Publications by Year: 2011


Mogil JS, Rice FL, Brennan TJ, et al. Secure Sign In. Curr. Pharm. Biotechnol. 2011.
Sam WJ, Mackey SC, Lötsch J, Drover DR. Morphine and its metabolites after patient-controlled analgesia: considerations for respiratory depression. J. Clin. Anesth. 2011;23(2):102-106.
STUDY OBJECTIVE: To assess concentrations of morphine and its metabolites after patient-controlled analgesia (PCA). DESIGN: Pilot pharmacokinetic study of morphine and pharmacokinetic simulation. SETTING: Post-anesthesia care room and ward of an academic teaching hospital. PATIENTS: 10 ASA physical status I, II, and III postoperative surgical patients. INTERVENTIONS: Patients received morphine via PCA by routine hospital protocols. MEASUREMENTS: The population mean plasma and effect-site concentrations of morphine, morphine-6-glucuronide (M6G), and morphine-3-glucuronide (M3G) was simulated in 4 patient group scenarios: morphine PCA used alone, morphine PCA used with continuous background morphine infusion of 0.5 mg/hr, morphine PCA used with continuous background morphine infusion of 1.0 mg/hr, and morphine PCA used with continuous background morphine infusion of 2.0 mg/hr. MAIN RESULTS: The 4 groups exhibited simulated peak morphine, M6G, and M3G effect-site concentrations at 8 to 24 hours post-infusion. The highest peak morphine, M6G, and M3G effect-site concentrations decreased in the following order by group: 2.0 mg/hr morphine infusion + PCA group, 1.0 mg/hr morphine infusion + PCA group, and 0.5. mg/hr morphine infusion + PCA group. CONCLUSIONS: Patients receiving morphine PCA should be monitored closely from 8 to 24 hours postoperatively. Morphine PCA given with background infusion rates up to 1.0 mg/hr does not offer distinct pharmacokinetic advantages over morphine PCA alone. Morphine PCA with background infusion rate of 2.0 mg/hr is associated with the greatest risk of respiratory depression.
Younger JW, Chu LF, Arcy NTD, Trott KE, Jastrzab LE, Mackey SC. Prescription opioid analgesics rapidly change the human brain. Pain. 2011;152(8):1803-1810.
Chronic opioid exposure is known to produce neuroplastic changes in animals; however, it is not known if opioids used over short periods of time and at analgesic dosages can similarly change brain structure in humans. In this longitudinal, magnetic resonance imaging study, 10 individuals with chronic low back pain were administered oral morphine daily for 1 month. High-resolution anatomical images of the brain were acquired immediately before and after the morphine administration period. Regional changes in gray matter volume were assessed on the whole brain using tensor-based morphometry, and those significant regional changes were then independently tested for correlation with morphine dosage. Thirteen regions evidenced significant volumetric change, and degree of change in several of the regions was correlated with morphine dosage. Dosage-correlated volumetric decrease was observed primarily in the right amygdala. Dosage-correlated volumetric increase was seen in the right hypothalamus, left inferior frontal gyrus, right ventral posterior cingulate, and right caudal pons. Follow-up scans that were conducted an average of 4.7 months after cessation of opioids demonstrated many of the morphine-induced changes to be persistent. In a separate study, 9 individuals consuming blinded placebo capsules for 6 weeks evidenced no significant morphologic changes over time. The results add to a growing body of literature showing that opioid exposure causes structural and functional changes in reward- and affect-processing circuitry. Morphologic changes occur rapidly in humans during new exposure to prescription opioid analgesics. Further research is needed to determine the clinical impact of those opioid-induced gray matter changes.
Pain often exists in the absence of observable injury; therefore, the gold standard for pain assessment has long been self-report. Because the inability to verbally communicate can prevent effective pain management, research efforts have focused on the development of a tool that accurately assesses pain without depending on self-report. Those previous efforts have not proven successful at substituting self-report with a clinically valid, physiology-based measure of pain. Recent neuroimaging data suggest that functional magnetic resonance imaging (fMRI) and support vector machine (SVM) learning can be jointly used to accurately assess cognitive states. Therefore, we hypothesized that an SVM trained on fMRI data can assess pain in the absence of self-report. In fMRI experiments, 24 individuals were presented painful and nonpainful thermal stimuli. Using eight individuals, we trained a linear SVM to distinguish these stimuli using whole-brain patterns of activity. We assessed the performance of this trained SVM model by testing it on 16 individuals whose data were not used for training. The whole-brain SVM was 81% accurate at distinguishing painful from non-painful stimuli (p\textless0.0000001). Using distance from the SVM hyperplane as a confidence measure, accuracy was further increased to 84%, albeit at the expense of excluding 15% of the stimuli that were the most difficult to classify. Overall performance of the SVM was primarily affected by activity in pain-processing regions of the brain including the primary somatosensory cortex, secondary somatosensory cortex, insular cortex, primary motor cortex, and cingulate cortex. Region of interest (ROI) analyses revealed that whole-brain patterns of activity led to more accurate classification than localized activity from individual brain regions. Our findings demonstrate that fMRI with SVM learning can assess pain without requiring any communication from the person being tested. We outline tasks that should be completed to advance this approach toward use in clinical settings.
Carroll I, Fischbein N, Barad M, Mackey S. Human response to unintended intrathecal injection of botulinum toxin. Pain Med. 2011;12(7):1094-1097.
OBJECTIVE: Describe the first reported human intrathecal (IT) botulinum toxin injection. DESIGN: Case report. SETTING AND PATIENTS: We report here the sequelae to an unintended IT injection of botulinum toxin type B (BTB) in a 60-year-old woman with chronic back pain. RESULTS: Following the IT administration of BTB, the patient experienced the onset of symmetric ascending stocking distribution painful dysesthesias, which persisted for approximately 6 months before receding. Objective neurologic deficits were not appreciated, and analgesic effects were prominently absent. CONCLUSIONS: Analgesic actions of botulinum toxins in animals and in humans have led to speculation that IT botulinum toxin might exert significant analgesic effects. The unusual and unexpected subsequent clinical course, neurologic sequelae, dysesthesias, and absence of analgesia suggest that botulinum toxin will not be a therapeutic modality to treat pain as proposed by those studying botulinum toxin in animal models.