How long does morphine stay in the system?

How Long Does Morphine Stay in the System?

Morphine has a plasma elimination half-life of 2-4 hours, but a terminal elimination phase extends to approximately 15 hours due to enterohepatic recirculation, with its active metabolites (M3G and M6G) persisting even longer at 11-13 hours. 1, 2

Immediate Pharmacokinetic Profile

Normal-release morphine:

• Peak plasma concentrations occur within 1 hour after oral administration 1
• Analgesic effect lasts approximately 4 hours 1
• Steady-state plasma levels are achieved within 24 hours (4-5 half-lives) after starting treatment 1

Modified-release morphine:

• Peak plasma concentrations are delayed to 2-6 hours after administration 1, 3
• Duration of analgesia extends to 12 or 24 hours depending on formulation 1

Metabolism and Elimination Timeline

Primary metabolic pathway:

• Morphine undergoes hepatic conjugation, with approximately 50% converted to morphine-3-glucuronide (M3G) and 15% to morphine-6-glucuronide (M6G) 4
• Only 10% of the dose is excreted unchanged in urine 4
• The initial distribution half-life is 2-4 hours, but a terminal elimination phase of 15.1 hours exists due to enterohepatic cycling 2

Metabolite persistence:

• M3G has a terminal half-life of 11.2 hours 2
• M6G (the analgesically active metabolite) has a terminal half-life of 12.9 hours 2
• These metabolites can accumulate to much higher plasma levels than morphine itself, with M3G:morphine ratios reaching 7.7:1 after IV administration and 29.9:1 after oral administration 2

Clinical Detection Windows

For practical purposes:

• Morphine's analgesic effects dissipate within 4 hours for immediate-release formulations 1
• Complete elimination from plasma takes approximately 3-5 days (5 terminal half-lives of 15 hours) 2
• Metabolites persist longer than parent morphine, particularly in patients with renal impairment 4, 5

Critical Factors Affecting Duration

Renal impairment:

• In renal failure, morphine clearance decreases and M3G/M6G accumulate to much higher levels, significantly prolonging systemic presence 4
• This accumulation can lead to neuroexcitatory toxicity (allodynia, myoclonus, seizures) even days after dosing 5

Hepatic impairment:

• Clearance decreases with corresponding increase in half-life in cirrhotic patients 4
• The M3G and M6G to morphine ratios decrease, indicating diminished metabolic activity 4

Route of administration:

• Oral bioavailability is only 20-40% due to extensive first-pass metabolism 4, 2
• Oral administration produces higher metabolite:morphine ratios compared to parenteral routes 2

Common Pitfall to Avoid

Do not assume morphine is "out of the system" after 8-12 hours based solely on the 2-4 hour half-life. The terminal elimination phase and metabolite persistence mean that morphine and its active/toxic metabolites remain detectable for 3-5 days, particularly in patients with renal impairment where M3G and M6G can accumulate to dangerous levels. 5, 2