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Background: The N-methyl-D-aspartate receptor antagonist ketamine is metabolized in the liver into its active metabolite norketamine. No human data are available on the relative contribution of norketamine to ketamine-induced analgesia and side effects. One approach to assess the ketamine and norketamine contributions is by measuring the ketamine effect at varying ketamine and norketamine plasma concentrations using the CYP450 inducer rifampicin.Methods: In 12 healthy male volunteers the effect of rifampicin versus placebo pretreatment on S-ketamine-induced analgesia and cognition was quantified; the S-ketamine dosage was 20 mg/h for 2 h. The relative ketamine and norketamine contribution to effect was estimated using a linear additive population pharmacokinetic-pharmacodynamic model.Results: S-ketamine produced significant analgesia, psychotropic effects (drug high), and cognitive impairment (including memory impairment and reduced psychomotor speed, reaction time, and cognitive flexibility). Modeling revealed a negative contribution of S-norketamine to S-ketamine- induced analgesia and absence of contribution to cognitive impairment. At ketamine and norketamine effect concentrations of 100 ng/ml and 50 ng/ml, respectively, the ketamine contribution to analgesia is -3.8 cm (visual analog pain score) versus a contribution of norketamine of +1.5 cm, causing an overall effect of -2.3 cm. The blood-effect site equilibration half-life ranged from 0 (cognitive flexibility) to 11.8 (pain intensity) min and was 6.1 min averaged across all endpoints.Conclusions: This first observation that norketamine produces effects in the opposite direction of ketamine requires additional proof. It can explain the observation of ketamine-related excitatory phenomena (such as hyperalgesia and allodynia) upon the termination of ketamine infusions. [ABSTRACT FROM AUTHOR]

Background: Low-dose ketamine is used as analgesic for acute and chronic pain. It is metabolized in the liver to norketamine via cytochrome P450 (CYP) enzymes. There are few human data on the involvement of CYP enzymes on the elimination of norketamine and its possible contribution to analgesic effect. The aim of this study was to investigate the effect of CYP enzyme induction by rifampicin on the pharmacokinetics of S-ketamine and its major metabolite, S-norketamine, in healthy volunteers.Methods: Twenty healthy male subjects received 20 mg/70 kg/h (n = 10) or 40 mg/70 kg/h (n = 10) intravenous S-ketamine for 2 h after either 5 days oral rifampicin (once daily 600 mg) or placebo treatment. During and 3 h after drug infusion, arterial plasma concentrations of S-ketamine and S-norketamine were obtained at regular intervals. The data were analyzed with a compartmental pharmacokinetic model consisting of three compartments for S-ketamine, three sequential metabolism compartments, and two S-norketamine compartments using the statistical package NONMEM® 7 (ICON Development Solutions, Ellicott City, MD).Results: Rifampicin caused a 10% and 50% reduction in the area-under-the-curve of the plasma concentrations of S-ketamine and S-norketamine, respectively. The compartmental analysis indicated a 13% and 200% increase in S-ketamine and S-norketamine elimination from their respective central compartments by rifampicin.Conclusions: : A novel observation is the large effect of rifampicin on S-norketamine concentrations and indicates that rifampicin induces the elimination of S-ketamine's metabolite, S-norketamine, probably via induction of the CYP3A4 and/or CYP2B6 enzymes. [ABSTRACT FROM AUTHOR]

AIMS: Pharmacological treatment of chronic (neuropathic) pain is often disappointing. In order to enhance our insight in the complex interaction between analgesic drug and chronic pain relief, we performed a pharmacokinetic-pharmacodynamic (PK-PD) modeling study on the effect of S(+)-ketamine on pain scores in Complex Regional Pain Syndrome type 1 (CRPS-1) patients. METHODS: Sixty CRPS-1 patients were randomly allocated to received a 100-h infusion of S(+)-ketamine or placebo. The drug infusion rate was slowly increased from 5mg/h (per 70kg) to 20mg/h based upon the effect/side effect profile. Pain scores and drug blood samples were obtained during the treatment phase and pain scores were further obtained weekly for another 11weeks. A population PK-PD model was developed to analyze the S(+)-ketamine-pain data. RESULTS: Plasma concentrations of S(+)-ketamine and its metabolite decreased rapidly upon the termination of S(+)-ketamine infusion. The chance for an analgesic effect from ketamine and placebo treatment was 67±10% and 23±9% (population value±SE), respectively. The pain data were well described by the PK-PD model with parameters C(50)=10.5±4.8ng/ml (95% ci 4.37-21.2ng/ml) and t½ for onset/offset=10.9±4.0days (5.3-20.5days). DISCUSSION: Long-term S(+)-ketamine treatment is effective in causing pain relief in CRPS-1 patients with analgesia outlasting the treatment period by 50days. These data suggest that ketamine initiated a cascade of events, including desensitization of excitatory receptor systems in the central nervous system, which persisted but slowly abated when ketamine molecules were no longer present. [ABSTRACT FROM AUTHOR]

Background: Opioid-induced respiratory depression is antagonized effectively by the competitive opioid receptor antagonist naloxone. However, to fully understand the complex opioid agonist-antagonist interaction, the effects of various naloxone doses on morphine and morphine-6-glucuronide (M6G)-induced respiratory depression were studied in healthy volunteers.Methods: Twenty-four subjects received 0.15 mg/kg morphine intravenously at t = 0 followed by placebo, 200 or 400 microg naloxone at t = 30 min. Thirty-two subjects received 0.3 mg/kg M6G intravenously at t = 0 followed by placebo, 25, 100, or 400 microg naloxone at t = 55 min. There were a total of 8 subjects per treatment group. Respiration was measured on a breath-to-breath basis at constant end-tidal Pco2. A mechanism-based pharmacokinetic-pharmacodynamic model consisting of a part describing biophase equilibration and a part describing receptor association-dissociation kinetics was used to analyze the data.Results: Naloxone reversal of M6G-induced respiratory depression developed more slowly than reversal of the respiratory effect of morphine. A simulation study revealed that this was related to the slower receptor association-dissociation kinetics of M6G (koff M6G = 0.0327 +/- 0.00455 min versus morphine 0.138 +/- 0.0148 min; values are typical +/-SE). Duration of naloxone reversal was longer for M6G. This was related to the three- to fourfold greater potency of naloxone as an antagonist against M6G compared with morphine. Increasing the naloxone dose had no effect on the speed of reversal, but it did extend reversal duration.Conclusions: Naloxone reversal of the opioid effect is dependent on the receptor association-dissociation kinetics of the opioid that needs reversal with respect to the rate of reversal. The pharmacodynamics of naloxone determines reversal magnitude and duration. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

AIMS: The aim of the study was to explore the analgesic effect of the N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine in acute experimental versus chronic spontaneous pain in Complex Regional Pain Syndrome type 1 (CRPS-1) patients. METHODS: Ten patients suffering from chronic CRPS-1 and with a Visual Analogue pain Score (VAS) of >5 were recruited. Seven intravenous 5-min low-dose S(+)-ketamine infusions with increasing doses at 20-min intervals were applied. Spontaneous pain ratings and VAS responses to experimental heat stimuli were obtained during infusion and for 3-h following infusion. RESULTS: CRPS pain: Ketamine produced potent analgesia with a significant VAS reduction from 6.2+/-0.2 to 0.4+/-0.3 cm at the end of infusion. Analgesia persisted beyond the infusion period (VAS=2.8+/-1.0 cm at 5-h), when measured plasma ketamine concentrations were low (<100 ng/ml). Experimental pain: Ketamine had a dose-dependent antinociceptive effect on experimental pain that ended immediately upon the termination of infusion. DISCUSSION: The data indicate that while ketamine's effect on acute experimental pain is driven by pharmacokinetics, its effect on CRPS pain persisted beyond the infusion period when drug concentrations were below the analgesia threshold for acute pain. This indicates a disease modulatory role for ketamine in CRPS-1 pain, possibly via desensitization of NMDAR in the spinal cord or restoration of inhibitory sensory control in the brain. [ABSTRACT FROM AUTHOR]

Background: In previous studies, the authors reported on the absorption and disposition kinetics of levobupivacaine and ropivacaine. The current study was designed to develop a population pharmacokinetic-pharmacodynamic model capable of linking the kinetic data to the analgesic effects of these local anesthetics (i.e., sensory neural blockade).Methods: A disposition compartmental model was fitted to concentration data of the intravenously administered deuterium-labeled anesthetics, and a model consisting of two parallel absorption compartments and the identified disposition compartments was fitted to concentration data of the concomitantly epidurally administered unlabeled anesthetics. The epidural segments were modeled by individual central and peripheral absorption compartments and effect sites, which were fitted to the simultaneously acquired pinprick data. A covariate model incorporated the effects of age.Results: The threshold for epidural anesthesia increased from the lower to the higher segments. The central effect compartment equilibration half-lives were approximately 15 min for levobupivacaine and 25 min for ropivacaine. For levobupivacaine, age reduced the equilibration half-lives at all segments; for ropivacaine, age increased the anesthetic sensitivity at segments T12 and higher.Conclusions: A population pharmacokinetic-pharmacodynamic model was developed that quantitatively described sensory blockade during epidural anesthesia, including the effects of age. The model may be useful to individualize dose requirements, to predict the time course of sensory blockade, and to study new local anesthetics. [ABSTRACT FROM AUTHOR]

Periodogram analysis of unequally spaced time-series, as part of many biological rhythm investigations, is complicated. The mathematical frameworkis scattered over the literature, and the interpretation of results is often debatable. In this paper, we show that the Lomb-Scargle method is the appropriate tool for periodogram analysis of unequally spaced data. A unique procedure of multiple period searching is derived, facilitating the assessment of the various rhythms that may be present in a time-series. All relevant mathematical and statistical aspects are considered in detail, and much attention is given to the correct interpretation of results. The use of the procedure is illustrated by examples, and problems that may be encountered are discussed. It is argued that, when following the procedure of multiple period searching, we can even benefit from the unequal spacing of a time-series in biological rhythm research. [ABSTRACT FROM AUTHOR]

Background: Morphine and hydromorphone have differing onsets, magnitudes, and durations of effects and side-effects. Differences between opioids in their interindividual variabilities in pharmacokinetics and pharmacodynamics might influence rational drug selection. Crossover drug studies can provide more informative interindividual variability data than parallel group studies. Using data from a crossover study of i.v. morphine and hydromorphone in healthy volunteers, we tested the hypothesis that morphine and hydromorphone differ in their interindividual pharmacokinetic variability., Methods: Arterial opioid and metabolite concentrations from a randomised crossover study in 51 volunteers receiving a 2-h infusion of hydromorphone (0.05 or 0.1 mg kg -1 i.v.) or morphine (total 0.1 or 0.2 mg kg -1 i.v.) 1-2 weeks apart were evaluated with a three-compartmental model for parent opioid and incorporating glucuronides using population modelling (NONMEM). The primary outcome was interindividual variability in pharmacokinetics, based on the coefficient of variation (%CV) of individual model parameters, calculated as √[exp(ω 2 )-1]×100 where ω 2 is the interindividual variability., Results: Data were analysed per drug and in a combined morphine-hydromorphone model. Both analyses indicate that interindividual variabilities for hydromorphone and morphine were comparable with %CV ranging from 9% to 31% for structural model parameters (combined analysis). Similarly, additive and relative residual errors had comparable variabilities, 20-40% and 72-87%, respectively, for morphine and hydromorphone (combined analysis)., Conclusions: Morphine and hydromorphone did not differ in a statistically significant or clinically meaningful manner in their interindividual pharmacokinetic variability. Interindividual pharmacokinetic variability does not appear a meaningful consideration in the choice between these two opioids., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

The anesthetic, analgesic and antidepressant drug ketamine produces dissociation with symptoms of psychosis and anxiety, an effect attributed to neuronal nitric oxide depletion following N -methyl-d-aspartate blockade. There is evidence that dissociation induced by racemic ketamine, containing both ketamine enantiomers (S- and R-ketamine) but not esketamine (the S-isomer) is inhibited by nitric oxide (NO) donor sodium nitroprusside (SNP). We tested whether a similar intervention would reduce racemic and esketamine-induced analgesia in a randomized double-blind placebo-controlled trial. Seventeen healthy volunteers were treated with 0.5 μg.kg -1 .min -1 SNP or placebo during a 3-h infusion of escalating doses of racemic ketamine (total dose 140 mg) or esketamine (70 mg). Pain pressure threshold (PPT) and arterial blood samples for measurement of S- and R-ketamine and their metabolites, S- and R-norketamine, were obtained. The data were analyzed with a population pharmacokinetic-pharmacodynamic model that incorporated the measured S- and R- ketamine and S- and R-norketamine isomers as input and PPT as output to the model. The potency of the 2 formulations in increasing PPT from baseline by 100% was 0.47 ± 0.12 (median ± standard error of the estimate) nmol/mL for esketamine and 0.62 ± 0.19 nmol/mL for racemic ketamine, reflecting the 52 ± 27% lower analgesic potency of R-ketamine versus S-ketamine. Modeling showed that SNP had no effect on S-ketamine potency but abolished the R-ketamine analgesic effect. Similar observations were made for S- and R-norketamine. Since SNP had no effect on S-ketamine analgesia, we conclude that SNP interacts on R-ketamine nociceptive pathways, possibly similar to its effects on R-ketamine activated dissociation pathways., Competing Interests: The authors declare the following competing financial interest(s): Prof. Dahan received consultancy fees from Enalare and from Trevena for work done outside of the scope of the current paper., (© 2024 The Authors. Published by American Chemical Society.)

Background: The use of anesthetics may result in depression of the hypoxic ventilatory response. Since there are no receptor-specific antagonists for most anesthetics, there is the need for agnostic respiratory stimulants that increase respiratory drive irrespective of its cause. The authors tested whether ENA-001, an agnostic respiratory stimulant that blocks carotid body BK-channels, could restore the hypoxic ventilatory response during propofol infusion. They hypothesize that ENA-001 is able to fully restore the hypoxic ventilatory response., Methods: In this randomized, double-blind crossover trial, 14 male and female healthy volunteers were randomized to receive placebo and low- and high-dose ENA-001 on three separate occasions. On each occasion, isohypercapnic hypoxic ventilatory responses were measured during a fixed sequence of placebo, followed by low- and high-dose propofol infusion. The authors conducted a population pharmacokinetic/pharmacodynamic analysis that included oxygen and carbon dioxide kinetics., Results: Twelve subjects completed the three sessions; no serious adverse events occurred. The propofol concentrations were 0.6 and 2.0 µg/ml at low and high dose, respectively. The ENA-001 concentrations were 0.6 and 1.0 µg/ml at low and high dose, respectively. The propofol concentration that reduced the hypoxic ventilatory response by 50% was 1.47 ± 0.20 µg/ml. The steady state ENA-001 concentration to increase the depressed ventilatory response by 50% was 0.51 ± 0.04 µg/ml. A concentration of 1 µg/ml ENA-001 was required for full reversal of the propofol effect at the propofol concentration that reduced the hypoxic ventilatory response by 50%., Conclusions: In this pilot study, the authors demonstrated that ENA-001 restored the hypoxic ventilatory response impaired by propofol. This finding is not only of clinical importance but also provides mechanistic insights into the peripheral stimulation of breathing with ENA-001 overcoming central depression by propofol., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.)

Background: Oliceridine (Olinvyk) is a μ-opioid receptor agonist that in contrast to conventional opioids preferentially engages the G-protein-coupled signaling pathway. This study was designed to determine the utility function of oliceridine versus morphine based on neurocognitive tests and cold pressor test., Methods: The study had a randomized, double-blind, placebo-controlled, partial block three-way crossover design. Experiments were performed in 20 male and female volunteers. The subjects received intravenous oliceridine (1 or 3 mg; cohorts of 10 subjects/dose), morphine (5 or 10 mg; cohorts of 10 subjects/dose), or placebo on three separate occasions. Before and after dosing, neurocognitive tests, cold pressor test, and plasma drug concentrations were obtained at regular intervals. Population pharmacokinetic-pharmacodynamic analyses served as the basis for construction of a utility function, which is an objective function of probability of benefit minus probability of harm. Antinociception served as the measure of benefit, and slowing of saccadic peak velocity and increased body sway as the measures of neurocognitive harm., Results: The oliceridine and morphine C50 values, i.e., the effect-site concentrations causing 50% effect, were as follows: antinociception, 13 ± 2 and 23 ± 7 ng/ml; saccadic peak velocity, 90 ± 14 and 54 ± 15 ng/ml; and body sway, 10 ± 2 and 5.6 ± 0.8 ng/ml, respectively. The ratio oliceridine/morphine of the therapeutic indices, C50(benefit)/C50(harm), were 0.34 (95% CI, 0.17 to 0.7; P < 0.01) for saccadic peak velocity and 0.33 (0.16 to 0.50; P < 0.01) for body sway. The oliceridine utility was positive across the effect-site concentration 5 to 77 ng/ml, indicative of a greater probability of benefit than harm. The morphine utility was not significantly different from 0 from 0 to 100 ng/ml. Over the concentration range 15 to 50 ng/ml, the oliceridine utility was superior to that of morphine (P < 0.01). Similar observations were made for body sway., Conclusions: These data indicate that over the clinical concentration range, oliceridine is an analgesic with a favorable safety profile over morphine when considering analgesia and neurocognitive function., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Opioids are effective analgesics, but they can have harmful adverse effects, such as addiction and potentially fatal respiratory depression. Naloxone is currently the only available treatment for reversing the negative effects of opioids, including respiratory depression. However, the effectiveness of naloxone, particularly after an opioid overdose, varies depending on the pharmacokinetics and the pharmacodynamics of the opioid that was overdosed. Long-acting opioids, and those with a high affinity at the µ-opioid receptor and/or slow receptor dissociation kinetics, are particularly resistant to the effects of naloxone. In this review, the authors examine the pharmacology of naloxone and its safety and limitations in reversing opioid-induced respiratory depression under different circumstances, including its ability to prevent cardiac arrest., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Background: Balancing between opioid analgesia and respiratory depression continues to challenge clinicians in perioperative, emergency department, and other acute care settings. Morphine and hydromorphone are postoperative analgesic standards. Nevertheless, their comparative effects and side effects, timing, and respective variabilities remain poorly understood. This study tested the hypothesis that IV morphine and hydromorphone differ in onset, magnitude, duration, and variability of analgesic and ventilatory effects., Methods: The authors conducted a randomized crossover study in healthy volunteers. Forty-two subjects received a 2-h IV infusion of hydromorphone (0.05 mg/kg) or morphine (0.2 mg/kg) 1 to 2 weeks apart. The authors measured arterial opioid concentrations, analgesia in response to heat pain (maximally tolerated temperature, and verbal analog pain scores at discrete preset temperatures to determine half-maximum temperature effect), dark-adapted pupil diameter and miosis, end-expired carbon dioxide, and respiratory rate for 12 h after dosing., Results: For morphine and hydromorphone, respectively, maximum miosis was less (3.9 [3.4 to 4.2] vs. 4.6 mm [4.0 to 5.0], P < 0.001; median and 25 to 75% quantiles) and occurred later (3.1 ± 0.9 vs. 2.3 ± 0.7 h after infusion start, P < 0.001; mean ± SD); maximum tolerated temperature was less (49 ± 2 vs. 50 ± 2°C, P < 0.001); verbal pain scores at end-infusion at the most informative stimulus (48.2°C) were 82 ± 4 and 59 ± 3 (P < 0.001); maximum end-expired CO2 was 47 (45 to 50) and 48 mmHg (46 to 51; P = 0.007) and occurred later (5.5 ± 2.8 vs. 3.0 ± 1.5 h after infusion start, P < 0.001); and respiratory nadir was 9 ± 1 and 11 ± 2 breaths/min (P < 0.001), and occurred at similar times. The area under the temperature tolerance-time curve was less for morphine (1.8 [0.0 to 4.4]) than hydromorphone (5.4°C-h [1.6 to 12.1] P < 0.001). Interindividual variability in clinical effects did not differ between opioids., Conclusions: For morphine compared to hydromorphone, analgesia and analgesia relative to respiratory depression were less, onset of miosis and respiratory depression was later, and duration of respiratory depression was longer. For each opioid, timing of the various clinical effects was not coincident. Results may enable more rational opioid selection, and suggest hydromorphone may have a better clinical profile., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

The widely prescribed opioid oxycodone may cause lethal respiratory depression. We compared the effects of oxycodone on breathing and antinociception in healthy young volunteers. After pharmacokinetic/pharmacodynamic (PK/PD) modeling, we constructed utility functions to combine the wanted and unwanted end points into a single function. We hypothesized that the function would be predominantly negative over the tested oxycodone concentration range. Twenty-four male and female volunteers received 20 (n = 12) or 40 (n = 12) mg oral oxycodone immediate-release tablets. Hypercapnic ventilatory responses (visit 1) or responses to 3 nociceptive assays (pain pressure, electrical, and thermal tests; visit 2) were measured at regular intervals for 7 hours. the PK/PD analyses, that included carbon dioxide kinetics, stood at the basis of the utility function: probability of antinociception minus probability of respiratory depression. Oxycodone had rapid onset/offset times (30-40 minutes) with potency values (effect-site concentration causing 50% of effect) ranging from 0.05 to 0.13 ng/mL for respiratory variables obtained at hypercapnia and antinociceptive responses. Ventilation at an extrapolated end-tidal carbon dioxide partial pressure of 55 mmHg, was used for creation of 3 utility functions, one for each of the nociceptive tests. Contrary to expectation, the utility functions were close to zero or positive over the clinical oxycodone concentration range. The similar or better likelihood for antinociception relative to respiratory depression may be related to oxycodone's receptor activation profile or to is high likeability that possibly alters the modulation of nociceptive input. Oxycodone differs from other μ-opioids, such as fentanyl, that have a consistent negative utility., (© 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: In humans, the effect of cannabis on ventilatory control is poorly studied, and consequently, the effect of Δ 9 -tetrahydrocannabinol (THC) remains unknown, particularly when THC is combined with an opioid. We studied the effect of THC on breathing without and with oxycodone pretreatment. We hypothesised that THC causes respiratory depression, which is amplified when THC and oxycodone are combined., Methods: In this randomised controlled crossover trial, healthy volunteers were administered inhaled Bedrocan® 100 mg (Bedrocan International B.V., Veendam, The Netherlands), a pharmaceutical-grade high-THC cannabis variant (21.8% THC; 0.1% cannabidiol), after placebo or oral oxycodone 20 mg pretreatment; THC was inhaled 1.5 and 4.5 h after placebo or oxycodone intake. The primary endpoint was isohypercapnic ventilation at an end-tidal Pco 2 of 55 mm Hg or 7.3 kPa (V E 55), measured at 1-h intervals for 7 h after placebo/oxycodone intake., Results: In 18 volunteers (age 22 yr [3]; 9 [50%] female), oxycodone produced a 30% decrease in V E 55, whereas placebo was without effect on V E 55. The first cannabis inhalation resulted in V E 55 changing from 20.3 (3.1) to 23.8 (2.4) L min -1 (P=0.06) after placebo, and from 11.8 (2.8) to 13.0 (3.9) L min -1 (P=0.83) after oxycodone. The second cannabis inhalation also had no effect on V E 55, but slightly increased sedation., Conclusions: In humans, THC has no effect on ventilatory control after placebo or oxycodone pretreatment., Clinical Trial Registration: 2021-000083-29 (EU Clinical Trials Register.)., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Opioids are commonly used painkillers and drugs of abuse and have serious toxic effects including potentially lethal respiratory depression. It remains unknown which respiratory parameter is the most sensitive biomarker of opioid-induced respiratory depression (OIRD). To evaluate this issue, we studied 24 volunteers and measured resting ventilation, resting end-tidal PCO 2 (P ET CO 2 ) and the hypercapnic ventilatory response (HCVR) before and at 1-h intervals following intake of the opioid tapentadol. Pharmacokinetic/pharmacodynamic analyses that included CO 2 kinetics were applied to model the responses with focus on resting variables obtained without added CO 2 , HCVR slope and ventilation at an extrapolated P ET CO 2 of 55 mmHg ( V ˙ E 55). The HCVR, particularly V ˙ E 55 followed by slope, was most sensitive in terms of potency; resting variables were least sensitive and responded slower to the opioid. Using V ˙ E 55 as biomarker in quantitative studies on OIRD allows standardized comparison among opioids in the assessment of their safety., Competing Interests: A.D. and M.N. received an educational grant from Grünenthal GmbH to perform the current study. A.D. and M.N. received speaker fee from Grünenthal, A.D. received consultancy fees from ENALARE (USA) and Trevena (USA) outside the content of the current project and holds ENALARE stock options. All other authors declare no competing interests. A.D. is chair of the scientific advisory board to MyCB1 (Amsterdam, the Netherlands) and is member of the ENALARE advisory board., (© 2023 The Author(s).)

Background: Oliceridine is a G protein-biased µ-opioid, a drug class that is associated with less respiratory depression than nonbiased opioids, such as morphine. The authors quantified the respiratory effects of oliceridine and morphine in elderly volunteers. The authors hypothesized that these opioids differ in their pharmacodynamic behavior, measured as effect on ventilation at an extrapolated end-tidal Pco2 at 55 mmHg, V̇E55., Methods: This four-arm double-blind, randomized, crossover study examined the respiratory effects of intravenous 0.5 or 2 mg oliceridine and 2 or 8 mg morphine in 18 healthy male and female volunteers, aged 55 to 89 yr, on four separate occasions. Participants' CYP2D6 genotypes were determined, hypercapnic ventilatory responses were obtained, and arterial blood samples were collected before and for 6 h after treatment. A population pharmacokinetic-pharmacodynamic analysis was performed on V̇E55, the primary endpoint; values reported are median ± standard error of the estimate., Results: Oliceridine at low dose was devoid of significant respiratory effects. High-dose oliceridine and both morphine doses caused a rapid onset of respiratory depression with peak effects occurring at 0.5 to 1 h after opioid dosing. After peak effect, compared with morphine, respiratory depression induced by oliceridine returned faster to baseline. The effect-site concentrations causing a 50% depression of V̇E55 were 29.9 ± 3.5 ng/ml (oliceridine) and 21.5 ± 4.6 ng/ml (morphine), the blood effect-site equilibration half-lives differed by a factor of 5: oliceridine 44.3 ± 6.1 min and morphine 214 ± 27 min. Three poor CYP2D6 oliceridine metabolizers exhibited a significant difference in oliceridine clearance by about 50%, causing higher oliceridine plasma concentrations after both low- and high-dose oliceridine, compared with the other participants., Conclusions: Oliceridine and morphine differ in their respiratory pharmacodynamics with a more rapid onset and offset of respiratory depression for oliceridine and a smaller magnitude of respiratory depression over time., (Copyright © 2023, the American Society of Anesthesiologists. All Rights Reserved.)

Background: Opioids continue to be widely prescribed for chronic noncancer pain, despite the awareness that opioids provide only short-time pain relief, lead to dose accumulation, have numerous adverse effects, and are difficult to wean. As an alternative, we previously showed advantages of using pharmaceutical-grade cannabis in a population of chronic pain patients with fibromyalgia. It remains unknown whether combining an opioid with pharmaceutical-grade cannabis has advantages, such as fewer side effects from lesser opioid consumption in chronic pain., Methods: Trial design: a single-center, randomized, three-arm, open-label, exploratory trial. Trial population: 60 patients with fibromyalgia according to the 2010 definition of the American College of Rheumatologists., Intervention: Patients will be randomized to receive up to 4 daily 5 mg oral oxycodone sustained release (SR) tablet, up to 5 times 150 mg inhaled cannabis (Bediol®, containing 6.3% Δ 9 -tetrahydrocannabinol and 8% cannabidiol), or the combination of both treatments. Treatment is aimed at self-titration with the daily maximum doses given. Treatment will continue for 6 weeks, after which there is a 6-week follow-up period. Main trial endpoint: The number of side effects observed during the course of treatment using a composite adverse effect score that includes the following 10 symptoms: dizziness (when getting up), sleepiness, insomnia, headache, nausea, vomiting, constipation, drug high, hallucinations, and paranoia. Secondary and tertiary endpoints include pain relief and number of oxycodone doses and cannabis inhalations., Discussion: The trial is designed to determine whether self-titration of oxycodone and cannabis will reduce side effects in chronic pain patients with fibromyalgia. TRIAL REGISTRATION {2A AND 2B}: EU trial register 2019-001861-33, URL https://www.clinicaltrialsregister.eu , on July 17, 2019; World Health Organization International Clinical Trials Research Platform NL7902, URL https://trialsearch.who.int , on July 26, 2019., (© 2023. The Author(s).)

In response to a surge of deaths from synthetic opioid overdoses, there have been increased efforts to distribute naloxone products in community settings. Prior research has assessed the effectiveness of naloxone in the hospital setting; however, it is challenging to assess naloxone dosing regimens in the community/first-responder setting, including reversal of respiratory depression effects of fentanyl and its derivatives (fentanyls). Here, we describe the development and validation of a mechanistic model that combines opioid mu receptor binding kinetics, opioid agonist and antagonist pharmacokinetics, and human respiratory and circulatory physiology, to evaluate naloxone dosing to reverse respiratory depression. Validation supports our model, which can quantitatively predict displacement of opioids by naloxone from opioid mu receptors in vitro, hypoxia-induced cardiac arrest in vivo, and opioid-induced respiratory depression in humans from different fentanyls. After validation, overdose simulations were performed with fentanyl and carfentanil followed by administration of different intramuscular naloxone products. Carfentanil induced more cardiac arrest events and was more difficult to reverse than fentanyl. Opioid receptor binding data indicated that carfentanil has substantially slower dissociation kinetics from the opioid receptor compared with nine other fentanyls tested, which likely contributes to the difficulty in reversing carfentanil. Administration of the same dose of naloxone intramuscularly from two different naloxone products with different formulations resulted in differences in the number of virtual patients experiencing cardiac arrest. This work provides a robust framework to evaluate dosing regimens of opioid receptor antagonists to reverse opioid-induced respiratory depression, including those caused by newly emerging synthetic opioids., (© 2022 The Authors. Clinical Pharmacology & Therapeutics © 2022 American Society for Clinical Pharmacology and Therapeutics. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Due the increasing need for storage of carbon dioxide (CO 2 ) more individuals are prone to be exposed to high concentrations of CO 2 accidentally released into atmosphere, with deleterious consequences. Methods: We tested the effect of increasing CO 2 concentrations in humans (6-12%) and rats (10-50%) at varying inhalation times (10-60 min). In humans, a continuous positive airway pressure helmet was used to deliver the gas mixture to the participants. Unrestrained rats were exposed to CO 2 in a transparent chamber. In both species regular arterial blood gas samples were obtained. After the studies, the lungs of the animals were examined for macroscopic and microscopic abnormalities. Results: In humans, CO 2 concentrations of 9% inhaled for >10 min, and higher concentrations inhaled for <10 min were poorly or not tolerated due to exhaustion, anxiety, dissociation or acidosis (pH < 7.2), despite intact oxygenation. In rats, concentrations of 30% and higher were associated with CO 2 narcosis, epilepsy, poor oxygenation and, at 50% CO 2 , spontaneous death. Lung hemorrhage and edema were observed in the rats at inhaled concentrations of 30% and higher. Conclusion: This study provides essential insight into the occurrence of physiological changes in humans and fatalities in rats after acute exposure to high levels of CO 2 . Humans tolerate 9% CO 2 and retain their ability to function coherently for up to 10 min. These data support reconsideration of the current CO 2 levels (<7.5%) that pose a risk to exposed individuals (<7.5%) as determined by governmental agencies to ≤9%., Competing Interests: Author CS is employed by Shell Global Solutions International BV. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 van der Schrier, van Velzen, Roozekrans, Sarton, Olofsen, Niesters, Smulders and Dahan.)

Ketamine is a versatile drug used for many indications and is administered via various routes. Here, we report on the pharmacodynamics of sublingual and buccal fast-dissolving oral-thin-films that contain 50 mg of S- ketamine in a population of healthy male and female volunteers. Twenty volunteers received one or two 50 mg S- ketamine oral thin films in a crossover design, placed for 10 min sublingually ( n = 15) or buccally ( n = 5). The following measurements were made for 6 h following the film placement: antinociception using three distinct pain assay; electrical, pressure, and heat pain, and drug high on an 11-point visual analog scale. Blood samples were obtained for the measurement of plasma S- ketamine, S -norketamine, and S -hydroxynorketamine concentrations. A population pharmacodynamic analysis was performed in NONMEM to construct a pharmacodynamic model of S -ketamine and its metabolites. P -values < 0.01 were considered significant. The sublingual and buccal 50 and 100 mg S- ketamine oral thin films were antinociceptive and produced drug high with effects lasting 2-6 h, although a clear dose-response relationship for antinociception could not be established. The effects were solely related to the parent compound with no contribution from S -norketamine or S -hydroxynorketamine. S -ketamine potency was lower for antinociception (C 50 ranging from 1.2 to 1.7 nmol/mL) than for drug high (C 50 0.3 nmol/ml). The onset/offset of effect as defined by the blood-effect-site equilibration half-life did not differ among endpoints and ranged from 0 to 5 min. In conclusion, the 50-mg S- ketamine oral thin film was safe and produced long-term antinociception in all three nociceptive assays with side effects inherent to the use of ketamine. The study was registered at the trial register of the Dutch Cochrane Center (www.trialregister.nl) under identifier NL9267 and the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database under number 2020-005185-33., Competing Interests: Authors PM and FH were employees of LTS Lohmann Therapie-Systeme AG, Andernach, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Simons, Olofsen, van Velzen, van Lemmen, van Dasselaar, Mohr, Hammes, van der Schrier, Niesters and Dahan.)

Ketamine is administered predominantly via the intravenous route for the various indications, including anesthesia, pain relief and treatment of depression. Here we report on the pharmacokinetics of sublingual and buccal fast-dissolving oral-thin-films that contain 50 mg of S -ketamine in a population of healthy male and female volunteers. Twenty volunteers received one or two oral thin films on separate occasions in a randomized crossover design. The oral thin films were placed sublingually ( n = 15) or buccally ( n = 5) and left to dissolve for 10 min in the mouth during which the subjects were not allowed to swallow. For 6 subsequent hours, pharmacokinetic blood samples were obtained after which 20 mg S -ketamine was infused intravenously and blood sampling continued for another 2-hours. A population pharmacokinetic analysis was performed in NONMEM pharmacokinetic model of S -ketamine and its metabolites S -norketamine and S -hydroxynorketamine; p < 0.01 were considered significant. S -ketamine bioavailability was 26 ± 1% (estimate ± standard error of the estimate) with a 20% lower bioavailability of the 100 mg oral thin film relative to the 50 mg film, although this difference did not reach the level of significance. Due to the large first pass-effect, 80% of S -ketamine was metabolized into S -norketamine leading to high plasma levels of S -norketamine following the oral thin film application with 56% of S -ketamine finally metabolized into S -hydroxynorketamine. No differences in pharmacokinetics were observed for the sublingual and buccal administration routes. The S -ketamine oral thin film is a safe and practical alternative to intravenous S -ketamine administration that results in relatively high plasma levels of S -ketamine and its two metabolites., Competing Interests: PM and FH are employees of LTS Lohmann Therapie-Systeme AG, Andernach, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Simons, Olofsen, van Velzen, van Lemmen, Mooren, van Dasselaar, Mohr, Hammes, van der Schrier, Niesters and Dahan.)

BACKGROUNDPotent synthetic opioids, such as fentanyl, are increasingly abused, resulting in unprecedented numbers of fatalities from respiratory depression. Treatment with the high-affinity mu-opioid receptor partial agonist buprenorphine may prevent fatalities by reducing binding of potent opioids to the opioid receptor, limiting respiratory depression.METHODSTo characterize buprenorphine-fentanyl interaction at the level of the mu-opioid receptor in 2 populations (opioid-naive individuals and individuals who chronically use high-dose opioids), the effects of escalating i.v. fentanyl doses with range 0.075-0.35 mg/70 kg (opioid naive) and 0.25-0.70 mg/70 kg (chronic opioid use) on iso-hypercapnic ventilation at 2-3 background doses of buprenorphine (target plasma concentrations range: 0.2-5 ng/mL) were quantified using receptor association/dissociation models combined with biophase distribution models.RESULTSBuprenorphine produced mild respiratory depression, while high doses of fentanyl caused pronounced respiratory depression and apnea in both populations. When combined with fentanyl, buprenorphine produced a receptor binding-dependent reduction of fentanyl-induced respiratory depression in both populations. In individuals with chronic opioid use, at buprenorphine plasma concentrations of 2 ng/mL or higher, a protective effect against high-dose fentanyl was observed.CONCLUSIONOverall, the results indicate that when buprenorphine mu-opioid receptor occupancy is sufficiently high, fentanyl is unable to activate the mu-opioid receptor and consequently will not cause further respiratory depression in addition to the mild respiratory effects of buprenorphine.TRIAL REGISTRATIONTrialregister.nl, no. NL7028 (https://www.trialregister.nl/trial/7028)FUNDINGIndivior Inc., North Chesterfield, Virginia, USA.

Background: Ketamine produces potent analgesia combined with psychedelic effects. It has been suggested that these two effects are associated and possibly that analgesia is generated by ketamine-induced dissociation. The authors performed a post hoc analysis of previously published data to quantify the pharmacodynamic properties of ketamine-induced antinociception and psychedelic symptoms. The hypothesis was that ketamine pharmacodynamics (i.e., concentration-effect relationship as well as effect onset and offset times) are not different for these two endpoints., Methods: Seventeen healthy male volunteers received escalating doses of S- and racemic ketamine on separate occasions. Before, during, and after ketamine infusion, changes in external perception were measured together with pain pressure threshold. A population pharmacokinetic-pharmacodynamic analysis was performed that took S- and R-ketamine and S- and R-norketamine plasma concentrations into account., Results: The pharmacodynamics of S-ketamine did not differ for antinociception and external perception with potency parameter (median [95% CI]) C50, 0.51 (0.38 to 0.66) nmol/ml; blood-effect site equilibration half-life, 8.3 [5.1 to 13.0] min), irrespective of administration form (racemic ketamine or S-ketamine). R-ketamine did not contribute to either endpoint. For both endpoints, S-norketamine had a small antagonistic effect., Conclusions: The authors conclude that their data support an association or connectivity between ketamine analgesia and dissociation. Given the intricacies of the study related to the pain model, measurement of dissociation, and complex modeling of the combination of ketamine and norketamine, it is the opinion of the authors that further studies are needed to detect functional connectivity between brain areas that produce the different ketamine effects., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

Background: Opioid-induced respiratory depression driven by ligand binding to mu-opioid receptors is a leading cause of opioid-related fatalities. Buprenorphine, a partial agonist, binds with high affinity to mu-opioid receptors but displays partial respiratory depression effects. The authors examined whether sustained buprenorphine plasma concentrations similar to those achieved with some extended-release injections used to treat opioid use disorder could reduce the frequency and magnitude of fentanyl-induced respiratory depression., Methods: In this two-period crossover, single-centre study, 14 healthy volunteers (single-blind, randomized) and eight opioid-tolerant patients taking daily opioid doses ≥90 mg oral morphine equivalents (open-label) received continuous intravenous buprenorphine or placebo for 360 minutes, targeting buprenorphine plasma concentrations of 0.2 or 0.5 ng/mL in healthy volunteers and 1.0, 2.0 or 5.0 ng/mL in opioid-tolerant patients. Upon reaching target concentrations, participants received up to four escalating intravenous doses of fentanyl. The primary endpoint was change in isohypercapnic minute ventilation (VE). Additionally, occurrence of apnea was recorded., Results: Fentanyl-induced changes in VE were smaller at higher buprenorphine plasma concentrations. In healthy volunteers, at target buprenorphine concentration of 0.5 ng/mL, the first and second fentanyl boluses reduced VE by [LSmean (95% CI)] 26% (13-40%) and 47% (37-59%) compared to 51% (38-64%) and 79% (69-89%) during placebo infusion (p = 0.001 and < .001, respectively). Discontinuations for apnea limited treatment comparisons beyond the second fentanyl injection. In opioid-tolerant patients, fentanyl reduced VE up to 49% (21-76%) during buprenorphine infusion (all concentration groups combined) versus up to 100% (68-132%) during placebo infusion (p = 0.006). In opioid-tolerant patients, the risk of experiencing apnea requiring verbal stimulation following fentanyl boluses was lower with buprenorphine than with placebo (odds ratio: 0.07; 95% CI: 0.0 to 0.3; p = 0.001)., Interpretation: Results from this proof-of-principle study provide the first clinical evidence that high sustained plasma concentrations of buprenorphine may protect against respiratory depression induced by potent opioids like fentanyl., Competing Interests: The authors have read the journal’s policy and have the following competing interests: RD, FG, SS, AH, and CL are paid employees of Indivior Inc. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Background: It is generally accepted that a neuraxial blockade strengthens the sedative effects of propofol. Deafferentation caused by neuraxial blockade is thought to play a key role., Objectives: The objective is to determine whether epidural blockade affects the bispectral index (BIS) of propofol and two other pharmacodynamic endpoints, mean arterial pressure (MAP) and cardiac output (CO)., Design: Randomised, placebo-controlled study., Setting: University hospital., Patients: Patients scheduled for surgery needing epidural analgesia., Intervention: 28 ASA one or two patients received 0, 50, 100 or 150 mg of epidural ropivacaine. After stabilisation of the epidural blockade, propofol was given by target-controlled infusion. The propofol plasma target concentrations were increased at 6-min intervals from 0 to 1, 2.5, 4 and 6 μg ml-1. The study was performed before surgery., Main Outcome Measures: Three endpoints, BIS, mean arterial blood pressure and CO were measured from baseline (prior to the administration of epidural ropivacaine) until 2 h after the start of propofol infusion. The propofol concentration-effect data were analysed to determine the interaction between epidural blockade and propofol sedation., Results: In the absence of propofol, the increase in number of epidural blocked segments from 0 to 15.5 (range 6 to 21) reduced the MAP by 30%, without affecting BIS or CO. In the absence of epidural blockade, the increase in propofol concentration to 6 μg ml-1 reduced BIS, MAP and CO. When combined, epidural anaesthesia and intravenous propofol exhibited no pharmacodynamic interaction on any of the three endpoints. In addition, epidural blockade did not affect the propofol effect-site equilibration half-life for its haemodynamic effects (11.5 ± 0.5 min) or for its effects on the BIS (4.6 ± 0.4 min)., Conclusion: Epidural blockade reduces the propofol requirements for sedative end points. This is not the result of a pharmacodynamic interaction., Trial Registration: Dutch trial register CCMO, Central Committee on Research Involving Human Subjects, trial number NL 32295.058.10., (Copyright © 2021 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Background: Ketamine has cardiac excitatory side-effects. Currently, data on the effects of ketamine and metabolite concentrations on cardiac output are scarce. We therefore developed a pharmacodynamic model derived from data from a randomised clinical trial. The current study is part of a larger clinical study evaluating the potential mitigating effect of sodium nitroprusside on the psychedelic effects of ketamine., Methods: Twenty healthy male subjects received escalating esketamine and racemic ketamine doses in combination with either placebo or sodium nitroprusside on four visits: (i) esketamine and placebo, (ii) esketamine and sodium nitroprusside, (iii) racemic ketamine and placebo, and (iv) racemic ketamine and sodium nitroprusside. During each visit, arterial blood samples were obtained and cardiac output was measured. Nonlinear mixed-effect modelling was used to analyse the cardiac output time-series data. Ketamine metabolites were added to the model in a sequential manner to evaluate the effects of metabolites., Results: A model including an S-ketamine and S-norketamine effect best described the data. Ketamine increased cardiac output, whereas modelling revealed that S-norketamine decreased cardiac output. No significant effects were detected for R-ketamine, metabolites other than S-norketamine, or sodium nitroprusside on cardiac output., Conclusions: S-Ketamine, but not R-ketamine, increased cardiac output in a dose-dependent manner. In contrast to S-ketamine, its metabolite S-norketamine reduced cardiac excitation in a dose-dependent manner., Clinical Trial Registration: Dutch Cochrane Center 5359., Competing Interests: Declarations of interest The authors declare that they have no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Chronic opioid consumption is associated with addiction, physical dependence, and tolerance. Tolerance results in dose escalation to maintain the desired opioid effect. Intake of high-dose or potent opioids may cause life-threatening respiratory depression, an effect that may be reduced by tolerance. We performed a pharmacokinetic-pharmacodynamic analysis of the respiratory effects of fentanyl in chronic opioid users and opioid-naïve subjects to quantify tolerance to respiratory depression. Fourteen opioid-naïve individuals and eight chronic opioid users received escalating doses of intravenous fentanyl (opioid-naïve subjects: 75-350 µg/70 kg; chronic users: 250-700 µg/70 kg). Isohypercapnic ventilation was measured and the fentanyl plasma concentration-ventilation data were analyzed using nonlinear mixed-effects modeling. Apneic events occurred in opioid-naïve subjects after a cumulative fentanyl dose (per 70 kg) of 225 (n = 3) and 475 µg (n = 6), and in 7 chronic opioid users after a cumulative dose of 600 (n = 2), 1,100 (n = 2), and 1,800 µg (n = 3). The time course of fentanyl's respiratory depressant effect was characterized using a biophase equilibration model in combination with an inhibitory maximum effect (E max ) model. Differences in tolerance between populations were successfully modeled. The effect-site concentration causing 50% ventilatory depression, was 0.42 ± 0.07 ng/mL in opioid-naïve subjects and 1.82 ± 0.39 ng/mL in chronic opioid users, indicative of a 4.3-fold sensitivity difference. Despite higher tolerance to fentanyl-induced respiratory depression, apnea still occurred in the opioid-tolerant population indicative of the potential danger of high-dose opioids in causing life-threatening respiratory depression in all individuals, opioid-naïve and opioid-tolerant., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Deep neuromuscular block is associated with improved working conditions during laparoscopic surgery when propofol is used as a general anaesthetic. However, whether deep neuromuscular block yields similar beneficial effects when anaesthesia is maintained using volatile inhalation anaesthesia has not been systematically investigated. Volatile anaesthetics, as opposed to intravenous agents, potentiate muscle relaxation, which potentially reduces the need for deep neuromuscular block to obtain optimal surgical conditions. We examined whether deep neuromuscular block improves surgical conditions over moderate neuromuscular block during sevoflurane anaesthesia., Methods: In this single-centre, prospective, randomised, double-blind study, 98 patients scheduled for elective renal surgery were randomised to receive deep (post-tetanic count 1-2 twitches) or a moderate neuromuscular block (train-of-four 1-2 twitches). Anaesthesia was maintained with sevoflurane and titrated to bispectral index values between 40 and 50. Pneumoperitoneum pressure was maintained at 12 mm Hg. The primary outcome was the difference in surgical conditions, scored at 15 min intervals by one of eight blinded surgeons using a 5-point Leiden-Surgical Rating Scale (L-SRS) that scores the quality of the surgical field from extremely poor 1 to optimal 5 ., Results: Deep neuromuscular block did not improve surgical conditions compared with moderate neuromuscular block: mean (standard deviation) L-SRS 4.8 (0.3) vs 4.8 (0.4), respectively (P=0.94). Secondary outcomes, including unplanned postoperative readmissions and prolonged hospital admission, were not significantly different., Conclusions: During sevoflurane anaesthesia, deep neuromuscular block did not improve surgical conditions over moderate neuromuscular block in normal-pressure laparoscopic renal surgery., Clinical Trial Registration: NL7844 (www.trialregister.nl)., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)