Blood–brain barrier transport of morphine in patients with severe brain trauma

• Published in: British journal of clinical pharmacology Vol. 57; no. 4; pp. 427 - 435
• Main Authors: Ederoth, Per, Tunblad, Karin, Bouw, René, Lundberg, C. Johan F., Ungerstedt, Urban, Nordström, Carl‐Henrik, Hammarlund‐Udenaes, Margareta
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01.04.2004; Blackwell Science; Blackwell Science Inc
• Subjects: Adult; Analgesics; Analgesics, Opioid - pharmacokinetics; Anestesi och intensivvård; Anesthesiology and Intensive Care; Area Under Curve; Biological and medical sciences; blood-brain barrier; Blood-Brain Barrier - metabolism; Brain Injuries - metabolism; brain injury; Clinical Medicine; Drug Disposition; Female; Half-Life; human; Humans; Kirurgi; Klinisk medicin; Male; Medical and Health Sciences; Medical sciences; MEDICIN; Medicin och hälsovetenskap; MEDICINE; microdialysis; Middle Aged; morphine; Morphine - pharmacokinetics; Neurologi; Neurology; Neuropharmacology; pharmacokinetics; Pharmacology. Drug treatments; Surgery; Human; blood-brain barrier; Opiates; Morphine; Narcotic analgesic; Blood brain barrier; Trauma; Encephalon; brain injury; Microdialysis; Central nervous system disease; Lesion; Pharmacokinetics
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1046/j.1365-2125.2003.02032.x

Aims In experimental studies, morphine pharmacokinetics is different in the brain compared with other tissues due to the properties of the blood–brain barrier, including action of efflux pumps. It was hypothesized in this clinical study that active efflux of morphine occurs also in human brain, and that brain injury would alter cerebral morphine pharmacokinetics. Methods Patients with traumatic brain injury, equipped with one to three microdialysis catheters in the brain and one in abdominal subcutaneous fat for metabolic monitoring, were studied. The cerebral catheter locations were classified as ‘better’ and ‘worse’ brain tissue, referring to the degree of injury. Morphine (10 mg) was infused intravenously over a 10‐min period in seven patients in the intensive care setting. Tissue and plasma morphine concentrations were obtained during the subsequent 3‐h period with microdialysis and regular blood sampling. Results The area under the concentration–time curve (AUC) ratio of unbound morphine in brain tissue to plasma was 0.64 (95% confidence interval 0.40, 0.87) in ‘better’ brain tissue (P < 0.05 vs. the subcutaneous fat/plasma ratio), 0.78 (0.49, 1.07) in ‘worse’ brain tissue and 1.00 (0.86, 1.13) in subcutaneous fat. The terminal half‐life and Tmax were longer in the brain vs. plasma and fat, respectively. The relative recovery for morphine was higher in ‘better’ than in ‘worse’ brain tissue. The Tmax value tended to be shorter in ‘worse’ brain tissue. Conclusions The unbound AUC ratio below unity in the ‘better’ human brain tissue demonstrates an active efflux of morphine across the blood–brain barrier. The ‘worse’ brain tissue shows a decrease in relative recovery for morphine and in some cases also an increase in permeability for morphine over the blood–brain barrier.