Surgery-induced inflammation reduces morphine distribution into cerebrospinal fluid

Abstract

Background: Inflammation-induced alterations in drug disposition during inflammatory conditions such as infection and surgery are common and may lead to altered drug responses and/or toxicities. Animal studies have shown that inflammation alters drug disposition into the brain, which has been attributed to regulatory effects of proinflammatory cytokines on blood-brain barrier drug efflux transporters, such as the ATP-binding cassette transporter P-glycoprotein. It is not known if such cytokine-blood-brain barrier drug transporter interactions occur and are important in humans. Objective: To advance knowledge in this area by investigating the effects of inflammation on drug distribution across the blood-brain barrier in humans. Specifically, the goal was to determine the effects of surgery-induced inflammation on morphine distribution across the blood-brain barrier. Methods: Patients undergoing elective aortic surgery that received morphine in their standard treatment were divided in two groups: cardiopulmonary bypass, CPB (n = 18) and non-CPB (n = 18) group, based on the surgery they received. Blood and cerebrospinal (CSF) samples were collected before, during and after the surgery. Plasma and CSF morphine, morphine-3 and morphine-6 glucuronide concentrations were determined by mass-spectrometry. Cytokines were quantified with Q-plex multiplex ELISA to characterize the surgical inflammatory response and albumin was measured in both plasma and CSF samples as a marker of passive blood-brain barrier permeability. Results: The plasma Cmax and area under the curve from 0 to 24 h (AUC0-24h) of interleukin-6 (IL-6), a known regulator of blood-brain barrier drug transporters were higher (P < 0.05) in the CPB group (1045 ± 1421 pg/ml and 9299 ± 12940 pg/ml*h) than in the non-bypass group (162.0 ± 135.4 pg/ml and 2069 ± 2053 pg/ml*h) indicating that individuals receiving CPB had a more robust systemic inflammatory response. The CSF/plasma morphine AUC0-24h ratio was significantly lower in the CPB than in non-CPB groups (1.09 ± 0.52 and 2.65 ± 1.97, respectively). Albumin CSF/Plasma ratio was increased in the CPB group following surgery, indicating possible increase of blood-brain barrier permeability. Conclusion: CSF morphine exposure is lower in individuals undergoing aortic aneurysm with CPB. This effect may be due to IL-6-mediated changes in blood-brain barrier drug uptake or efflux transporter function and may be one explanation for altered drug effect in the critically ill patient. Implications: Altered drug disposition can cause adverse drug reactions (ADRs), which will lead to higher mortality, prolonged hospitalization and increased medical costs. Patients with cardiovascular diseases are particularly at high risk of ADRs and opioid analgesics are frequently associated with ADRs. By studying patients receiving cardiac surgeries and morphine, we have obtained a better understanding of morphine’s distribution across blood-brain barrier under inflammatory conditions, which may help reduce ADRs in future clinical practice.