapid onset than morphine despite higher pKa potentially due to active CNS uptake | |
| Clearance (ml.kg-1.min-1) | 13 | |
| Metabolism | Hepatic demethylation to noroxycodone (80%, via CYP3A) and the more potent and active oxymorphone (20%, via CYP2D6). t1/2β 200 minutes. | Hepatic to active norbuprenorphine |
| Elimination | Renal elimination of active drug and metabolites | 70% biliary, 30% renal elimination, t1/2β 40 hours |
| Time to Peak Effect (IV) | 5 minutes | |
| Duration (IV) | 4 hours | |
| Equianalgesic Dose (IV, to 10mg IV morphine) | 10mg. Note 10mg PO oxycodone is ≈ 15mg PO morphine due to higher first pass metabolism of morphine |
Comparison of Synthetic Opioids
| Property | Fentanyl | Alfentanil | Remifentanil |
|---|---|---|---|
| Receptor | MOP | MOP | MOP |
| Route of Administration | SC/IM/IV/Epidural/Intrathecal/Transdermal | IV | IV (contains glycine, so cannot be administered intrathecally) |
| pKa | 8.4, < 10% unionised at pH 7.4 | 6.5, 90% unionised at pH 7.4 conferring rapid onset | 7.3 means 58% unionised at physiologic pH. |
| Absorption | Rapid onset of action (< 30s, peak at 5min) due to lipid solubility (600x that of morphine). | 90x more lipid soluble than morphine, but more rapid onset than fentanyl. This is due to: 1. Low pKa means a greater proportion is unionised at physiological pH. 2. Lower potency of alfentanil compared to fentanyl means a greater dose is required (Bowman's Principle) |
20x more lipid soluble than morphine. |
| Distribution | 600x as lipid soluble as morphine conferring a larger VD (4L.kg-1). 85% protein bound. | 90x as lipid soluble as morphine, small VD of 0.6L.kg-1. 90% protein bound | 20x as lipid soluble as morphine, very small VD of 0.4L.kg-1. 70% protein bound. CSHT is constant due to rapid metabolism. |
| Clearance (ml.kg-1.min-1) | 13 | 6 | 40 |
| Metabolism | Significant first pass pulmonary endothelial uptake. Hepatic demethylation to inactive norfentanyl. t1/2β of 190 minutes, longer than morphine due to higher lipid solubility and VD. | Shorter elimination t1/2β than fentanyl (100 minutes) despite lower clearance due to lower VD. Prolonged with administration of midazolam due to CYP3A3/4 competition. | Rapid metabolism by plasma and tissue esterases - t1/2β 10 minutes |
| Elimination | Renal elimination of inactive metabolites | Renal elimination of metabolites | Renal of inactive metabolites |
| Time to Peak Effect (IV) | 5 minutes | 90 seconds | 1-3 minutes |
| Duration (IV) | Variable depending on dose and distribution. With doses > 3μg.kg-1 tissues become saturated and the duration of action is significantly prolonged | 5-10 minutes | Offset 5-10 minutes from ceasing infusion |
| Equianalgesic Dose (IV, to 10mg IV morphine) | 150mcg | 1mg | 50mcg |
References
- Peck TE, Hill SA. Pharmacology for Anaesthesia and Intensive Care. 4th Ed. Cambridge University Press. 2014.
- Smith S, Scarth E, Sasada M. Drugs in Anaesthesia and Intensive Care. 4th Ed. Oxford University Press. 2011.
- Petkov V. Essential Pharmacology For The ANZCA Primary Examination. Vesselin Petkov. 2012.
- ANZCA July/September 2010
- Schug SA, Palmer GM, Scott DA, Halliwell R, Trinca J. Acute Pain Management: Scientific Evidence. 4th Ed. 2015. Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine.