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What We Already Know About This Topic: The ventilatory response to hypoxia is a critical reflex that is impaired by neuromuscular blocking drugs. However, the degree to which this reflex is restored after reversal of blockade is unknown.What This Article Tells Us That Is New: Despite full reversal of neuromuscular blockade at the thumb using different drug classes, this hypoxic chemoreflex is not fully restored.Background: The ventilatory response to hypoxia is a life-saving chemoreflex originating at the carotid bodies that is impaired by nondepolarizing neuromuscular blocking agents. This study evaluated the effect of three strategies for reversal of a partial neuromuscular block on ventilatory control in 34 healthy male volunteers on the chemoreflex. The hypothesis was that the hypoxic ventilatory response is fully restored following the return to a train-of-four ratio of 1.Methods: In this single-center, experimental, randomized, controlled trial, ventilatory responses to 5-min hypoxia (oxygen saturation, 80 ± 2%) and ventilation at hyperoxic isohypercapnia (end-tidal carbon dioxide concentration, 55 mmHg) were obtained at baseline, during rocuronium-induced partial neuromuscular block (train-of-four ratio of 0.7 measured at the adductor pollicis muscle by electromyography), and following reversal until the train-of-four ratio reached unity with placebo (n = 12), 1 mg neostigmine/0.5 mg atropine (n = 11), or 2 mg/kg sugammadex (n = 11).Results: This study confirmed that low-dose rocuronium reduced the ventilatory response to hypoxia from 0.55 ± 0.22 (baseline) to 0.31 ± 0.21 l · min · % (train-of-four ratio, 0.7; P < 0.001). Following full reversal as measured at the thumb, there was persistent residual blunting of the hypoxic ventilatory response (0.45 ± 0.16 l · min · %; train-of-four ratio, 1.0; P < 0.001). Treatment effect was not significant (analysis of covariance, P = 0.299) with chemoreflex impairment in 5 (45%) subjects following sugammadex reversal, in 7 subjects (64%) following neostigmine reversal, and in 10 subjects (83%) after spontaneous reversal to a train-of-four ratio of 1.Conclusions: Despite full reversal of partial neuromuscular block at the thumb, impairment of the peripheral chemoreflex may persist at train-of-four ratios greater than 0.9 following reversal with neostigmine and sugammadex or spontaneous recovery of the neuromuscular block. [ABSTRACT FROM AUTHOR]

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 CO2 chemosensitivity, CO2-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. [ABSTRACT FROM AUTHOR]

Background: The multidimensional index of nociception, the nociception level, outperforms blood pressure and heart rate in detection of nociceptive events during anesthesia. We hypothesized that nociception level-guided analgesia reduces opioid consumption and suboptimal anesthesia events such as low blood pressure and use of vasoactive medication.Methods: In this single-blinded randomized study, 80 American Society of Anesthesiologists class I-III adult patients of either sex, scheduled for major abdominal procedures under remifentanil/propofol anesthesia by target-controlled infusion, were included. During the procedure nociception level, noninvasive blood pressure, and heart rate were monitored. Patients were randomized to receive standard clinical care or nociception level-guided analgesia. In the nociception level-guided group, remifentanil concentration was reduced when index values were less than 10 or increased when values were above 25 for at least 1 min, in steps of 0.5 to 1.0 ng/ml. Propofol was titrated to bispectral index values between 45 and 55. The primary outcomes of the study were remifentanil and propofol consumption and inadequate anesthesia events.Results: Compared with standard care, remifentanil administration was reduced in nociception level-guided patients from (mean ± SD) 0.119 ± 0.033 to 0.086 ± 0.032 μg · kg · min (mean difference, 0.039 μg · kg · min; 95% CI, 0.025-0.052 μg · kg · min; P < 0.001). Among nociception level-guided patients, 2 of 40 (5%) experienced a hypotensive event (mean arterial pressure values less than 55 mm Hg) versus 11 of 40 (28%) patients in the control group (relative risk, 0.271; 95% CI, 0.08-0.77; P = 0.006). In the nociception level-guided group, 16 of 40 (40%) patients received vasoactive medication versus 25 of 40 (63%) patients in the standard care group (relative risk, 0.64; 95% CI, 0.40-0.99; P = 0.044).Conclusions: Nociception level-guided analgesia during major abdominal surgery resulted in 30% less remifentanil consumption. [ABSTRACT FROM AUTHOR]

In this experimental randomized placebo-controlled 4-way crossover trial, we explored the analgesic effects of inhaled pharmaceutical-grade cannabis in 20 chronic pain patients with fibromyalgia. We tested 4 different cannabis varieties with exact knowledge on their [INCREMENT]-tetrahydrocannabinol (THC) and cannabidiol (CBD) content: Bedrocan (22.4-mg THC, <1-mg CBD; Bedrocan International BV, Veendam, the Netherlands), Bediol (13.4-mg THC, 17.8-mg CBD; Bedrocan International BV, Veendam, the Netherlands), Bedrolite (18.4-mg CBD, <1-mg THC; Bedrocan International BV, Veendam, the Netherlands), and a placebo variety without any THC or CBD. After a single vapor inhalation, THC and CBD plasma concentrations, pressure and electrical pain thresholds, spontaneous pain scores, and drug high were measured for 3 hours. None of the treatments had an effect greater than placebo on spontaneous or electrical pain responses, although more subjects receiving Bediol displayed a 30% decrease in pain scores compared to placebo (90% vs 55% of patients, P = 0.01), with spontaneous pain scores correlating with the magnitude of drug high (ρ = -0.5, P < 0.001). Cannabis varieties containing THC caused a significant increase in pressure pain threshold relative to placebo (P < 0.01). Cannabidiol inhalation increased THC plasma concentrations but diminished THC-induced analgesic effects, indicative of synergistic pharmacokinetic but antagonistic pharmacodynamic interactions of THC and CBD. This experimental trial shows the complex behavior of inhaled cannabinoids in chronic pain patients with just small analgesic responses after a single inhalation. Further studies are needed to determine long-term treatment effects on spontaneous pain scores, THC-CBD interactions, and the role of psychotropic symptoms on pain relief. [ABSTRACT FROM AUTHOR]

The ventilatory control system is highly vulnerable to exogenous administered opioid analgesics. Particularly respiratory depression is a potentially lethal complication that may occur when opioids are overdosed or consumed in combination with other depressants such as sleep medication or alcohol. Fatalities occur in acute and chronic pain patients on opioid therapy and individuals that abuse prescription or illicit opioids for their hedonistic pleasure. One important strategy to mitigate opioid-induced respiratory depression is cotreatment with nonopioid respiratory stimulants. Effective stimulants prevent respiratory depression without affecting the analgesic opioid response. Several pharmaceutical classes of nonopioid respiratory stimulants are currently under investigation. The majority acts at sites within the brainstem respiratory network including drugs that act at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (ampakines), 5-hydroxytryptamine receptor agonists, phospodiesterase-4 inhibitors, D1-dopamine receptor agonists, the endogenous peptide glycyl-glutamine, and thyrotropin-releasing hormone. Others act peripherally at potassium channels expressed on oxygen-sensing cells of the carotid bodies, such as doxapram and GAL021 (Galleon Pharmaceuticals Corp., USA). In this review we critically appraise the efficacy of these agents. We conclude that none of the experimental drugs are adequate for therapeutic use in opioid-induced respiratory depression and all need further study of efficacy and toxicity. All discussed drugs, however, do highlight potential mechanisms of action and possible templates for further study and development. [ABSTRACT FROM AUTHOR]

Background: Previous studies integrated opioid benefit and harm into one single function-the utility function-to determine the drug toxicity (respiratory depression) in light of its wanted effect (analgesia). This study further refined the concept of the utility function using the respiratory and analgesic effects of the opioid analgesic alfentanil as example.Methods: Data from three previous studies in 48 healthy volunteers were combined and reanalyzed using a population pharmacokinetic-pharmacodynamic analysis to create utility probability functions. Four specific conditions were defined: probability of adequate analgesia without severe respiratory depression, probability of adequate analgesia with severe respiratory depression, probability of inadequate analgesia without severe respiratory depression, and probability of inadequate analgesia with severe respiratory depression.Results: The four conditions were successfully identified with probabilities varying depending on the opioid effect-site concentration. The optimum analgesia probability without serious respiratory depression is reached at an alfentanil effect-site concentration of 68 ng/ml, and exceeds the probability of the most unwanted effect, inadequate analgesia with severe respiratory depression (odds ratio, 4.0). At higher effect-site concentrations the probability of analgesia is reduced and exceeded by the probability of serious respiratory depression.Conclusions: The utility function was successfully further developed, allowing assessment of specific conditions in terms of wanted and unwanted effects. This approach can be used to compare the toxic effects of drugs relative to their intended effect and may be a useful tool in the development of new compounds to assess their advantage over existing drugs. [ABSTRACT FROM AUTHOR]

Objectives: We determined whether adding cannabis to oxycodone for chronic non-cancer pain management could reduce treatment-related adverse effects (AEs) while maintaining effective analgesia., Methods: In this open-label study, fibromyalgia patients aged ≥18 years were randomized to receive 5 mg oxycodone tablets (max. four times/day), 150 mg of inhaled cannabis containing 6.3% Δ 9 -tetrahydrocannabinol and 8% cannabidiol (max. times inhalation sessions/day), or a combination of both for 6 weeks. The primary endpoint was treatment-related adverse events, assessed using a 10-point composite adverse event (cAE) score; additionally, we recorded daily reported pain relief and daily tablet and cannabis consumption., Results: In total, 23 patients were treated with oxycodone, 29 with cannabis, and 29 with the oxycodone/cannabis combination. Three patients from the oxycodone group (13%) and 18 patients from the cannabis groups (31%, 9 in each group) withdrew from the trial within 2-3 weeks because of the severity of AEs. There were no differences in treatment-related cAE scores among the three groups that completed the study ( p  = 0.70). The analgesic responder rate showed a ≥1- point reduction in pain in 50% and a ≥2-point reduction in 20% of patients, while 50% of patients experienced no treatment benefit. The combination treatment reduced oxycodone tablet consumption by 35% ( p  = 0.02), but it did not affect the number of cannabis inhalation sessions., Conclusions: Cannabis combined with oxycodone offered no advantage over either treatment alone, except for a reduction in opioid tablet intake; however, the overall drug load was the highest in the combination group. Moreover, cannabis was poorly tolerated and led to treatment discontinuation in one-third of participants treated with cannabis., Clinical Trial Registration: The trial was registered at the WHO International Clinical Trials Registry Platform (trialsearch.who.int) on July 26, 2019, identifier NL7902., Competing Interests: AD reported receiving personal fees from Trevena and Enalare outside the submitted work. 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 van Dam, Kramers, Schellekens, Bouvy, van Dorp, Kowal, Olofsen, Dahan, Niesters and van Velzen.)

Background: Recent advances in artificial intelligence (AI) have enabled development of natural language algorithms capable of generating coherent texts. We evaluated the quality, validity, and safety of this generative AI in preoperative anaesthetic planning., Methods: In this exploratory, single-centre, convergent mixed-method study, 10 clinical vignettes were randomly selected, and ChatGPT (OpenAI, 4.0) was prompted to create anaesthetic plans, including cardiopulmonary risk assessment, intraoperative anaesthesia technique, and postoperative management. A quantitative assessment compared these plans with those made by eight senior anaesthesia consultants. A qualitative assessment was performed by an adjudication committee through focus group discussion and thematic analysis. Agreement on cardiopulmonary risk assessment was calculated using weighted Kappa, with descriptive data representation for other outcomes., Results: ChatGPT anaesthetic plans showed variable agreement with consultants' plans. ChatGPT, the survey panel, and adjudication committee frequently disagreed on cardiopulmonary risk estimation. The ChatGPT answers were repetitive and lacked variety, evidenced by the strong preference for general anaesthesia and absence of locoregional techniques. It also showed inconsistent choices regarding airway management, postoperative analgesia, and medication use. While some differences were not deemed clinically significant, subpar postoperative pain management advice and failure to recommend tracheal intubation for patients at high risk for pulmonary aspiration were considered inappropriate recommendations., Conclusions: Preoperative anaesthetic plans generated by ChatGPT did not consistently meet minimum clinical standards and were unlikely the result of clinical reasoning. Therefore, ChatGPT is currently not recommended for preoperative planning. Future large language models trained on anaesthesia-specific datasets might improve performance but should undergo vigorous evaluation before use in clinical practice., Competing Interests: Declaration of interest MAM is founder of medical data platform Delphyr, which is unrelated to this work. All other authors declare that they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The acute hypoxic ventilatory response is a critical chemoreflex originating at the carotid bodies. This study investigates the impact of low-dose i.v. esketamine on the ventilatory response to 20 min of isocapnic hypoxia to test the hypothesis that esketamine does not affect hypoxic ventilation., Methods: In this open-label study, 18 healthy subjects received a 3-h escalating i.v. infusion of esketamine, totalling 1.0 mg kg -1 . Before the esketamine infusion (control condition) and during the last 30 min of infusion, the ventilatory response to 20 min of isocapnic hypoxia (oxygen saturation ∼80%) was measured. We assessed the increase in ventilation from baseline to its peak during the first 5 min of isocapnic hypoxia (hypoxic ventilatory response) and the increase in ventilation from baseline to 20 min of isocapnic hypoxia (sustained hypoxia). Haemodynamics and acute brain function were also measured., Results: Independent of hypoxia, a small excitatory effect of ketamine on isocapnic ventilation was observed: the mean increase in ventilation (95% confidence interval) was 3.1 (2.4-3.7) L min -1 (P<0.0001). Esketamine had no effect on the isocapnic ventilatory response to acute and sustained hypoxia but increased MAP (+10 mm Hg) and heart rate (+10 beats min -1 ), similarly during normoxia and hypoxia. Esketamine increased anxiety and alertness and affected external perception., Conclusions: I.V. esketamine up to 1 mg kg -1 does not affect the ventilatory response to hypoxia, but affects haemodynamics and acute brain function. Increases in anxiety and alertness could be a cause of the sustained ventilatory response to hypoxia during esketamine infusion., Clinical Trial Registration: The trial was registered at the ISRCTN registry on June 27, 2023 under identifier ISRCTN 42617929 (https://www.isrctn.com/ISRCTN42617929)., (Copyright © 2024 The Authors. 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.)

Educational Challenge: Medical education must equip future professionals with the necessary skills to navigate the complex healthcare landscape. Clinical knowledge is essential, and critical and creative thinking skills are vital to meet the challenges of the system. Design thinking offers a structured approach that integrates creativity and innovation, yet its application in medical education is absent., Solution and Implementation: The compulsory MasterMinds Challenge course at Leiden University Medical Center utilizes design thinking principles to address real world healthcare challenges. Final-year medical students participated in a two-day program. The course encompassed empathizing with stakeholders, problem definition, ideation, prototyping, and refining solutions. Presentation skills were emphasized, culminating in a symposium where teams showcase their outcomes. Implementation of the MasterMinds Challenge course was successful with 33 sessions delivered to 1217 medical students. Challenges covered various healthcare topics, yielding creative yet practical outcomes. Students appreciate the real world healthcare challenge, team-based approach, and the applicability of design thinking principles. Challenge owners expressed satisfaction with students' commitment, creativity, and empathizing abilities., Lessons Learned and Next Steps: To further enhance the MasterMinds Challenge course, a more longitudinal format is being designed, enabling greater autonomy and emphasizing the refining and implementation phases. The course can be extended to medical postgraduate professionals and interdisciplinary collaborations, fostering innovative ideas beyond current practices. By developing problem-solving skills, the MasterMinds Challenge course contributes to a future-proof medical education program and prepares students to meet the evolving needs of healthcare.

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.)

Introduction: Drug-induced respiratory depression is potentially fatal and can be caused by various drugs such as synthetic opioids and tranquilizers. The only class of respiratory depressants that has a specific reversal agent are opioids, such as naloxone. These reversal agents have limited utility in situations of polysubstance ingestion with agents from multiple respiratory depressant classes. Hence, there is an unmet need for drugs that stimulate breathing irrespective of the underlying cause of respiratory depression, i.e. mechanism agnostic respiratory stimulants., Areas Covered: In this review, we discuss agnostic respiratory stimulants, tested in humans with promising results, i.e. ampakines, drugs that act at the carotid bodies, N-methyl-D-aspartate receptor antagonist ketamine, and orexin receptor-2-agonist danavorexton, and others that demonstrated positive effects in animals but not yet in humans., Expert Opinion: Rapid, effective rescuing of individuals who overdosed on respiratory depressants saves lives. While naloxone is the preferred drug for reversing opioid-induced respiratory depression, its effectiveness is limited in cases involving non-opioids. While several agnostic respiratory stimulants showed promise in humans, further research is needed to optimize dosing, evaluate safety and efficacy in deeper respiratory depression (apnea). Additionally, future studies should combine agnostic stimulants with naloxone, to improve rapid, effective rescue from drug overdoses.

Background: There is lack of data on opioid (over)use for migraine in Europe., Methods: We performed a cross-sectional study in a large Dutch cohort using a web-based questionnaire to assess opioid use in individuals with migraine. Primary outcome was to assess opioid use for the treatment of migraine attacks. As secondary outcomes we specified use of opioids (duration of use, type of opioids, prescriber) and compared between persons with episodic migraine versus chronic migraine. Descriptive statistics, unpaired T-tests, Chi-square and Mann-Whitney U tests were used., Results: In total n = 3712 patients participated, 13% ever used opioids for headache. In opioid users, 27% did this for >1 month, and 11% for >1 year, and 2% without prescription. The majority of prescribing physicians were general practitioners (46%), followed by neurologists (35%), other specialists (9%), or emergency room doctors (8%). Opioids were used as acute treatment in 63%, in 16% as preventive treatment, and in 21% for both indications. Chronic migraine patients reported more opioid use compared with episodic migraine (22% versus 12%, p < 0.001), with also more prolonged use (>1 month: 34% chronic migraine versus 24% episodic migraine, p < 0.003)., Conclusion: Opioid use is more frequent and prolonged in chronic migraine patients. Further education for both doctors and migraine subjects and providing multimodal pain management strategies are needed to reduce opioid use in persons with migraine.

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: 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 this pooled analysis of two randomized clinical trials, intraoperative opioid dosing based on the nociception level-index produced less pain compared to standard care with a difference in pain scores in the post-anesthesia care unit of 1.5 (95% CI 0.8-2.2) points on an 11-point scale. The proportion of patients with severe pain was lower by 70%. Severe postoperative pain remains a significant problem and associates with several adverse outcomes. Here, we determined whether the application of a monitor that detects intraoperative nociceptive events, based on machine learning technology, and treatment of such events reduces pain scores in the post-anesthesia care unit (PACU). To that end, we performed a pooled analysis of two trials in adult patients, undergoing elective major abdominal surgery, on the effect of intraoperative nociception level monitor (NOL)-guided fentanyl dosing on PACU pain was performed. Patients received NOL-guided fentanyl dosing or standard care (fentanyl dosing based on hemodynamic parameters). Goal of the intervention was to keep NOL at values that indicated absence of nociception. The primary endpoint of the study was the median pain score obtained in the first 90 min in the PACU. Pain scores were collected at 15 min intervals on an 11-point Likert scale. Data from 125 patients (55 men, 70 women, age range 21-86 years) were analyzed. Sixty-one patients received NOL-guided fentanyl dosing and 64 standard care. Median PACU pain score was 1.5 points (0.8-2.2) lower in the NOL group compared to the standard care; the proportion of patients with severe pain was 70% lower in the NOL group ( p  = 0.045). The only significant factor associated with increased odds for severe pain was the standard of care compared to NOL treatment (OR 6.0, 95% CI 1.4 -25.9, p  = 0.017). The use of a machine learning-based technology to guide opioid dosing during major abdominal surgery resulted in reduced PACU pain scores with less patients in severe pain., Competing Interests: AD: received consultancy fees from Medasense Biometrics Ltd. (Ramat Gan, Israel). 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., (© 2023 van der Wal, Meijer, Fuica, Silman, Boon, Martini, van Velzen, Dahan, Niesters and Gozal.)

Background: To assess the prevalence, incidence, location, and behavior of chronic pre- and postoperative pain in bariatric surgery, and the use of analgesics., Methods: A cross-sectional e-survey was conducted on 3928 post-bariatric patients and four-time points for pain assessment were evaluated: preoperative, on the ward, day 1 at home postoperatively, and present time (at the time of the e-survey). A numerical rating scale (NRS) was used to assess the level of pain (0 to 10). The general incidence of chronic pain was calculated, as also, subgroups were defined as group A (pre and postoperative chronic pain), B (preoperative pain, and no longer postoperative), and C (preoperative painless, postoperative chronic pain). Besides the pain intensity, location of pain, and the use of analgesics were investigated., Results: A total of 3279 patients (83.9%) responded to the survey. Preoperative and postoperative chronic pain was found in 343 (10.5%) and 264 (8.1%) patients, respectively. In group A, chronic pain was present in 4.8% of the patients; in group B, it was present in 5.7%; and in group C in 3.3% of the patients. Furthermore, in 4.5% of patients pain was located in the abdomen, which was higher as compared to before surgery (+ 2.3%, p < 0.001). The ORs for present postoperative chronic pain were OR 1.45, 1.7, and 1.71 (p = 0.002, 0.003, 0.003) compared to respectively preoperative chronic pain, pain at the ward, and pain at day 1 after surgery. Among all participants, 4.6% consumed chronic analgesics. Of these, paracetamol was used most frequently (3.8%), followed by tramadol (1.3%) and oxycodone (0.5%)., Conclusions: In this e-survey, chronic postoperative abdominal pain was prominent in patients after bariatric surgery. Of patients, 3.3% that were without preoperative chronic pain developed chronic pain after surgery. Opioid consumption in the queried population was relatively low., (© 2022. The Author(s).)

As socio-technological environments shape and direct listener behaviour, an ecological account is needed that encompasses listening in complexity (i.e., multiple listeners, multiple sounds and their sources, and multiple sound-induced actions that ensure the success of a mission). In this study, we explored sound-induced action under the framework of "acoustic biotopes" (a notion of ecological acoustics by Smolders, Aertsen, and Johanessma, 1979 and 1982) in a specific socio-technological environment, i.e., the context of an orthopaedic operating room. Our approach is based on literature research into the topics of environmental psychology and auditory perception and action and in situ observations in healthcare with field recordings, participatory observations, and interviews on the spot. The results suggest a human-centered definition of sound-induced action in acoustic biotopes: Acoustic biotope is an active and shared sound environment with entangled interactions and sound-induced actions taking place in a specific space that has a critical function. Listening in highly functional environments is an individual experience and is influenced by hearing function, physical position and role in an environment, and the task at hand. There is a range of active and passive sound listeners as a function of their attentive state and listeners as sound sources within the acoustic biotope. There are many different sound sources and sound locals in socio-technological environments and sounds have great potential to serve critical information to operators. Overall, our study provides a holistic, multi-layered and yet a listener-centric view on the organisation of complex spaces and the results can immediately be applicable for rethinking the acoustic environment for ORs for better listening and sound-induced action.

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.)

Although postoperative adverse respiratory events, defined by a decrease in respiratory rate (RR) and/or a drop in oxygen saturation (SpO 2 ), occur frequently, many of such events are missed. The purpose of the current study was to assess whether continuous monitoring of the integrated pulmonary index (IPI), a composite index of SpO 2 , RR, end-tidal PCO 2 and heart rate, alters our ability to identify and prevent adverse respiratory events in postoperative patients. Eighty postoperative patients were subjected to continuous respiratory monitoring during the first postoperative night using RR and pulse oximetry and the IPI monitor. Patients were randomized to receive intervention based on standard care (observational) or based on the IPI monitor (interventional). Nurses were asked to respond to adverse respiratory events with an intervention to improve the patient's respiratory condition. There was no difference in the number of patients that experienced at least one adverse respiratory event: 21 and 16 in observational and interventional group, respectively (p = 0.218). Compared to the observational group, the use of the IPI monitor led to an increase in the number of interventions performed by nurses to improve the respiratory status of the patient (average 13 versus 39 interventions, p < 0.001). This difference was associated with a significant reduction of the median number of events per patient (2.5 versus 6, p < 0.05) and a shorter median duration of events (62 s versus 75 s, p < 0.001). The use of the IPI monitor in postoperative patients did not result in a reduction of the number of patients experiencing adverse respiratory events, compared to standard clinical care. However, it did lead to an increased number of nurse interventions and a decreased number and duration of respiratory events in patients that experienced postoperative adverse respiratory events., (© 2020. The Author(s).)

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.)

Introduction: Chronic low back pain (CLBP) is one of the most common chronic pain conditions in pain practice., Objectives: In the current study, we describe phenotypes of patients with CLBP based on the status of their endogenous pain modulatory system., Methods: Conditioned pain modulation (a measure of central pain inhibition), temporal summation (TS, a measure of pain facilitation), and offset analgesia (a measure of temporal filtering of nociception) were evaluated in 53 patients with CLBP at painful and nonpainful sites. Next, in a double-blind, randomized, placebo-controlled trial, 40 patients with defective conditioned pain modulation responses received treatment with tapentadol prolonged-release or placebo for 3 months., Results: The majority of patients (87%) demonstrated loss of central pain inhibition combined with segmentally increased TS and reduced offset analgesia at the lower back region. During treatment, tapentadol reduced pain intensity more than placebo (tapentadol -19.5 ± 2.1 mm versus placebo -7.1 ± 1.8 mm, P = 0.025). Furthermore, tapentadol significantly decreased pain facilitation by reduction of TS responses at the lower back (tapentadol -0.94 ± 1.9 versus placebo 0.01 ± 1.5, P = 0.020), which correlated with pain reduction ( P < 0.001)., Conclusion: Patients with CLBP demonstrated different phenotypes of endogenous pain modulation. In patients with reduced conditioned pain modulation, tapentadol produced long-term pain relief that coincided with reduction of signs of pain facilitation. These data indicate that the endogenous pain system may be used as a biomarker in the pharmacological treatment of CLBP, enabling an individualized, mechanism-based treatment approach., Competing Interests: The authors have no conflicts of interest to declare. This investigator initiated trial study was sponsored in part by Grünenthal GmbH, Aachen, Germany. Grünenthal had no influence on the design of the study and was not involved in the study execution, data analysis, or writing of the manuscript. T. van de Donk and A. Dahan received speakers fee from Grünenthal BV (the Netherlands).Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

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.)

Monitors that estimate nociception during anesthesia may be used to guide opioid and other analgesics administration to optimize anesthesia care and possibly outcome. We reviewed the literature to evaluate current evidence of the effect of nociception-guided management over standard anesthesia practice during surgery. A systematic review of the literature on the effect of nociception monitoring on anesthesia practice was conducted. Reports were eligible if they compared nociception-guided anesthesia to standard practice during surgery. Primary endpoint of this review is intraoperative opioid consumption. Secondary endpoints included hemodynamic control, postoperative pain and pain treatment. We identified 12 randomized controlled trials that compared one of five different nociception monitoring techniques to standard anesthesia care. Most studies were single center studies of small sample size. Six studies reported intraoperative opioid consumption as primary outcome. There was considerable variability with respect to surgical procedure and anesthesia technique. For nociception monitors that were investigated by more than one study, analysis of the pooled data was performed. The surgical plethysmographic index was the only monitor for which an intra operative opioid sparing effect was found. For the other monitors, either no effect was detected, or pooled analysis could not be performed due to paucity of study data. On secondary outcomes, no consistent effect of nociception-guided anesthesia could be established. Although some nociception monitors show promising results, no definitive conclusions regarding the effect of nociception monitoring on intraoperative opioid consumption or other anesthesia related outcome can be drawn.Clinical trial number PROSPERO ID 102913.

Opioids are complex drugs that produce profit (most importantly analgesia) as well as a myriad of adverse effects including gastrointestinal motility disturbances, abuse and addiction, sedation and potentially lethal respiratory depression (RD). Consequently, opioid treatment requires careful evaluation in terms of benefit on the one hand and harm on the other. Considering benefit and harm from an economic perspective, opioid treatment should lead to profit maximization with decision theory defining utility as (profit - loss). We here focus on the most devastating opioid adverse effect, RD and define opioid utility U = P(benefit) - P(harm), where P(benefit) is the probability of opioid-induced analgesia and P(harm) the probability of opioid-induced RD. Other utility functions are also discussed including the utility U = P(benefit AND NOT harm), the most wanted opioid effect, i.e., analgesia without RD, and utility surfaces, which depict the continuum of probabilities of presence or absence of analgesia in combination with the presence or absence of RD. Utility functions are constructed from pharmacokinetic and pharmacodynamic data sets, although pragmatic utility functions may be constructed when pharmacokinetic data are not available. We here discuss utilities of several opioids including the partial mu-opioid-receptor agonist buprenorphine, the full opioid receptor agonists fentanyl and alfentanil, and the bifunctional opioid cebranopadol, which acts at mu-opioid and nociception/orphanin FQ-receptors. We argue that utility functions give clinicians the opportunity to make an informed decision when opioid analgesics are needed for pain relief, in which opioids with a positive utility function are preferred over opioids with negative functions. Furthermore, utility functions of subpopulations will give an extra insight as a utility functions measured in one subgroup (e.g., patients with postoperative pain, good opioid responders) may not be mirrored in other patient subgroups (e.g., neuropathic pain patients, poor opioid responders).

It is not straightforward to simultaneously evaluate the beneficial and harmful effects of pain management, since different drugs may possess different analgesia and adverse effect profiles. Utility functions, derived from the pharmacokinetics and pharmacodynamics of individual outcome parameters, have been constructed to address this problem. Here, we construct "pragmatic" utility functions based on measurements of benefit and harm, but without making assumptions about the underlying pharmacokinetics and pharmacodynamics. Using data from two previous studies, utility functions were designed by estimating the probability of occurrence of benefit and harm and combining these into one function. Study 1 was a clinical trial on the effect of oral pregabalin on pain relief in chronic pancreatitis patients, with endpoint analgesia and dizziness monitored for 21 days. Study 2 was an experimental study on the effect of intravenous fentanyl on antinociception and respiratory depression in healthy volunteers. From study 1, the utility function was negative the first week of treatment, indicative of the greater probability of dizziness than analgesia, but positive thereafter. From study 2, the utility function showed a nadir 30 minutes after dosing, after which the probability function slowly increased toward zero. A pragmatic utility function based on the probability of two binary outcomes, analgesia and adverse effect, was successfully constructed using data from the two previous studies. The results yielded valuable insights into the utility of treatment and may be highly educative for physicians and potentially used in development of potent analgesics without serious side effects., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Tapentadol is a centrally acting analgesic with μ-agonistic activity combined with noradrenaline reuptake inhibition. Its mechanism of action relies on improvement of descending pain inhibition. In the current study, tapentadol's ability to enhance conditioned pain modulation (CPM, an experimental measure of descending pain inhibition) was evaluated in fibromyalgia patients with absent or reduced CPM responses., Methods: A total of 34 fibromyalgia patients completed this double-blind trial. Patients were randomized to receive treatment with tapentadol sustained-release or placebo for a 3-month period with 1-month follow-up. At baseline, the cornea nerve fibre state (CNFS) was quantified to determine the presence of nerve fibre pathology and assess its value in the prediction of the analgesic response., Results: Tapentadol significantly increased CPM responses during treatment with an average increase from baseline of 20.5 ± 12.5% (tapentadol) versus 3.0 ± 11.2% (placebo; p = 0.042). No treatment effect was observed for the absolute pain scores, however, analgesia responder rate analyses demonstrated a treatment effect in favour of tapentadol. Pain relief (a reduction in pain score ≥ 30%) was predicted by the presence of a normal CNFS (p = 0.035). Patients with an abnormal CNFS had no analgesic effect from tapentadol despite an increase in CPM., Conclusions: In chronic pain patients with fibromyalgia, the increase in endogenous pain inhibition by tapentadol was translated into analgesia in patients with a normal CNFS. In those with abnormal CNFS, tapentadol treatment was without analgesic effect., Significance: In this double-blind randomized placebo-controlled trial, we showed that tapentadol significantly enhanced the descending pain inhibition in fibromyalgia patients. Tapentadol-induced pain relief was only present in patients with a normal CNFS., (© 2019 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFICR®.)

Importance: An increase in opioid prescription has been observed in the Netherlands. It is vital to understand this increase and to identify risk factors for opioid prescription to ensure that health interventions remain appropriately targeted., Objectives: To determine the prevalence of opioid prescriptions and adverse events associated with opioids, and to identify risk factors associated with opioid prescription in the Dutch population., Design, Setting, and Participants: This cohort study used national statistics from the Netherlands from January 1, 2013, to December 31, 2017, including the full Dutch population of 16 779 575 people in 2013 and 17 081 507 people in 2017. Data from the Dutch Health Monitor surveys of 2012 and 2016 were also included. Databases were anonymized prior to analysis. All analyses were performed between December 2018 and February 2019., Exposure: Opioid prescription., Main Outcomes and Measures: The main outcomes were the dynamics of opioid prescriptions, hospital admissions for opioid overdose, and opioid overdose mortalities. The secondary outcome was risk factors associated with opioid prescription., Results: In 2013, 814 211 individuals (4.9% of the total population) received an opioid prescription. In 2017, 1 027 019 individuals (6.0% of the total population) received at least 1 opioid prescription (mean [SD] age, 59.3 [18.5] years; 613 203 [59.7%] women). The rate of hospital admissions for opioid overdose was 9.2 per 100 000 inhabitants in 2013 and 13.1 per 100 000 inhabitants in 2017 (relative risk, 1.43 [95% CI, 1.34-1.52]). Similarly, an increased risk of opioid overdose death was observed, from 0.83 per 100 000 inhabitants in 2013 to 1.2 per 100 000 inhabitants in 2017 (relative risk, 1.49 [95% CI, 1.20-1.85]). Based on data from the 2012 Dutch Health Monitor survey, risk factors associated with opioid prescription included being older than 65 years (odds ratio [OR], 4.20 [95% CI, 3.98-4.43]), having only a primary school education (OR, 3.62 [95% CI, 3.46-3.77]), being widowed (OR, 3.30 [95% CI, 3.13-3.49]), reporting always feeling symptoms of depression (OR, 3.77 [95% CI, 3.41-4.18]), and reporting poor or very poor physical health (OR, 10.40 [95% CI, 10.01-10.81]). Self-reported back pain (OR, 4.34 [95% CI, 4.23-4.46]) and rheumatoid arthritis or fibromyalgia (OR, 3.77 [95% CI, 3.65-3.90]) were also associated with opioid prescription. However, unemployment (OR, 1.05 [95% CI, 0.96-1.13]) was not associated with opioid prescription, and alcohol use disorder (OR, 0.76 [95% CI, 0.73-0.80]) was negatively associated with opioid prescription., Conclusions and Relevance: This study found that opioid prescriptions have increased in the Netherlands. Although the risk of adverse events is still relatively low, there is an urgent need to review pain management to prevent a further increase in opioid prescription.

Background: There are indications that pain perception is altered in patients with obesity, which complicates postoperative pain treatment. An essential part for adequate pain treatment is the capacity of the patient to grade pain., Objectives: The aim of this study was to identify the differences in pain perception and pain processing in patients with without obesity., Setting: Dutch Obesity Clinic West; private practice and the Leiden University Medical Center, the Netherlands; university hospital., Methods: Forty-one patients with severe obesity (body mass index 42.9±4.9 kg/m 2 ) and 35 control patients (body mass index 23.2±2.8 kg/m 2 ) received multiple random thermal and electrical stimuli to the skin, in intensity in between pain threshold and tolerance. The consistency of scoring was assessed by a penalty score system and stratified into good, moderate, and poor cohorts., Results: The penalty scores differed significantly between patients with obesity and controls with higher penalty scores in patients with obesity for both nociceptive assays. Combining the results of the heat and electrical tests indicated that just 28% of the patients with obesity had a penalty score in the good cohort, indicative of consistency in grading incoming stimuli, in contrast to 60% of control patients., Conclusion: Individuals with severe obesity displayed hypoalgesia to noxious electrical stimuli together with difficulty in grading experimental noxious thermal and electrical stimuli in between pain threshold and tolerance. We argue that the latter may have a significant effect on pain treatment and consequently needs to be taken into account when treating the patients with obesity for acute or chronic pain., (Copyright © 2017 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Although erythropoietin ameliorates experimental type 2 diabetes with neuropathy, serious side effects limit its potential clinical use. ARA 290, a nonhematopoietic peptide designed from the structure of erythropoietin, interacts selectively with the innate repair receptor that mediates tissue protection. ARA 290 has shown efficacy in preclinical and clinical studies of metabolic control and neuropathy. To evaluate the potential activity of ARA 290 in type 2 diabetes and painful neuropathy, subjects were enrolled in this phase 2 study. ARA 290 (4 mg) or placebo were self-administered subcutaneously daily for 28 d and the subjects followed for an additional month without further treatment. No potential safety issues were identified. Subjects receiving ARA 290 exhibited an improvement in hemoglobin A(1c) (Hb A(1c)) and lipid profiles throughout the 56 d observation period. Neuropathic symptoms as assessed by the PainDetect questionnaire improved significantly in the ARA 290 group. Mean corneal nerve fiber density (CNFD) was reduced significantly compared with normal controls and subjects with a mean CNFD >1 standard deviation from normal showed a significant increase in CNFD compared with no change in the placebo group. These observations suggest that ARA 290 may benefit both metabolic control and neuropathy in subjects with type 2 diabetes and deserves continued clinical evaluation.