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

Abstract

AimsIn 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. MethodsPatients 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. ResultsThe 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 T max 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 T max value tended to be shorter in 'worse' brain tissue. ConclusionsThe 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.

Microdialysis as an Important Technique in Systems Pharmacology—a Historical and Methodological Review

“…Morphine was studied in rats, in pigs with induced meningitis, and in humans with traumatic brain injury (1,100,105). Modeling of the blood-brain barrier transport was made on the rodent data but not of the pig or human data.…”

“…From ref. (104) with permission from the publisher brain injuries, where microdialysis catheters are placed for surveillance of the status of the brain tissue (27,(100)(101)(102).…”

Brain Microdialysis Study of Meropenem in Two Patients with Acute Brain Injury

“…Microdialysis is a well-established technique that has been used to characterize the distribution of many drugs, including antibiotics (12), in various tissues, including brain tissue, in both animals (4) and humans. However, only very few microdialysis studies have been conducted with humans to characterize the brain distribution of exogenous compounds, either in patients requiring surgery for brain tumor resection (1,14) or in neurotrauma patients undergoing brain microdialysis for intensive-care monitoring (3,7). Not only are there limited numbers of patients potentially eligible for such studies, but also the technical difficulties requiring well-trained multidisciplinary teams limit such studies (1,3,14).…”

“…The retrodialysis-by-drug method is the most frequently used method to estimate in vivo probe recoveries in the clinical setting (6,7,13). It is preferable to the retrodialysis-by-calibrator method and to the no-net-flux method previously used for rifampin determinations in brain (14), which is only applicable after constant infusion at steady state.…”

Microdialysate concentration changes do not provide sufficient information to evaluate metabolic effects of lactate supplementation in brain-injured patients

“…However, if the microdialysis technique is utilized for scientific, quantitative measurements, it is necessary to measure continuously relative recovery. 8 …”