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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.)

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.)

Study Objective: Quantitative neuromuscular monitoring is traditionally evaluated at the adductor pollicis muscle. By contrast, the TOF-Cuff compressomyograph evaluates neuromuscular block (NMB) at the upper arm. However, compressomyography has not been fully validated against other monitoring entities. This study evaluates the agreement between NMB measured by compressomyography at the upper arm and electromyography at the adductor pollicis muscle during various levels of neuromuscular block in patients with and without obesity., Interventions: NMB was measured at the upper arm by compressomyography (TOF-Cuff) and by electromyography (GE-NMT) at the adductor pollicis., Design: Prospective, multicenter, observational study., Setting: Secondary and tertiary care hospitals' operating theatres., Patients: 200 non-obese and 50 obese patients., Measurements: During onset and offset of deep (post-tetanic-count 1-15 twitches), moderate (Train-of-Four-count 1-3 twitches) and shallow (Train-of-Four-ratio 0.01-1.0) depths of NMB were measured in obese and non-obese patients. The bias and limits of agreement of both devices were calculated using a Bland-Altman analysis for repeated measurements. Data obtained during spontaneous recovery (i.e. without the use of reversal agents) were used in the primary analyses., Main Results: Data from enrolled patients yielded 942 paired post-tetanic-counts, 1175 paired train-of-four-counts and 1574 paired train-of-four ratios during spontaneous recovery. In non-obese patients, mean bias (95% CI) between the two devices was 3.405 (2.294 to 4.517) during deep NMB; -0.023 (-0.205 to 0.160) during moderate NMB and 0.312 (0.287 to 0.338) during shallow NMB. In obese patients, bias was -0.170 (-2.872 to 2.531); 0.178 (-0.202 to 0.558); 0.384 (0.299 to 0.469) for deep, moderate and shallow NMB respectively., Conclusions: There is variable disagreement between the level of NMB measured at the upper arm by compressomyography and at the adductor pollicis muscle measured by electromyography, throughout the various stages of NMB in obese and non-obese patients. Recovery of NMB on compressomyography preceded recovery on electromyography, which may have consequences for reversal and extubation decisions in clinical practice., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)

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.)

Background: The majority of postoperative patients report moderate to severe pain, possibly related to opioid underdosing or overdosing during surgery. Objective guidance of opioid dosing using the Nociception Level (NOL) index, a multiparameter artificial intelligence-driven index designed to monitor nociception during surgery, may lead to a more appropriate analgesic regimen, with effects beyond surgery. We tested whether NOL-guided opioid dosing during general anaesthesia results in less postoperative pain., Methods: In this two-centre RCT, 50 patients undergoing abdominal surgery under fentanyl/sevoflurane anaesthesia were randomised to NOL-guided fentanyl dosing or standard care in which fentanyl dosing was based on haemodynamics. The primary endpoint of the study was postoperative pain assessed in the PACU., Results: Median postoperative pain scores were 3.2 (inter-quartile range 1.3-4.3) and 4.8 (3.0-5.3) in NOL-guided and standard care groups, respectively (P=0.006). Postoperative morphine consumption (standard deviation) was 0.06 (0.07) mg kg -1 (NOL-guided group) and 0.09 (0.09) mg kg -1 (control group; P=0.204). During surgery, fentanyl dosing was not different between groups (NOL-guided group: 6.4 [4.2] μg kg -1 vs standard care: 6.0 [2.2] μg kg -1 , P=0.749), although the variation between patients was greater in the NOL-guided group (% coefficient of variation 66% in the NOL-guided group vs 37% in the standard care group)., Conclusions: Despite absence of differences in fentanyl and morphine consumption during and after surgery, a 1.6-point improvement in postoperative pain scores was observed in the NOL-guided group. We attribute this to NOL-driven rather than BP- and HR-driven fentanyl dosing during anaesthesia., Clinical Trial Registration: www.trialregister.nl under identifier NL7845., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Recent studies show activity of ketamine metabolites, such as hydroxynorketamine, in producing rapid relief of depression-related symptoms and analgesia. To improve our understanding of the pharmacokinetics of ketamine and metabolites norketamine, dehydronorketamine, and hydroxynorketamine, we developed a population pharmacokinetic model of ketamine and metabolites after i.v. administration of racemic ketamine and the S-isomer (esketamine). Pharmacokinetic data were derived from an RCT on the efficacy of sodium nitroprusside (SNP) in reducing the psychotomimetic side-effects of ketamine in human volunteers., Methods: Three increasing i.v. doses of esketamine and racemic ketamine were administered to 20 healthy volunteers, and arterial plasma samples were obtained for measurement of ketamine and metabolites. Subjects were randomised to receive esketamine/SNP, esketamine/placebo, racemic ketamine/SNP, and racemic ketamine/placebo on four separate occasions. The time-plasma concentration data of ketamine and metabolites were analysed using a population compartmental model approach., Results: The pharmacokinetics of ketamine and metabolites were adequately described by a seven-compartment model with two ketamine, norketamine, and hydroxynorketamine compartments and one dehydronorketamine compartment with metabolic compartments in-between ketamine and norketamine, and norketamine and dehydronorketamine main compartments. Significant differences were found between S- and R-ketamine enantiomer pharmacokinetics, with up to 50% lower clearances for the R-enantiomers, irrespective of formulation. Whilst SNP had a significant effect on ketamine clearances, simulations showed only minor effects of SNP on total ketamine pharmacokinetics., Conclusions: The model is of adequate quality for use in future pharmacokinetic and pharmacodynamic studies into the efficacy and side-effects of ketamine and metabolites., Clinical Trial Registration: Dutch Cochrane Center 5359., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Opioids are potent painkillers but come with serious adverse effects ranging from addiction to potentially lethal respiratory depression. A variety of drugs with separate mechanisms of action are available to prevent or reverse opioid-induced respiratory depression (OIRD)., Methods: The authors reviewed human studies on reversal of OIRD using models that describe and predict the time course of pharmacokinetics (PK) and pharmacodynamics (PD) of opioids and reversal agents and link PK to PD., Results: The PKPD models differ in their basic structure to capture the specific pharmacological mechanisms by which reversal agents interact with opioid effects on breathing. The effect of naloxone, a competitive opioid receptor antagonist, is described by the combined effect-compartment receptor-binding model to quantify rate limitation at the level of drug distribution and receptor kinetics. The effects of reversal agents that act through non-opioidergic pathways, such as ketamine and the experimental drug GAL021, are described by physiological models, in which stimulants act at CO 2 chemosensitivity, CO 2 -independent ventilation, or both. The PKPD analyses show that although all reversal strategies may be effective under certain circumstances, there are conditions at which reversal is less efficacious and sometimes even impossible., Conclusions: Model-based drug development is needed to design an 'ideal' reversal agent-that is, one that is not influenced by opioid receptor kinetics, does not interfere with opioid analgesia, has a rapid onset of action with long-lasting effects, and is devoid of adverse effects., (Copyright © 2019 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Animal studies suggest that N-methyl-d-aspartate receptor (NMDAR) hypofunction and subsequent decline in intracellular nitric oxide (NO) are responsible for development of ketamine-induced psychedelic symptoms. To examine this mechanism in humans, we administered the NO donor sodium nitroprusside during infusion of racemic ketamine (RS-ketamine), containing equal amounts of S(+)- and R(-)-ketamine isomers, or esketamine, containing just the S(+)-isomer., Methods: In this randomised, double blind, placebo-controlled crossover study, healthy volunteers were treated with sodium nitroprusside 0.5 μg kg -1  min -1 or placebo during administration of escalating doses of RS-ketamine (total dose 140 mg) or esketamine (70 mg). Drug high, internal and external perception, obtained using the Bowdle questionnaire, were scored over time on a visual analogue scale. The area-under-the-time-effect-curve (AUC) was calculated for each end-point., Results: Sodium nitroprusside significantly reduced drug high AUC [mean (standard deviation); placebo 9070 (4630) vs sodium nitroprusside 7100 (3320), P=0.02], internal perception AUC [placebo 1310 (1250) vs nitroprusside 748 (786), P<0.01] and external perception AUC [placebo 4110 (2840) vs nitroprusside 2890 (2120), P=0.02] during RS-ketamine infusion, but was without effect on any of these measures during esketamine infusion., Conclusions: These data suggest that NO depletion plays a role in RS-ketamine-induced psychedelic symptoms in humans. The sodium nitroprusside effect was observed for R(-)- but not S(+)-isomer-induced psychedelic symptoms. Further studies are needed to corroborate our findings and assess whether higher sodium nitroprusside doses will reduce esketamine-induced psychedelic symptoms., Clinical Trial Registration: NTR 5359., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Opioids can produce life-threatening respiratory depression. This study tested whether subanaesthetic doses of esketamine stimulate breathing in an established human model of opioid-induced respiratory depression., Methods: In a study with a randomised, double blind, placebo controlled, crossover design, 12 healthy, young volunteers of either sex received a dose escalating infusion of esketamine (cumulative dose 40 mg infused in 1 h) on top of remifentanil-induced respiratory depression. A population pharmacokinetic-pharmacodynamic analysis was performed with sites of drug action at baseline ventilation, ventilatory CO 2 -chemosensitivity, or both., Results: Remifentanil reduced isohypercapnic ventilation (end-tidal PCO 2 6.5 kPa) by approximately 40% (from 20 to 12 litre min -1 ) in esketamine and placebo arms of the study, through an effect on baseline ventilation and ventilatory CO 2 sensitivity. The reduction in ventilation was related to a remifentanil effect on ventilatory CO 2 sensitivity (~39%) and on baseline ventilation (~61%). Esketamine increased breathing through an exclusive stimulatory effect on ventilatory CO 2 sensitivity. The remifentanil concentration that reduced ventilatory CO 2 sensitivity by 50% (C 50 ) was doubled at an esketamine concentration of 127 (84-191) ng ml -1 [median (interquartile range)]; the esketamine effect was rapid and driven by plasma pharmacokinetics. Placebo had no systematic effect on opioid-induced respiratory depression., Conclusions: Esketamine effectively countered remifentanil-induced respiratory depression, an effect that was attributed to an increase in remifentanil-reduced ventilatory CO 2 chemosensitivity., (Copyright © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: There is a clinical need for potent opioids that produce little or no respiratory depression. In the current study we compared the respiratory effects of tapentadol, a mu-opioid receptor agonist and noradrenaline reuptake inhibitor, and oxycodone, a selective mu-opioid receptor agonist. We hypothesize that tapentadol 100 mg has a lesser effect on the control of breathing than oxycodone 20 mg., Methods: Fifteen healthy volunteers were randomized to receive oral tapentadol (100 and 150 mg), oxycodone 20 mg or placebo immediate release tablets in a crossover double-blind randomized design. The main end-point of the study was the effect of treatment on the ventilatory response to hypercapnia and ventilation at an extrapolated end-tidal PCO2 of 7.3 kPa (55 mmHg, VE55); VE55 was assessed prior and for 6-h following drug intake., Results: All three treatments had typical opioid effects on the hypercapnic ventilatory response: a shift to the right coupled to a decrease of the response slope. Oxycodone 20 mg had a significantly larger respiratory depressant effect than tapentadol 100 mg (mean difference -5.0 L min-1, 95% confidence interval: -7.1 to -2.9 L min-1, P<0.01), but not larger than tapentadol 150 mg (oxycodone vs. tapentadol 150 mg: P>0.05)., Conclusions: In this exploratory study we observed that both tapentadol and oxycodone produce respiratory depression. Tapentadol 100 mg but not 150 mg had a modest respiratory advantage over oxycodone 20 mg. Further studies are needed to explore how these results translate to the clinical setting., (© The Author 2017. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Background: The commonality between chronic conditions that are treated with low-dose ketamine, such as specific chronic pain conditions, depression, and post-traumatic stress disorder, can be found in relation to the stress system, particularly the hypothalamus-pituitary-adrenal axis. In this study we assess the effect of ketamine on the stress system by measuring plasma and saliva cortisol production during and following exposure to low-dose ketamine., Methods: In a double-blind, randomized, placebo-controlled study, the influence of subanaesthetic ketamine (0.29 mg kg(-1) h(-1) for 1 h, followed by 0.57 mg kg(-1) h(-1) for another hour) was studied with repeated plasma and saliva cortisol samples in 12 healthy male volunteers. A pharmacokinetic-pharmacodynamic model was used to describe the circadian rhythm-dependent ketamine-induced production of cortisol., Results: The endogenous mean baseline cortisol production was 7.9 (SE 1.5) nM min(-1). Consistent with the circadian rhythm, cortisol production decayed by 1.25 nM min(-1) h(-1). Ketamine doubled the cortisol production at a concentration of 165 (SE 35) ng ml(-1). The salivary cortisol concentration closely mirrored the plasma concentration and was exponentially related to the plasma concentration with, at 100 ng ml(-1) ketamine, a saliva:plasma ratio of 0.036 (se 0.006)., Conclusions: Ketamine has an appreciable effect on cortisol production. This may impact on critical physiological and psychological functions., Clinical Trial Registration: This study was registered in the Dutch Trial Register under number NTR2717 at www.trialregister.nl., (© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Postoperative monitoring of ventilation is largely restricted to the measurement of haemoglobin-oxygen saturation and respiratory rate (RR) derived from the ECG. measurement is inadequate when used with supplemental oxygen and ECG-derived RR is subject to artifacts. A new monitor measures RR by quantifying the humidity of exhaled air (respiR8(®))., Methods: The accuracy of the system was tested using a breathing simulator. In healthy volunteers, the respiR8(®) monitor was compared with two other methods of measuring RR: capnometry and counting of thoracic breathing movements. The ability of the monitor to track changes in RR resulting from the infusion of 2.5 μg kg(-1) fentanyl was assessed and compared with RR measured from a validated flow measurement system. The RR in 50 postoperative patients measured with the respiR8(®) was compared with that derived from the ECG. RR values were compared by population-based Bland-Altman analyses., Results: The respiR8(®) monitor was accurate in the range required in clinical practice. There was a close agreement between RR from respiR8(®), capnometry, and manual counting of respiratory movements without bias (limits of agreement ±1 bpm). The respiR8(®) monitor was well able to accurately track RR changes from fentanyl. In postoperative patients, RR from respiR8(®) and ECG had a bias of 1.7 (5.7) bpm due to greater RR values observed from the ECG due to artifacts., Conclusions: The respiR8(®) gives an accurate measurement of RR and is useful in postoperative care.

Background: It would be useful to have an open-source electroencephalographic (EEG) index of gamma-amino-butyric acid (GABA)-ergic anaesthetic drug effect that is resistant to eye-blink artifact, responds rapidly to changes in EEG pattern, and can be linked to underlying neurophysiological and neuropharmacological mechanisms that control the conscious state., Methods: The EEG waveform can be described as a sequence of ordinal patterns. The permutation entropy (PE) describes the relative occurrence of each of these patterns. It is high ( approximately 1.0) when the signal has predominantly high frequencies and low ( approximately 0.4) when the signal consists of only low frequencies. The response of the PE to various computer-generated EEG-like waveforms was assessed. A composite PE index (CPEI) was developed, which was the sum of two simple PEs and included a small measurement-noise threshold (0.5 microV). We also applied the CPEI to two small pilot EEG data sets from patients receiving sevoflurane (n=21) or propofol (n=9) anaesthesia., Results: With minimal pre-processing or artifact rejection, the CPEI reliably tracked the anaesthetic-related EEG changes, namely loss of high frequencies, spindle-like waves, and delta waves. Using NONMEM, it was possible to construct adequate pharmacokinetic-pharmacodynamic models from the data. The CPEI was comparable with models derived using the bispectral index [BIS R(2)=0.88 (0.08) vs CPEI R(2)=0.91 (0.06) for the propofol data] and M-entropy indices [M-entropy R(2)=0.91 (0.06) vs CPEI R(2)=0.87 (0.09) for the sevoflurane data]., Conclusions: PE of the EEG shows promise as a simple measure of GABAergic anaesthetic drug effect.

Background: We measured the effect of two weight adjusted i.v. doses (0.2 mg per 70 kg and 0.4 mg per 70 kg) of the potent opioid buprenorphine on analgesia and respiratory depression in healthy volunteers. The aim of the study was to compare buprenorphine's behaviour with respect to the occurrence of ceiling (or apparent maximum) in these typical micro-opioid protein-(MOP) receptor effects., Methods: Ten subjects (5 males) received 0.2 mg per 70 kg, 10 others (5 males) 0.4 mg per 70 kg i.v. buprenorphine. Steady-state inspired minute ventilation at a fixed end-tidal Pco(2) of 7 kPa was measured before drug infusion and at regular intervals after drug infusion. Experimental pain was induced using transcutaneous electrical stimulation and a gradually increasing current. Pain tolerance was measured at regular intervals before and after drug infusion. The studies lasted 8 h., Results: After infusion of the drug ventilation showed a rapid decline and reached peak depression between 150 and 180 min after drug administration. This effect was dose-independent with respect to timing and magnitude. At peak respiratory depression minute ventilation was 13.1 (sd 1.8) litre min(-1) in the 0.2 mg group vs 12.0 (sd 1.3) litre min(-1) in the 0.4 mg group (n.s.). At buprenorphine 0.2 mg a small short-lived analgesic effect was observed with a maximum increase in pain tolerance current of 6.7 (sd 2.8) mA occurring at 75 min after drug administration. Peak analgesic effect was 29% above baseline current. In contrast, buprenorphine 0.4 mg caused a large and long-lived analgesic effect with a maximum increase in pain tolerance current of 23.8 (sd 7.4) mA occurring at 130 min after drug administration. Peak analgesic effect was 160% above baseline current (0.4 vs 0.2 mg, P<0.01)., Conclusions: While buprenorphine's analgesic effect increased significantly, respiratory depression was similar in magnitude and timing for the two doses tested. We conclude that over the dose range tested buprenorphine displays ceiling in respiratory effect but none in analgesic effect.

Background: There is evidence from animal studies suggesting the existence of a ceiling effect for buprenorphine-induced respiratory depression. To study whether an apparent ceiling effect exists for respiratory depression induced by buprenorphine, we compared the respiratory effects of buprenorphine and fentanyl in humans and rats., Methods: In healthy volunteers, the opioids were infused i.v. over 90 s and measurements of minute ventilation at a fixed end-tidal PCO2 of 7 kPa were obtained for 7 h. Buprenorphine doses were 0.7, 1.4, 4.3 and 8.6 microg kg(-1) (n=20 subjects) and fentanyl doses 1.1, 2.1, 2.9, 4.3 and 7.1 microg kg(-1) (n=21). Seven subjects received placebo. In rats, both opioids were infused i.v. over 20 min, and arterial PCO2 was measured 5, 10, 15 and 20 min after the start of fentanyl infusion and 30, 150, 270 and 390 min after the start of buprenorphine infusion. Doses tested were buprenorphine 0, 100, 300, 1000 and 3000 microg kg(-1) and fentanyl 0, 50, 68 and 90 microg kg(-1)., Results: In humans, fentanyl produced a dose-dependent depression of minute ventilation with apnoea at doses > or = 2.9 microg kg(-1); buprenorphine caused depression of minute ventilation which levelled off at doses > or = 3.0 microg kg(-1) to about 50% of baseline. In rats, the relationship of arterial PCO2 and fentanyl dose was linear, with maximum respiratory depression at 20 min (maximum PaCO2 8.0 kPa). Irrespective of the time at which measurements were obtained, buprenorphine showed a non-linear effect on PaCO2, with a ceiling effect at doses > 1.4 microg kg(-1). The effect on PaCO2 was modest (maximum value measured, 5.5 kPa)., Conclusions: Our data confirm a ceiling effect of buprenorphine but not fentanyl with respect to respiratory depression.

We have studied the pulmonary uptake of sufentanil in patients during and after a short infusion of the drug. We studied 10 patients undergoing elective coronary artery bypass surgery during anaesthesia with 0.4-0.8% enflurane, before surgery. Sufentanil 50 micrograms min-1 was given over 10 min by a constant rate infusion. During infusion and for 20 min thereafter, blood samples were obtained from the distal port of the pulmonary artery catheter and from a radial artery catheter. Uptake and release of sufentanil into and from the lungs were examined by mass balance and compartmental analyses. At the end of the infusion a mean of 48.9 (SD 18.6)% of the dose was retained in the lungs, and 20 min after infusion retention was 18.4 (22.4)%. Smokers had significantly higher pulmonary retention of sufentanil. The pulmonary volume of distribution of sufentanil, estimated from the two-compartment model, was 20.9 (7.7) litre. We conclude that pulmonary uptake of sufentanil is significant, if the drug is given as an infusion.