What is the half-life of morphine?

Morphine Half-Life

The plasma elimination half-life of morphine is 2-4 hours, regardless of route of administration (oral, intravenous, or intrathecal), with steady state achieved within 24 hours (4-5 half-lives). 1, 2

Standard Pharmacokinetic Parameters

• Elimination half-life: 2-4 hours in patients with normal renal and hepatic function 1, 3, 2
• Time to steady state: 24 hours (within 4-5 half-lives) after starting treatment or following any dose adjustment 1, 3
• Peak plasma concentration timing:
  • Immediate release formulations: 0.25-1.0 hours 1
  • Modified release formulations: 2-4 hours 1
• Duration of analgesia:
  • Immediate release: 4 hours 1
  • Modified release: 12 hours 1

Clinical Implications for Dose Titration

The 24-hour interval to reach steady state is the critical timeframe for re-evaluating patients and adjusting doses. 1 This applies regardless of whether you are using immediate release or modified release formulations, as the elimination half-life remains constant at 2-4 hours. 1

• When titrating morphine doses, wait at least 24 hours between dose adjustments to allow steady state to be achieved 1, 3
• Review total daily morphine requirements (including rescue doses) at this 24-hour interval 1
• Adjust the regular dose based on breakthrough medication usage during this period 1

Important Pharmacokinetic Nuances

Terminal Half-Life vs. Elimination Half-Life

A critical distinction exists between the clinically relevant elimination half-life and the terminal half-life. While the effective elimination half-life is 2-4 hours, some studies involving longer plasma sampling periods (up to 72 hours) have identified a much longer terminal half-life of approximately 15 hours. 2, 4 This prolonged terminal phase is likely due to enterohepatic cycling, where morphine and its metabolites are secreted in bile and reabsorbed. 4 However, this terminal phase represents only a small fraction of the total drug and is not clinically relevant for routine dosing decisions. 2

Route of Administration Does Not Affect Half-Life

The elimination half-life remains 2-4 hours regardless of whether morphine is given orally, intravenously, intrathecally, or by any other route. 1, 3, 2 This is because the half-life reflects systemic clearance once the drug enters the bloodstream, not the route of administration. 3 What does differ by route is the bioavailability and peak concentration timing, not the elimination kinetics. 2

Special Populations Requiring Dose Adjustment

Hepatic Impairment

In patients with severe liver cirrhosis, morphine clearance decreases significantly and elimination half-life increases to approximately 4.2 hours (range 3.6-4.8 hours). 5 More importantly:

• Oral bioavailability increases dramatically to approximately 101% (compared to <40% in normal patients) due to reduced first-pass metabolism 2, 5
• Plasma clearance decreases to 11.4 mL/min/kg (compared to 20-30 mL/min/kg in normal patients) 2, 5
• The metabolic ratio of morphine-3-glucuronide to morphine is significantly lower 5
• These patients require cautious dosing with both oral and intravenous morphine, with lower starting doses and longer intervals between dose adjustments 5

Renal Impairment

In renal failure, while the elimination half-life of morphine itself may not change dramatically, the active metabolites (M3G and M6G) accumulate to much higher plasma levels. 2 This creates a clinical scenario where:

• The AUC of morphine increases and clearance decreases 2
• Metabolites accumulate because they are primarily renally excreted 2
• Patients may experience prolonged effects despite the unchanged morphine half-life 2

Pediatric Populations

Morphine half-life varies significantly by age in children: 1

• Neonates (term to 30 days): 7.6 hours (range 4.5-13.3 hours) 1
• Infants 1-3 months: 6.2 hours (range 5-10 hours) 1
• Infants 6 months-2.5 years: 2.9 hours (range 1.4-7.8 hours) 1
• Children: 1-2 hours 1

This age-dependent variation is critical when converting from continuous infusions or determining observation periods after overdose in pediatric patients. 1

Common Pitfalls to Avoid

• Do not adjust morphine doses more frequently than every 24 hours during initial titration, as steady state has not been achieved and you risk overshooting the therapeutic target 1, 3
• Do not assume that modified release formulations have a longer elimination half-life than immediate release—both have the same 2-4 hour half-life; only the absorption profile differs 1, 2
• Do not use the terminal half-life (15 hours) for clinical dosing decisions—this represents enterohepatic cycling and is not relevant for routine dose adjustments 2, 4
• In hepatic impairment, do not assume oral morphine will have low bioavailability—it may approach 100% due to loss of first-pass metabolism 5
• In overdose situations, do not discharge patients after brief observation based solely on the 2-4 hour half-life—modified release formulations and metabolite accumulation require extended monitoring 6