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Topical application of lidocaine is an effective approach for treatment of post-herpetic neuralgia and other painful neuropathies. Lidocaine inhibits voltage-gated Na(+) channels and it most likely reduces excitability of cutaneous sensory neurons which can be hyperexcitable or spontaneously active in states of neuropathic pain. However, lidocaine and other local anesthetics also exert a pronounced neurotoxicity and they activate the irritant receptors TRPV1 and TRPA1. In this randomized and double-blinded study, we explored the ability of lidocaine patches (5%) to alter sensory function and epidermal nerve fiber density in skin of healthy volunteers. As assessed by quantitative sensory testing, significantly elevated thresholds for touch, pin prick pain and mechanically induced wind-up were observed in skin treated with lidocaine patches. These effects reversed to baseline values within 2days after termination of the treatment. Pressure pain and thresholds for heat and cold-induced pain were not affected by the lidocaine patch. A moderate but significant decrease in epidermal nerve fiber density was observed in skin blister roofs obtained after 42days of treatment with lidocaine patches. The placebo patch did not induce any changes in sensory thresholds or nerve fiber density. In conclusion, lidocaine patches seem to have differential effects on sensory modalities in healthy skin. A degeneration of epidermal nerve fibers has previously been demonstrated for patches containing the TRPV1-agonist capsaicin and our findings suggest that this effect might also be relevant for lidocaine patches. These data warrant further studies on molecular mechanisms mediating a relief of neuropathic pain by topical lidocaine. [ABSTRACT FROM AUTHOR]

The orofacial formalin test is established in rats and was recently transferred to mice. The aim of this study was to determine the ideal formalin concentration for testing analgesic drugs, to examine alternatives for the assessment of nociceptive and non-nociceptive behavior as well as the effects of morphine and age on formalin-induced nociception. Formalin (.5, 1, 2.5, 5, 7.5, 10, and 15%) was injected into the vibrissa of mice. The cumulative nociceptive behavior was measured as well as nociceptive and non-nociceptive behavior based on a score that was recorded over a 5-second observation period once per minute. We also examined the effects of morphine on the nociceptive response induced by 2.5% formalin. Age-dependent differences were tested in the third part of the experiment. NONMEM was used to model the pharmacodynamic effects of formalin and morphine. Injection of formalin lead to a concentration-dependent increase in cumulative nociceptive behavior ratings as well as the specific nociceptive behavior 3 of scratching injection site with hindpaw (score 3). The formalin concentrations that lead to 50% of the maximum effect were 2.6 and 3.3%, respectively, for the continuous rating method and the scoring method. Morphine dose dependently suppressed the nociceptive behavior and the number of score 3 ratings of the nociceptive behavior. Age differences in behavior could not be detected by either analytic method. PERSPECTIVE: To improve the existing behavioral nociceptive assay for pain processed by the trigeminal system, we determined an ideal formalin concentration for the orofacial formalin test in mice, evaluated alternative timesaving analysis approaches, and investigated effects of morphine and age on formalin-induced nociception. [ABSTRACT FROM AUTHOR]

Background and Objective: Studies with rocuronium showed a delayed onset and prolonged recovery in patients with Duchenne muscular dystrophy (DMD). The objective of this study was to identify the pharmacokinetic and/or pharmacodynamic origin of these alterations.Methods: Twenty-five male patients (15 with DMD, 10 controls, aged 10-18 years) were studied. Patients were anaesthetized with propofol and sufentanil. Neuromuscular transmission was monitored by acceleromyography. Patients received a single intravenous dose of 0.3 mg kg(-1) rocuronium. In five patients of the DMD group, pharmacokinetic modelling was performed from arterial rocuronium concentrations. The time course of neuromuscular block was analysed with a sigmoid E(max) model including an effect compartment.Results: The pharmacokinetics of rocuronium in DMD patients were Vc 63 +/- 14 ml kg(-1), Cl 3.0 +/- 1.0 ml min(-1) kg(-1), half-lives 2.0 +/- 0.6, 20 +/- 10 and 129 +/- 98 min, SE. For both the DMD and the control group, the time course of neuromuscular block could be described by a sigmoid E(max) model using the estimated pharmacokinetic parameters of the DMD group. In patients with DMD, the equilibration between the central and effect compartment was significantly slower (T(1/2)ke0: 9.7 +/- 0.3 vs. 1.3 +/- 0.1 min) and the EC(50) was significantly smaller (512 +/- 20 vs. 1170 +/- 64 ng ml(-1)), whereas the ED(50) was 0.16 +/- 0.02 mg kg(-1) in both groups.Conclusion: The pharmacodynamics of rocuronium were significantly altered in patients with DMD, whereas the pharmacokinetics seemed to be similar to those in healthy adults. Patients with DMD were more sensitive with respect to effect site concentration but not with respect to dose. [ABSTRACT FROM AUTHOR]

BACKGROUND: The authors investigated the suitability of different electroencephalographic parameters to quantify the anesthetic effect of desflurane, isoflurane, and sevoflurane in rats. METHODS: Ten male Sprague-Dawley rats were anesthetized in a randomized crossover design with maximum values of 11% desflurane, 2.1% isoflurane, and 3.5% sevoflurane. The electroencephalogram was recorded with implanted electrodes and a wireless telemetry system. Concentration-effect relations and signal-to-noise ratios were determined for the approximate entropy and for the median frequency and the spectral edge frequency, which were modified to account for spikes and burst suppression. The prediction probability Pk with respect to the response to a painful stimulus was determined. RESULTS: All drugs produced deep anesthesia with burst suppression and no response at the highest concentrations. The occurrence of spikes and burst suppression made a modification of median frequency and spectral edge frequency necessary to obtain Pk values greater than 0.5 and monotonic sigmoid concentration-effect relations. The Pk values were between 0.89 and 0.98, with significantly higher values for modified median frequency and spectral edge frequency during desflurane and sevoflurane. The signal-to-noise ratios were between 3.0 and 6.4 dB, with significantly better values for modified spectral edge frequency and approximate entropy during sevoflurane. CONCLUSIONS: If modified for spikes and burst suppression, median frequency and spectral edge frequency as well as the unmodified approximate entropy were able to assess the anesthetic effect of desflurane, isoflurane, and sevoflurane in rats. For sevoflurane, the modified spectral edge frequency was best with regard to signal-to-noise ratio and prediction probability. [ABSTRACT FROM AUTHOR]

Unlabelled: During the last five years several authors have reported largely satisfactory results, using the steroid intravenous anaesthetic eltanolone (pregnanolone) for induction of anaesthesia after administering a bolus dose. Until now, however, no investigations have been undertaken, dealing with the infusion pharmacokinetics of eltanolone after arterial blood sampling and using slow induction to quantify the concentration-effect relationship. Secondary objectives were to assess the haemodynamic and respiratory effects.Material and Methods: Eltanolone emulsion was administered to 12 healthy male volunteers using a computer-controlled infusion device. Linearly increasing serum concentrations were generated for two consecutive times with an anticipated slope of 0.075 microgram ml-1 min-1 and with a targeted concentration of 2 micrograms ml-1. During and following the infusion, EEG was recorded and clinical signs were assessed as measure of the hypnotic effect. Thus, the time intervals from start of infusion until the volunteers fell asleep, until they did no longer respond to loud verbal commands, until loss of the corneal reflex and until the appearance of burst suppression patterns in the EEG were recorded. The latter sign was used as endpoint for the infusion. After the cessation of the infusion the time intervals until the disappearance of burst suppression and the reappearance of the clinical signs were recorded until full orientation was regained. Arterial blood samples were frequently drawn up to 720 min following the cessation of the last infusion cycle. Eltanolone serum concentrations were measured by a specific GC-MS assay. Pharmacokinetics were analysed with NONMEM by an open three compartment model. The serum concentrations were correlated with the corresponding clinical signs to quantify the concentration-effect relationship. Blood pressure, heart rate and oxygen saturation were measured continuously and the arterial pCO2 was analysed every 6 min.Results: The model-dependent pharmacokinetic parameters of eltanolone were characterized by a high total clearance (1.75 +/- 0.22 l min-1), small volumes of distribution (Vc = 7.7 +/- 3.4 l; Vdss = 92 +/- 22 l and relatively short half-lives (t1/2 alpha = 1.5 +/- 0.6 min; t1/2 beta = 27 +/- 5 min; t1/2 gamma = 184 +/- 32 min). (Table 2). The clinical signs revealed a good hypnotic effect, resulting in burst suppression periods in the EEG after 19 min during the first and 15 min during the second infusion cycle. The slow induction enabled a thorough observation of the induction phase. During the first infusion cycle cessation of counting occurred after 7.7 +/- 1.3 min (mean +/- SD), reaction to verbal contact was lost after 10.4 +/- 1.3 min and the corneal reflex was lost only in about one half of the volunteers after 17.9 +/- 2.8. During recovery, the corneal reflex reappeared 9.4 +/- 2.4 min after stop of infusion, first reactions to loud verbal commands were recorded after 24.2 +/- 4.3 min and full orientation was regained after 34.7 +/- 6.2 min. During the second cycle all signs disappeared faster and were regained later. The correlation between clinical signs and corresponding serum concentrations revealed, that in both cycles the disappearance occurred at clearly higher concentrations than the reappearance. The decrease of the systolic arterial pressure showed a maximum of 31% compared to the baseline values, which was statistically significant (P < 0.05). Diastolic arterial blood pressure decreased of about 10%, while heart rate increased significantly of about 24% (P < 0.05). Oxygen saturation remained stable with values between 96 and 100% with the exception of one volunteer. Apnoea was not recorded during the entire observation period. The median value of all pCO2 analyses was 41 mmHg with a range of 25-60 mmHg. The only serious undesirable effect was a seizure during awakening in one volunteer which coincided with polyspike waves in his raw-EEG recordings. (ABSTRACT TR [ABSTRACT FROM AUTHOR]

The long-term stability of drug concentrations in human plasma samples when stored under normal laboratory conditions over several years is important for research purposes and clinical re-evaluation, but also for forensic toxicology. Fifty human plasma samples from a former clinical trial were re-analyzed after storage at -20°C for 11 years. Plasma samples were extracted using solid-phase extraction. Isotope labelled sufentanil-D5 was used as internal standard. Sufentanil plasma concentrations were determined by ultra-performance liquid chromatography (UPLC) with gradient elution, followed by tandem mass spectrometry with electrospray ionization. The linear dynamic range (LDR) was 25 - 2500 pg/mL, the limit of detection was 10 pg/mL, and the lower limit of quantification was 25 pg/mL. Intra- and inter-assay error did not exceed 6%. The deviation of the measured sufentanil plasma concentrations between the reanalysis and the first analysis was -63 ± 14% (mean ± SD). Therefore, sufentanil concentrations in human plasma were not stable in samples frozen at -20°C over 11 years., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Background: The pharmacokinetic properties of the new benzodiazepine remimazolam have been studied only in adults. We investigated the pharmacokinetics of remimazolam after i.v. infusion in anaesthetised paediatric patients., Methods: Twenty-four children (2-6 yr, ASA physical status 1-2, BMI 15-18 kg m -2 ) undergoing general anaesthesia with sevoflurane were enrolled. During surgery, remimazolam was administered as an i.v. infusion over 1 h at 5 mg kg -1 h -1 for 5 min, followed by 1.5 mg kg -1 h -1 for 55 min. Plasma concentrations of remimazolam and its metabolite CNS7054 were determined from arterial blood samples using ultra-high performance liquid chromatography-mass spectrometry. Pharmacokinetic modelling was performed by population analysis., Results: Pharmacokinetics were best described by a three-compartment model for remimazolam and a two-compartment model for CNS7054 linked by a transit compartment. Remimazolam showed a high clearance of 15.9 (12.9, 18.2) ml kg -1 min -1 (median, Q 25 , Q 75 ), a small central volume of distribution of 0.11 (0.08, 0.14) L kg -1 and a short terminal half-life of 67 (49, 85) min. The context-sensitive half-time after an infusion of 4 h was 17 (12, 21) min. The metabolite CNS7054 showed a low clearance of 0.89 (0.33, 1.40) ml kg -1 min -1 , a small central volume of distribution of 0.011 (0.005, 0.016) L kg -1 , and a long terminal half-life of 321 (230, 770) min., Conclusions: Remimazolam in children was characterised by a high clearance and short context-sensitive half-time. When normalised to weight, pharmacokinetic properties were similar to those reported for adults., Clinical Trial Registration: ChiCTR2200057629., (Copyright © 2023 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Objectives: To compare the efficacy, safety, and side effects of hydromorphone and morphine administered as patient-controlled analgesia (PCA) for postoperative pain therapy after cardiac surgery with median sternotomy., Design: A retrospective analysis of data from 2 prospective, single-blinded, randomized trials., Setting: A single-center intensive care unit at a university hospital., Participants: Forty-one adult patients undergoing cardiac surgery with median sternotomy., Interventions: Postoperative pain therapy at the intensive care unit was performed by PCA with intravenously administered bolus doses of 0.2 mg of hydromorphone (n = 21) or 2 mg of morphine (n = 20)., Measurements and Main Results: Pain at rest and under deep inspiration regularly was assessed using the 11-point numerical rating scale (NRS). Blood pressure, heart rate, cardiac output, oxygen saturation, and respiratory rate were monitored, and adverse events were registered. The median (range) NRS rating at rest was 1.5 (0-5) after hydromorphone and 0.5 (0-5) after morphine, respectively (p = 0.41). The median NRS rating under deep inspiration was 3 (0-6) after hydromorphone and 4 (0-7) after morphine, respectively (p = 0.074). The dose ratio of morphine to hydromorphone during PCA was 5.7 (95% confidence interval: 2.9-7.6). Hemodynamics and respiration were stable and did not differ significantly. Postoperative nausea and vomiting were the most frequent adverse events, which were observed in 29% of the patients after hydromorphone and in 35% after morphine, respectively (p = 0.74)., Conclusions: There were no significant differences in analgesic efficacy and safety between hydromorphone and morphine when used for postoperative pain therapy with PCA after cardiac surgery with median sternotomy., Competing Interests: Conflict of Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The long-term stability of drugs under normal laboratory storage conditions (-20°C) for years is important for research purposes, clinical re-evaluation, and also for forensic toxicology. To evaluate the stability of the analgesic opioid hydromorphone, 44 human frozen plasma samples of a former clinical trial were reanalyzed after at least three years. Blood samples were disposed using solid-phase extraction with an additional substitution of stable isotope labelled hydromorphone as an internal standard. Hydromorphone concentrations were determined by ultra-performance liquid chromatography (UPLC) with gradient elution, followed by tandem mass spectrometry with electrospray ionization. Calibration curves demonstrated linearity of the assay in the concentration range of 0.3-20 ng/mL hydromorphone. The limit of detection of the hydromorphone plasma concentration was 0.001 ng/mL, and the lower limit of quantification was 0.3 ng/mL. Intra- and interassay errors did not exceed 16%. The percentage deviation of the measured hydromorphone plasma concentrations between the reanalysis and the first analysis was -1.07% ± 14.8% (mean ± SD). These results demonstrate that hydromorphone concentration in human plasma was stable when the samples were frozen at -20°C over three years. This finding is of value for re-evaluations or delayed analyses for research purposes and in pharmacokinetic studies, such as in forensic medicine., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Andreas Wehrfritz et al.)

Background: Remifentanil is an effective drug in peri-operative pain therapy, but it can also induce and aggravate hyperalgesia. Supplemental administration of N2O may help to reduce remifentanil-induced hyperalgesia., Objective: To evaluate the effect of 35 and 50% N2O on hyperalgesia and pain after remifentanil infusion., Design: Single site, phase 1, double-blind, placebo-controlled, randomised crossover study., Setting: University Hospital, Germany from January 2012 to April 2012., Participants: Twenty-one healthy male volunteers., Interventions: Transcutaneous electrical stimulation induced spontaneous acute pain and stable areas of hyperalgesia. Each volunteer underwent the following four sessions in a randomised order: 50 to 50% N2-O2 and intravenous (i.v.) 0.9% saline infusion (placebo); 50 to 50% N2-O2 and i.v. remifentanil infusion at 0.1 μg kg-1 min-1 (remifentanil); 35 to 15 to 50% N2O-N2-O2 and i.v. remifentanil infusion at 0.1 μg kg-1 min-1 (tested drug) and 50 to 50% N2O-O2 and i.v. remifentanil infusion at 0.1 μg kg-1 min-1 (gas active control). Gas mixtures were inhaled for 60 min; i.v. drugs were administered for 30 min., Main Outcome Measures: Areas of pin-prick hyperalgesia, areas of touch-evoked allodynia and pain intensity on a visual analogue scale were assessed repeatedly for 160 min., Results: Data from 20 volunteers were analysed. There were significant treatment and treatment-by-time effects regarding areas of hyperalgesia (P < 0.001). After the treatment period, the area of hyperalgesia was significantly reduced (P < 0.001) in the tested drug and in the gas active control (30.6 ± 9.25 and 24.4 ± 7.3 cm2, respectively) compared with remifentanil (51.0 ± 17.0 cm2). There was also a significant difference between the gas active control and the tested drug sessions (P < 0.001). For the area of allodynia and pain rating, results were consistent with the results for hyperalgesia., Conclusions: Administration of 35% N2O significantly reduced hyperalgesia, allodynia and pain intensity induced after remifentanil. It might therefore be suitable in peri-operative pain relief characterised by hyperalgesia and allodynia, such as postoperative pain, and may help to reduce opioid demand., Trial Registration: EudraCT-No.: 2011-000966-37., (Copyright © 2021 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Background and Objective: Morphine is a standard analgesic drug for postoperative pain therapy. This study aimed to evaluate the pharmacokinetics of morphine and its active metabolite morphine-6-glucuronide (M6G) in cardiac surgery  patients during postoperative analgesia., Methods: Twenty-five adult patients undergoing cardiac surgery received postoperative pain therapy by patient-controlled analgesia with intravenous bolus doses of morphine. Plasma concentrations of morphine and M6G were determined from arterial samples. Population pharmacokinetic parameters were estimated using nonlinear mixed-effects modeling., Results: Data from twenty-one patients (aged 44-79 years) were analyzed. Pharmacokinetics were best described by a three-compartment model for morphine and a two-compartment model for M6G, linked by a transit compartment. Mean (±SD) population estimates for morphine were: clearance (CL) = 1.35±0.40 L/min, central volume of distribution (V 1 ) = 8.1±2.2 L, steady-state volume of distribution (V ss ) = 207±83 L, terminal elimination half-life (T 1/2 γ ) = 177±50 min. Clearance of morphine was proportional to cardiac output. Mean (±SD) population estimates for M6G were: CL = 0.098±0.037 L/min, V 1 = 5.5±0.8 L, V ss = 15.8±0.8 L, T 1/2 β = 227±74 min. The time to peak concentration of M6G after a bolus dose of morphine was 53±20 min. Clearance of M6G was proportional to estimated glomerular filtration rate., Conclusions: The pharmacokinetics of morphine and M6G in pain therapy of cardiac surgery  patients could be well described by standard compartmental models. Cardiac output was identified as a significant covariate for morphine clearance, whereas renal function was identified as the most significant covariate for clearance of M6G. These effects should be particularly considered if morphine is administered as a continuous infusion. The developed pharmacokinetic model also enables patient-controlled target-controlled infusion for pain therapy with morphine., Trial Registration: Clinical Trials NCT02483221 (June 26, 2015).

Background: The challenge of managing acute postoperative pain is the well tolerated and effective administration of analgesics with a minimum of side effects. The standard therapeutic approach is patient-controlled analgesia (PCA) with systemic opioids. To overcome problems of oscillating opioid concentrations, we studied patient-controlled analgesia by target-controlled infusion (TCI-PCA) as an alternative., Objective: To compare efficacy, safety and side effects of standard PCA with TCI-PCA for postoperative pain therapy with hydromorphone., Design: Single-blinded, randomised trial., Setting: University Hospital, Germany from December 2013 to April 2015., Participants: Fifty adults undergoing cardiac surgery., Interventions: Postoperative pain therapy on the ICU was managed with intravenous (i.v.) hydromorphone and patients randomised to TCI-PCA with target plasma concentrations between 0.8 and 10 ng ml, or PCA with bolus doses of 0.2 mg. Pain was regularly assessed using the 11-point numerical rating scale (NRS). Blood pressure, heart rate, oxygen saturation and cardiac output were continuously monitored, and adverse events were registered throughout the study., Main Outcome Measures: NRS pain ratings, hydromorphone doses, haemodynamic effects and side effects., Results: NRS pain ratings, total doses of hydromorphone and haemodynamic data did not differ significantly between TCI-PCA and PCA. The number of bolus doses during PCA was significantly higher than the number of target increases during TCI-PCA (P = 0.006). The number of negative requests was also significantly higher during PCA than during TCI-PCA (P = 0.02). The respiratory rate on the first postoperative morning was 25 ± 6 min during TCI-PCA, compared with 19 ± 4 min during PCA (P = 0.022). Nausea occurred in 30% after TCI-PCA and 24% after PCA (P = 0.46)., Conclusion: TCI-PCA was effective and well tolerated in acute postoperative pain management after cardiac surgery. Further studies are needed to evaluate this approach in clinical practice., Trial Registration: EudraCT Number: 2013-002875-16, and ClinicalTrials.gov Identifier: NCT02035709.