Clinical Trial: Problems With Morphine Use in Patients With a Severe Brain Injury
Study Status: Completed
Recruit Status: Unknown status
Study Type: Interventional
Official Title: Changes in Morphine Handling and Response in Patients With Brain Trauma
Brief Summary: Hypothesis: During severe brain trauma (injury, surgery) the ensuing inflammatory response in the central nervous system (CNS) results in a decrease in the expression of the transporter protein p-glycoprotein (PGP) in the blood brain barrier. This loss results in the penetration into the brain of certain drugs that are normally excluded by the transporter protein. In this study the working hypothesis is that the agitation observed in patients with CNS trauma treated with morphine is related to the inflammation evoked loss of PGP in the blood brain barrier and the accumulation of the morphine metabolite 3-morphine glucuronide.
Detailed Summary:
It is well established that the metabolism, distribution and elimination of certain drugs is affected by inflammatory processes. This results from the expression of cytochrome and drug transporter proteins that are altered during the generation of host defense mechanisms. This has major implications in inflammation and infection when the capacity of the liver and other organs to handle drugs are severely compromised. From studies in animals individual cytochrome P450 isozymes and p-glycoprotein (PGP) are down regulated at the level of gene transcription with a resulting decrease in the corresponding mRNA, protein and enzyme/transporter activity. The loss in drug metabolism and transport is channeled predominantly through the production of cytokines which ultimately modify specific transcription factors. Other proposed mechanisms that apply to specific cytochrome P450s involve post translational steps including enzyme modification and increased degradation. When inflammatory responses are confined to the brain there is a loss of cytochrome P450 and PGP not only in the brain but also in peripheral tissues. This involves a yet to be identified mode of signaling between the brain and periphery but it does involve the production of cytokines from a peripheral source.
In clinical medicine there are numerous examples of a decreased capacity to handle drugs during infections and disease states that involve an inflammatory component. This often results in altered drug responses and increased toxicities. Inflammation mediated alterations in the metabolism of endogenous compounds can also lead to altered physiology. Recently it has been shown in rodents that inflammatory responses within the brain alter drug disposition in the brain and in peripheral systems. Of particular note to the use of drugs in patients with a brain trauma is a recent study in our laboratory carried out in rod
Sponsor: Dalhousie University
Current Primary Outcome: see the ratios of cerebrospinal fluid (CSF)/blood increase with time as the inflammation progresses [ Time Frame: prospective ]
Original Primary Outcome: see the ratios of CSF/blood increase with time as the inflammation progresses
Current Secondary Outcome: ratios of morphine and its metabolites in CSF and blood with the RASS will determine if observed CNS stimulation occurs at a time when the levels of 3-morphine glucuronide is high on the brain side of the blood brain barrier [ Time Frame: prospective ]
Original Secondary Outcome: ratios of morphine and its metobolites in CSF and blood with the RASS will determine if observed CNS stimulation occurs at a time when the levels of 3-morphine glucuronide is high on the brain side of the blood brain barrier
Information By: Dalhousie University
Dates:
Date Received: September 12, 2005
Date Started: January 2005
Date Completion: April 2008
Last Updated: April 8, 2008
Last Verified: September 2006
