Lesion-Constrained Electrical Source Imaging: A Novel Approach in Epilepsy Surgery for Tuberous Sclerosis Complex.

PURPOSE: Electrical source imaging may yield ambiguous results in multilesional epilepsy. The aim of this study was to test the clinical utility of lesion-constrained electrical source imaging in epilepsy surgery in children with tuberous sclerosis complex. METHODS: Lesion-constrained electrical source imaging is a novel method based on a proposed head model in which the source solution is constrained to lesions. Using a goodness of fit analysis, we rank-ordered individual tubers by their ability to approximate interictal and ictal EEG data. The overlap with the surgical resection cavity was determined qualitatively, and placed findings in the context of epilepsy surgical outcome, and compared with the low-resolution brain electromagnetic tomography solution. RESULTS: Low-resolution brain electromagnetic tomography predicted the surgical cavity in only one patient with good outcome (true positive) and localized to outside of the cavity in two patients with a good outcome (false negative). In one patient with a poor outcome, the interictal low-resolution brain electromagnetic tomography solution overlapped with the cavity (false positive). Lesion-constrained electrical source imaging of ictal EEG data identified tubers concordant with the resection zone in three patients with a good surgical outcome (true positive) and appropriately discordant in three other patients with a poor outcome (true negative). CONCLUSIONS: Lesion-constrained electrical source imaging on low-resolution EEG data provides complementary information in the presurgical workup for patients with tuberous sclerosis complex, although further validation is required. In the appropriate clinical context, the yield of source localization on low-resolution EEG data may be increased by reduction of the solution space.

Analgesic and Respiratory Depressant Effects of R-dihydroetorphine: A Pharmacokinetic-Pharmacodynamic Analysis in Healthy Male Volunteers.

BACKGROUND: There is an ongoing need for potent opioids with less adverse effects than commonly used opioids. R-dihydroetorphine is a full opioid receptor agonist with relatively high affinity at the µ-, δ- and κ-opioid receptors and low affinity at the nociception/orphanin FQ receptor. The authors quantified its antinociceptive and respiratory effects in healthy volunteers. The authors hypothesized that given its receptor profile, R-dihydroetorphine will exhibit an apparent plateau in respiratory depression, but not in antinociception. METHODS: The authors performed a population pharmacokinetic-pharmacodynamic study (Eudract registration No. 2009-010880-17). Four intravenous R-dihydroetorphine doses were studied: 12.5, 75, 125, and 150 ng/kg (infused more than 10 min) in 4 of 4, 6 of 6, 6 of 6, and 4 of 4 male subjects in pain and respiratory studies, respectively. The authors measured isohypercapnic ventilation, pain threshold, and tolerance responses to electrical noxious stimulation and arterial blood samples for pharmacokinetic analysis. RESULTS: R-dihydroetorphine displayed a dose-dependent increase in peak plasma concentrations at the end of the infusion. Concentration-effect relationships differed significantly between endpoints. R-dihydroetorphine produced respiratory depression best described by a sigmoid EMAX-model. A 50% reduction in ventilation in between baseline and minimum ventilation was observed at an R-dihydroetorphine concentration of 17 ± 4 pg/ml (median ± standard error of the estimate). The maximum reduction in ventilation observed was at 33% of baseline. In contrast, over the dose range studied, R-dihydroetorphine produced dose-dependent analgesia best described by a linear model. A 50% increase in stimulus intensity was observed at 34 ± 11 pg/ml. CONCLUSIONS: Over the dose range studied, R-dihydroetorphine exhibited a plateau in respiratory depression, but not in analgesia. Whether these experimental advantages extrapolate to the clinical setting and whether analgesia has no plateau at higher concentrations than investigated requires further studies.

Respiratory Effects of the Nociceptin/Orphanin FQ Peptide and Opioid Receptor Agonist, Cebranopadol, in Healthy Human Volunteers.

BACKGROUND: Cebranopadol is a novel strong analgesic that coactivates the nociceptin/orphanin FQ receptor and classical opioid receptors. There are indications that activation of the nociceptin/orphanin FQ receptor is related to ceiling in respiratory depression. In this phase 1 clinical trial, we performed a pharmacokinetic-pharmacodynamic study to quantify cebranopadol's respiratory effects. METHODS: Twelve healthy male volunteers received 600 µg oral cebranopadol as a single dose. The following main endpoints were obtained at regular time intervals for 10 to 11 h after drug intake: ventilation at an elevated clamped end-tidal pressure of carbon dioxide, pain threshold and tolerance to a transcutaneous electrical stimulus train, and plasma cebranopadol concentrations. The data were analyzed using sigmoid Emax (respiration) and power (antinociception) models. RESULTS: Cebranopadol displayed typical opioid-like effects including miosis, analgesia, and respiratory depression. The blood-effect-site equilibration half-life for respiratory depression and analgesia was 1.2 ± 0.4 h (median ± standard error of the estimate) and 8.1 ± 2.5 h, respectively. The effect-site concentration causing 50% respiratory depression was 62 ± 4 pg/ml; the effect-site concentration causing 25% increase in currents to obtain pain threshold and tolerance was 97 ± 29 pg/ml. The model estimate for minimum ventilation was greater than zero at 4.9 ± 0.7 l/min (95% CI, 3.5 to 6.6 l/min). CONCLUSIONS: At the dose tested, cebranopadol produced respiratory depression with an estimate for minimum ventilation greater than 0 l/min. This is a major advantage over full µ-opioid receptor agonists that will produce apnea at high concentrations. Further clinical studies are needed to assess whether such behavior persists at higher doses.

Erythropoietin does not have effects on the ventilatory and pulmonary vascular response to acute hypoxia in men and women.

NEW FINDINGS: What is the central question of this study? Does a clinically relevant intravenous dose of erythropoeitin affect the hypoxic ventilatory response and/or hypoxic pulmonary vasoconstriction in healthy humans? What is the main finding and its importance? Erythropoeitin does not influence the ventilatory and pulmonary vascular responses to acute hypoxia in men or women. Sustained and chronic hypoxia lead to an increase in pulmonary ventilation (hypoxic ventilatory response, HVR) and to an increase in pulmonary vascular resistance (hypoxic pulmonary vasoconstriction, HPV). In this study, we examined the effect of a clinical i.v. dose of recombinant human erythropoietin (50 IU kg-1 ) on the isocapnic HVR and HPV in seven male and seven female subjects by exposing them to hypoxia for 20 min (end-tidal PO2  âˆ¼50 mmHg) while measuring their ventilation and estimating pulmonary arterial pressure from the maximal velocity of the regurgitant jet over the tricuspid valve during systole (ΔPmax ) with echocardiography. In the placebo session, after 5 and 20 min men responded with an increase in ventilation by 0.0056 and 0.0023 l min-1  kg-1   %SpO2-1 , respectively, indicating the presence of hypoxic ventilatory depression. In women, the increase in ventilation was 0.0067 and 0.0047 l min-1  kg-1   %SpO2-1 , respectively. In both sexes, erythropoietin did not alter these responses significantly. In the placebo session, mean ΔPmax increased by 6.1 ± 0.7 mmHg in men (P = 0.035) and by 8.4 ± 1.4 mmHg in women (P = 0.020) during the hypoxic exposure, whereby women had a âˆ¼5 mmHg lower end-tidal PCO2 . Erythropoietin did not alter these responses; in men, ΔPmax increased by 7.5 ± 1.1 mmHg (n.s. versus placebo) and in women by 9.7 ± 2.2 mmHg (n.s. versus placebo). We conclude that women tended to have a greater HPV in placebo conditions and that a clinical dose of erythropoietin has no effect on the HVR and HPV in either sex.

Fentanyl utility function: a risk-benefit composite of pain relief and breathing responses.

INTRODUCTION: Integrating opioid risk and benefit into a single function may give a useful single measure of the opioid's positive and negative effects. An explorative study on the effects of fentanyl on antinociception and respiratory depression was performed to construct fentanyl risk-benefit (utility) functions. METHODS: Twelve volunteers received a 3.5-µg/kg fentanyl intravenous injection on 2 separate study days. On one occasion, ventilation at a clamped increased carbon dioxide concentration was measured and on another the pain tolerance to electrical stimulation. In both sessions, arterial plasma samples were obtained. The data were analyzed with a population pharmacokinetic-pharmacodynamic model. A simulation study was performed, using the model parameter estimates and their variances, in which simulated subjects received 3.5 µg/kg of fentanyl. The resultant distributions were used to calculate the utility functions, defined as the probability of at least 50% analgesia (an increase in pain tolerance by ≥50%) minus the probability of at least 50% respiratory depression (a reduction in ventilation by ≥50%). Utility functions were constructed in concentration and time domains. RESULTS: Fentanyl produced significant respiratory depression and analgesia. The pharmacokinetic and pharmacodynamic models adequately described the data. The constructed utility functions were negative at effect-site concentrations of greater than 0.5 ng/ml in the first 90 min after the 3.5 µg/kg bolus infusion. CONCLUSIONS: Utility functions based on fentanyl's experimental effects on respiration and pain relief were successfully constructed. These functions are useful in multiple effect comparisons among experimental drugs. Further studies are required to assess whether this risk-benefit analysis is valuable in clinical practice.

Non-analgesic effects of opioids: opioid-induced respiratory depression.

Opioids induce respiratory depression via activation of µ-opioid receptors at specific sites in the central nervous system including the pre-Bötzinger complex, a respiratory rhythm generating area in the pons. Full opioid agonists like morphine and fentanyl affect breathing with onset and offset profiles that are primarily determined by opioid transfer to the receptor site, while the effects of partial opioid agonists such as buprenorphine are governed by transfer to the receptor site together with receptor kinetics, in particular dissociation kinetics. Opioid-induced respiratory depression is potentially fatal but may be reversed by the opioid receptor antagonist naloxone, an agent with a short elimination half-life (30 min). The rate-limiting factor in naloxone-reversal of opioid effect is the receptor kinetics of the opioid agonists that requires reversal. Agents with slow dissociation kinetics (buprenorphine) require a continuous naloxone infusion while agents with rapid kinetics (fentanyl) will show complete reversal upon a single naloxone dose. Since naloxone is non-selective and will reverse analgesia as well, efforts are focused on the development of compounds that reverse opioid-induced respiratory depression without affecting analgesic efficacy. Such agents include ampakines and serotonin agonists which are aimed at selectively enhancing central respiratory drive. A novel approach is aimed at the reduction of respiratory depression from opioid-activation of (micro-)glia cells in the pons and brainstem using micro-glia cell stabilizers. Since this approach simultaneously enhances opioid analgesic efficacy it seems an attractive alternative to the classical reversal strategies with naloxone.

Modeling the non-steady state respiratory effects of remifentanil in awake and propofol-sedated healthy volunteers.

BACKGROUND: Few studies address the dynamic effect of opioids on respiration. Models with intact feedback control of carbon dioxide on ventilation (non-steady-state models) that correctly incorporate the complex interaction among drug concentration, end-tidal partial pressure of carbon dioxide concentration, and ventilation yield reliable descriptions and predictions of the behavior of opioids. The authors measured the effect of remifentanil on respiration and developed a model of remifentanil-induced respiratory depression. METHODS: Ten male healthy volunteers received remifentanil infusions with different infusion speeds (target concentrations: 4-9 ng/ml; at infusion rates: 0.17-9 ng x ml x min) while awake and at the background of low-dose propofol. The data were analyzed with a nonlinear model consisting of two additive linear parts, one describing the depressant effect of remifentanil and the other describing the stimulatory effect of carbon dioxide on ventilation. RESULTS: The model adequately described the data including the occurrence of apnea. Most important model parameters were as follows: C50 for respiratory depression 1.6 +/- 0.03 ng/ml, gain of the respiratory controller (G) 0.42 - 0.1 l x min x Torr, and remifentanil blood effect site equilibration half-life (t(1/2)ke0) 0.53 +/- 0.2 min. Propofol caused a 20-50% reduction of C50 and G but had no effect on t(1/2)ke0. Apnea occurred during propofol infusion only. A simulation study revealed an increase in apnea duration at infusion speeds of 2.5-0.5 ng x ml x min followed by a reduction. At an infusion speed of < or = 0.31 ng x ml x min, no apnea was seen. CONCLUSIONS: The effect of varying remifentanil infusions with and without a background of low-dose propofol on ventilation and end-tidal partial pressure of carbon dioxide concentration was described successfully using a non-steady-state model of the ventilatory control system. The model allows meaningful simulations and predictions.

Opioid chronopharmacology: influence of timing of infusion on fentanyl's analgesic efficacy in healthy human volunteers.

Chronopharmacology studies the effect of the timing of drug administration on drug effect. Here, we measured the influence of 4 timing moments on fentanyl-induced antinociception in healthy volunteers. Eight subjects received 2.1 µg/kg intravenous fentanyl at 2 pm and 2 am, with at least 2 weeks between occasions, and 8 others at 8 am and 8 pm. Heat pain measurements using a thermode placed on the skin were taken at regular intervals for 3 hours, and verbal analog scores (VAS) were then obtained. The data were modeled with a sinusoid function using the statistical package NONMEM. The study was registered at trialregister.nl under number NTR1254. A significant circadian sinusoidal rhythm in the antinociceptive effect of fentanyl was observed. Variations were observed for peak analgesic effect, duration of effect, and the occurrence of hyperalgesia. A peak in pain relief occurred late in the afternoon (5:30 pm) and a trough in the early morning hours (5:30 am). The difference between the peak and trough in pain relief corresponds to a difference in VAS of 1.3-2 cm. Only when given at 2 am, did fentanyl cause a small but significant period of hyperalgesia following analgesia. No significant changes were observed for baseline pain, sedation, or the increase in end-tidal CO(2). The variations in fentanyl's antinociceptive behavior are well explained by a chronopharmacodynamic effect originating at the circadian clock in the hypothalamus. This may be a direct effect through shared pathways of the circadian and opioid systems or an indirect effect via diurnal variations in hormones or endogenous opioid peptides that rhythmically change the pain response and/or analgesic response to fentanyl.