Disambiguating pharmacological mechanisms from placebo in neuropathic pain using functional neuroimaging.

BACKGROUND: A lack of objective outcome measures and overreliance on subjective pain reports in early proof-of-concept studies contribute to the high attrition of potentially effective new analgesics. We studied the utility of neuroimaging in providing objective evidence of neural activity related to drug modulation or a placebo effect in a double-blind, randomized, placebo-controlled, three-way crossover trial. METHODS: We chronically administered pregabalin or tramadol (first-line and second-line analgesics, respectively), recommended for neuropathic pain, in 16 post-traumatic neuropathic pain patients. We measured subjective pain reports, allodynia-evoked neural activity, and brain resting state functional connectivity from patients during the three sessions and resting state data at baseline from patients after washout of their current medication. All data were collected using a 3 T MRI scanner. RESULTS: When compared with placebo only, pregabalin significantly suppressed allodynia-evoked neural activity in several nociceptive and pain-processing areas of the brain, despite the absence of behavioural analgesia. Furthermore, placebo significantly increased functional connectivity between the rostral anterior cingulate and the brainstem, a core component of the placebo neural network. CONCLUSIONS: Functional neuroimaging provided objective evidence of pharmacodynamic efficacy in a proof-of-concept study setting where subjective pain outcome measures are often unreliable. Additionally, we provide evidence confirming the neural mechanism underpinning placebo analgesia as identified in acute experimental imaging studies in patients during the placebo arm of a clinical trial. We explore how brain penetrant active drugs potentially interact with this mechanism. CLINICAL TRIAL REGISTRATION: NCT0061015.

Hemodynamic effects during induction, laryngoscopy, and intubation with eltanolone (5 beta-pregnanolone) or propofol. A study in ASA I and II patients.

STUDY OBJECTIVE: To evaluate the cardiovascular changes following induction of anesthesia, laryngoscopy, and intubation in patients receiving a bolus dose of either eltanolone or propofol. DESIGN: Randomized, controlled, blind, prospective clinical study. SETTING: General operating theaters of a university hospital. PATIENTS: 40 ASA status I and II patients scheduled for elective surgery. INTERVENTIONS: Patients were premedicated with oral temazepam 20 mg. Anesthesia was induced with either eltanolone 0.58 mg/kg or propofol 1.7 mg/kg, neuromuscular blockade was achieved with vecuronium 0.1 mg/kg, and anesthesia was maintained with enflurane 0.5% to 1.0% in nitrous oxide (67%). MEASUREMENTS AND MAIN RESULTS: Blood pressure was measured using an automatic oscillometric technique, heart rate (HR) was derived from the ECG, oxygen saturation was measured by pulse oximetry, and cardiac output (Q) was measured by a thoracic bioimpedance technique. Induction of anesthesia with either drug, eltanolone or propofol, decreased arterial systolic (SAP) and diastolic (DAP) blood pressure, Q, and stroke volume (SV). HR increased. Systemic vascular resistance (SVR) was unaltered. After laryngoscopy and intubation, SAP and DAP increased secondary to an increase in SVR. HR also increased; SV decreased in patients receiving eltanolone. Side effects (e.g., apnea occurring for more than 30 seconds, involuntary movements, limb hypertonus) occurred at a similar incidence with both treatments, but pain following injection was greater with propofol (59% vs. 9%). CONCLUSIONS: Patients receiving either eltanolone or propofol showed similar cardiovascular changes to induction of anesthesia, although there were greater increases in arterial pressure and HR in those patients receiving eltanolone.

The influence of preload on post-systolic shortening in ischaemic myocardium.

Post-systolic shortening is a wall motion abnormality defined as shortening of cardiac muscle after the end of ejection and usually regarded as a manifestation of ischaemia. This study was designed to determine whether changes in preload may alter the magnitude of ischaemia-induced post-systolic shortening. Eleven beagles were anaesthetized (halothane 0.8%) and instrumented for measurement of pressures, flows and dimensions in the apical subendocardium supplied by the left anterior descending coronary artery. Myocardial ischaemia was obtained by tightening a micrometer-controlled snare around the left anterior descending coronary artery. Post-systolic shortening, calculated as end-systolic length minus minimum length divided by end-systolic length, was measured at different levels of preload. Increasing the preload from 4 to 17 mmHg caused a significant reduction in post-systolic shortening (8.9% vs. 12.9%, P < 0.05, Student's paired t-test); post-systolic shortening was negatively correlated with coronary perfusion pressure (r = 0.35, P < 0.01) and positively correlated with systolic bulging. This study demonstrates that the amount of post-systolic shortening depends on the volume status, which therefore has to be taken into account in interpreting regional wall motion abnormalities, such as those detected by echocardiography.

Effects of propofol and thiopentone, and benzodiazepine premedication on heart rate variability measured by spectral analysis.

We studied the effects of temazepam premedication and induction of anaesthesia with thiopentone or propofol on the heart rate power spectrum in 47 patients undergoing elective minor surgery. Eighteen patients received temazepam 20 mg orally as premedication. There was a significant reduction in high frequency power and total power, and an increase in the ratio of low to high frequency power after induction of anaesthesia with either propofol or thiopentone. Patients who had received temazepam premedication had significantly greater low frequency, high frequency and total power than those who were not premedicated. There was no significant difference between premedicated and unpremedicated patients in the ratio of low to ventilatory frequency power.

Post-ischemic diastolic dysfunction.

Though a sustained post-ischemic decrease in contractile function has been clearly established, post-ischemic diastolic function has not been thoroughly investigated. Accordingly, 11 anesthetized (isoflurane 1%) open-chest beagles were instrumented to measure left ventricular pressure and dimensions (circumferential length and wall thickness) in an apicoanterior area supplied by the left anterior descending coronary artery (LAD). Pressure-dimension relations were modified by stepwise infusion and withdrawal of 200 mL of the animals' own blood during baseline, 45 minutes partial occlusion of the LAD (systolic bulging), and 60 minutes after the onset of reperfusion. Stiffness constants were derived from the end-diastolic pressure-length and stress-strain relations, respectively. Myocardial ischemia was associated with significant (P < 0.05) alterations of the following parameters of diastolic function: (1) 47% increase in end-diastolic pressure; (2) 22% decrease in peak negative dP/dt; (3) 9% increase in the time constant of isovolumic relaxation (tau); (4) postcystolic contraction; (5) 6% increase in end-diastolic length and 10% decrease in end-diastolic thickness; (6) 12% increase in unstressed length (creep) and 13% decrease in unstressed thickness; (7) 51% increase in chamber stiffness and a 63% increase in myocardial stiffness; and (8) 40% decrease in the peak lengthening rate. After 60 minutes of reperfusion, only end-diastolic pressure and tau had returned to baseline values whereas systolic shortening fraction, postsystolic contraction, and end-diastolic and unstressed dimensions had only partially recovered. No recovery occurred in peak negative dP/dt, chamber stiffness, myocardial stiffness, and peak lengthening rate. Thus, both myocardial ischemia and reperfusion are associated with complex changes in global and regional left ventricular diastolic function.

Graded myocardial ischemia is associated with a decrease in diastolic distensibility of the remote nonischemic myocardium in the anesthetized dog.

OBJECTIVES: This study was designed to investigate the changes in regional distensibility of the ischemic segment and of a remote nonischemic segment brought about by graded myocardial ischemia. BACKGROUND: Ventricular distensibility is a major determinant of left ventricular end-diastolic pressure. The effects of graded myocardial ischemia on the regional distensibility of the ischemic area have not been studied. Moreover, there are few data on the effects of myocardial ischemia on the regional distensibility of the nonischemic myocardium. METHODS: Nine anesthetized open chest mongrel dogs were fitted with instruments to measure left ventricular pressure and circumferential length (sonomicrometry) in the ischemic segment and in a nonischemic segment. The pressure-length relation was modified by stepwise infusion and withdrawal of 200 ml of each dog's own blood over 30 min in five consecutive stages of regional ischemia. Unstressed dimensions were obtained by repeated inferior vena cava occlusions. In both segments, regional distensibility was assessed at end-diastole by means of the constants of the pressure-length (chamber stiffness), the pressure-strain and the force-strain (myocardial stiffness) relations. RESULTS: In the ischemic segment, partial and complete coronary occlusions were associated with a twofold increase in the chamber stiffness constant, the pressure-strain constant and the myocardial stiffness constant, whereas in the nonischemic segment the chamber stiffness constant, the pressure-strain constant and the myocardial stiffness constant increased by 50%. CONCLUSIONS: Regional myocardial ischemia is associated with a decrease in distensibility of both the ischemic and the remote nonischemic myocardium.