Clinical Pharmacokinetics of Morphine

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Abstract
Morphine (M) is recommended by the World Health Organization as the treatment of choice for moderate-to-severe cancer pain. Development of sensitive radioimmunoassays (RIA) and high-performance liquid chromatography in the past 20 years has allowed study of the pharmacokinetics of M, which remain incompletely understood. Data derived by RIA must be interpreted with caution due to cross-reactivity with anti-sera by metabolites, impairing assay specificity. The pharmacokinetics of M have been determined for various clinical situations, but there is large interpatient variability for most parameters. M is readily absorbed from all routes of administration, except transdermal, and it can be injected spinally. Peak plasma levels are achieved within 15–20 min of intramuscular and subcutaneous administration, and within 30–90 min after oral. Peak levels after oral administration are much lower than after parenteral routes, since oral M undergoes extensive first-pass metabolism in the liver. With repeated administration, the oral-parenteral relative potency ratio is 1:3. M can be administered epidurally or intrathecally and has also been given intracerebroventricularly. Epidural M enters the subarachnoid space, but is also absorbed into the systemic circulation. Only 5% of a dose crosses the dura. M administered in the lumbar region is quickly redistributed in the cerebrospinal fluid in a rostral direction, explaining the high incidence of systemic side effects following spinal administration. After absorption, M is rapidly and widely distributed and crosses the blood-brain barrier. With therapeutic doses, plasma protein binding is only 20–35%, and the volume of distribution is 1–6 L/kg. The primary site of M metabolism is the liver, and the dose should be reduced in patients with liver disease. Glucuronidation is the main metabolic pathway, but the principal metabolite, morphine-3-glucuronide (M3G), is inactive. Morphine-6-glucuronide (M6G) is produced in smaller amounts than M3G, but is pharmacologically active and many times more potent than M. The ratio of M6G to M in plasma, after a dose of M, is ∼10:1, and the ratio does not change with increasing doses or prolonged treatment. Normorphine (NM) is also active, and is formed to a greater extent after oral administration; it is not, however, usually found in plasma. NM may be neurotoxic. M and its metabolites are excreted by the kidney, but urinary free M accounts for <10% of an administered dose. In patients with renal insufficiency, the metabolites accumulate, though M itself is still excreted. Accumulated M6G can produce signs of narcotic overdose, so the dose of M should be reduced in patients with renal failure. The elimination half-life of M is approximately 2 h (range 1–8 h) and is independent of route of administration. Total body clearance is approximately 21 ml/min/kg, the same as hepatic blood flow.