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Chris H Martini,1 GH Maarten Honing,1 Lori D Bash,2 Erik Olofsen,1 Marieke Niesters,1 Monique van Velzen,1 Albert Dahan,1 Martijn Boon1 1Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands; 2Center for Observational and Real- World Evidence (CORE), Merck & Co., Inc, Kenilworth, NJ, USACorrespondence: Chris H Martini, Department of Anesthesiology, Leiden University Medical Center, Albinusdreef 2, Leiden, 2333, ZA, the Netherlands, Tel +31 71 526 2301, Email c.h.martini@lumc.nlIntroduction: Muscle relaxants are often given during general anesthesia to facilitate endotracheal intubation. However lingering effects after anesthesia-end may lead to respiratory compromise in the PACU. Strategies to reduce these adverse events include monitoring neuromuscular block, the use of short-acting agents and active pharmacological reversal before extubation. At Leiden University Medical Center (LUMC), a tertiary care academic hospital in the Netherlands, various muscle relaxants and reversal agents are freely available to all clinicians without restrictions. In this setting, we intended to evaluate how patient and surgical characteristics impacted the use of these agents for a variety of non-cardiac surgeries.Material and Methods: This is a retrospective database study of adult patients that had received elective, non-cardiac surgery and general anesthesia with endotracheal intubation between 2016 and 2020 at LUMC in the Netherlands. Exclusion criteria consisted of patients pharmacologically reversed with both sugammadex and neostigmine during the same procedure, diagnosed with myasthenia gravis, receiving pyridostigmine therapy, or with renal failure (eGFR < 30 mL.min.1.73m2).Results: We retrieved 23,373 patient records of which 9742 were excluded because one or more exclusion criteria were met. The final cohort consisted of 13,631 cases. Rocuronium was the most commonly used muscle relaxant (88.5%); sugammadex was the most commonly used reversal agent (99.9% of those pharmacologically reversed). Of all cases that received rocuronium as muscle relaxant, 76.9% of patients were not reversed, while 23.1% were reversed with sugammadex. The odds of reversal increased with age, BMI, ASA class (1– 3) and shorter duration of surgery.Conclusion: In an unrestricted clinical environment, rocuronium and sugammadex are the preferred agents for muscle relaxation and reversal. Pharmacologic reversal of neuromuscular block was uncommon overall, but more likely in older and obese patients, higher ASA classification and shorter lasting procedures. Sugammadex has largely replaced neostigmine for this purpose.Keywords: neuromuscular blockade, muscle relaxants, sugammadex

Suzanne JL Broens,1 Xuan He,1 Rachel Evley,2 Erik Olofsen,1 Marieke Niesters,1 Ravi P Mahajan,2 Albert Dahan,1 Monique van Velzen1 1Department of Anesthesiology, Leiden University Medical Centre, Leiden, the Netherlands; 2Nottingham University Hospital NHS Trust, Queen’s Medical Centre, Nottingham, UK Abstract: There is limited information on the occurrence of respiratory events in postoperative patients after discharge from the postanesthesia care unit. We studied the respiratory rate (RR) of 68 patients aged 60 years and above during the first 6 hours following elective surgery under general anesthesia to assess the frequency of respiratory events in the care unit and on the ward. RR was derived from the continuous RR counter RespiR8, measuring RR by quantifying the humidity of exhaled air. One-minute-averaged RRs were collected and analyzed to assess the frequency of postoperative bradypnea (RR 1–6 breaths/minute) and apnea (cessation of inspiratory flow ≥60 seconds). Values were median (interquartile range) or mean (SD). The median RR was 13 (10–15) breaths/minute. In the 6-hour postoperative period, 78% and 57% of patients experienced at least one bradypnea or apnea event, respectively. A median of ten (3.5–24) bradypnea and three (1–11) apnea events were detected per patient. The occurrence of respiratory events in the postanesthesia care unit (PACU) was a predictor of events on the ward (bradypnea, r2=0.4, P

Christian Martini1,*, Ashraf Yassen2,*, Erik Olofsen1, Paul Passier2, Malcom Stoker3, Albert Dahan1 1Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands; 2Global Clinical Pharmacology and Exploratory Development, Astellas Pharma Global Development Europe, Leiderdorp, The Netherlands; 3Global Medical Sciences, Astellas Pharma Global Development Europe, Leiderdorp, The Netherlands*These authors contributed equally to this workAbstract: Treatment of chronic pain is associated with high variability in the response to pharmacological interventions. A mathematical pharmacodynamic model was developed to quantify the magnitude and onset/offset times of effect of a single capsaicin 8% patch application in the treatment of painful diabetic peripheral neuropathy in 91 patients. In addition, a mixture model was applied to objectively match patterns in pain-associated behavior. The model identified four distinct subgroups that responded differently to treatment: 3.3% of patients (subgroup 1) showed worsening of pain; 31% (subgroup 2) showed no change; 32% (subgroup 3) showed a quick reduction in pain that reached a nadir in week 3, followed by a slow return towards baseline (16% ± 6% pain reduction in week 12); 34% (subgroup 4) showed a quick reduction in pain that persisted (70% ± 5% reduction in week 12). The estimate of the response-onset rate constant, obtained for subgroups 1, 3, and 4, was 0.76 ± 0.12 week-1 (median ± SE), indicating that every 0.91 weeks the pain score reduces or increases by 50% relative to the score of the previous week (= t½). The response-offset rate constant could be determined for subgroup 3 only and was 0.09 ± 0.04 week-1 (t½ 7.8 weeks). The analysis allowed separation of a heterogeneous neuropathic pain population into four homogenous subgroups with distinct behaviors in response to treatment with capsaicin. It is argued that this model-based approach may have added value in analyzing longitudinal chronic pain data and allows optimization of treatment algorithms for patients suffering from chronic pain conditions.Keywords: diabetic neuropathic pain, capsaicin 8%, modeling, mixture model

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]

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]

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]

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.)

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).)