Monique van Velzen

Opioids, most intravenous anesthetics and various illicit substances can cause fatal respiratory depression by depressing central respiratory networks. ENA-001, a ventilatory modulator targeting the carotid bodies, has emerged as a potential countermeasure without impairing analgesia or hypnosis. We conducted a literature review to evaluate the efficacy and safety of ENA-001. This scoping review summarizes the current evidence base for ENA-001 from in vitro, animal experiments, and human volunteer studies. A comprehensive search was conducted across several electronic databases to identify all available literature describing its effects as a respiratory stimulant and as a reversal agent of drug-induced respiratory depression. We identified eight relevant publications, four describing data in humans and four using animal models (mice, rats, and non-human primates). ENA-001 increased ventilation and attenuated respiratory depression induced by morphine and the combination of xylazine and fentanyl. The primary site of action was localized to the carotid bodies, specifically the pore-forming α-subunit of the KCa1.1 (BK) channel. In humans, ENA-001 increased minute ventilation and reduced end-tidal carbon dioxide under poikilocapnic conditions. In experimental human models of alfentanil- and propofol-induced respiratory depression, ENA-001 significantly improved isohypercapnic minute ventilation and fully restored the hypoxic ventilatory response, respectively, without impairing sedation or analgesia. Across all studies, the safety profile was favorable, with no serious adverse events reported. In conclusion, ENA-001 is a first-in-class, peripherally acting respiratory stimulant that effectively reverses drug-induced respiratory depression. These findings support its continued clinical development for opioid- and anesthetic-induced respiratory compromise.

Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease that causes motor ( e.g., chorea) and non-motor symptoms ( e.g., neurocognitive, neuropsychiatric and autonomic disturbances). Pain is a frequently reported non-motor symptom in HD, with a prevalence of around 40% in the manifest stage. Despite its high prevalence, patients with HD seem to be at risk for undertreatment of pain, as reflected by the lower analgesic use in HD in the advanced stages. The relatively low use of analgesics may result from under-recognition and inadequate assessment of pain, particularly in the advanced stages of HD. As HD progresses, pain recognition and assessment become increasingly challenging due to the emergence and progression of motor and neurocognitive symptoms. In contrast, the high prevalence of pain may be attributable to disturbances in the pain processing in terms of endogenous pain inhibition or pain facilitation. Despite the availability of specifically developed and internationally standardized experimental pain assessments to test psychometrics properties of observational pain scales and disturbances in pain processing, studies using these pain assessments in HD are too limited to permit definitive conclusions. Methods: A cross-sectional experimental study will be conducted in twenty genetically and clinically confirmed adult-onset HD patients. The primary aim is to assess the feasibility of the experimental design, which comprises three different standardized pain assessments, using a predefined feasibility checklist. Discussion: If feasibility is demonstrated, future studies using the comprehensive experimental design, including individually tailored experimental painful stimuli, are expected to provide insight into the psychometric properties of the Pain Assessment in Impaired Cognition scale (PAIC15) and the potential demonstration of altered pain processing in HD, supporting the development of improved pain management regimens. In particular, the motor symptoms ( e.g., facial chorea) of HD may have an adverse impact on the psychometric properties of the PAIC15. Trial registration: Trial registration on ClinicalTrials.gov with number: NCT06693466. Medical Research Ethics Committee Leiden, The Hague and Delft registration number: P24.014.

Background: Chronic pain affects approximately 1.5 billion individuals worldwide, and currently available treatments often fail to provide adequate analgesia. Consequently, there is a need to explore novel analgesic compounds, including tetrodotoxin. In this study, we evaluated sensory and respiratory biomarkers of tetrodotoxin exposure in healthy volunteers. Methods: Twenty‐five healthy participants (mean age 23 years) were enrolled in a single‐blind, dose escalation study conducted over two days. Participants received subcutaneous injections of tetrodotoxin at doses of 30 μg and 45 μg. Changes from baseline to 1 h post administration were assessed using quantitative sensory testing, olfactory function testing, hypoxic ventilatory response measurements and standardised neurological examinations. Results: Administration of 30 μg tetrodotoxin resulted in significant alterations in mechanical detection threshold, pressure pain threshold and electrical pain tolerance. At the 45 μg dose, a modest effect on the cold pressor test was observed. No significant changes were detected in hypoxic ventilatory response or olfactory function at either dose. Tetrodotoxin was well tolerated, and no serious adverse events were reported. Conclusions: These findings suggest that subcutaneous tetrodotoxin at doses of 30 μg and 45 μg produces modest effects on specific sensory parameters in healthy individuals and demonstrates a favourable short‐term safety profile. Significance Statement: This study provides the first comprehensive assessment of tetrodotoxin's effects on sensory and respiratory function in healthy humans. It shows that 30 μg and 45 μg doses selectively modulate mechanical detection and pressure pain thresholds without affecting olfaction, neurological performance or hypoxic ventilatory response. These findings confirm the short‐term safety of tetrodotoxin and advance understanding of its human pharmacodynamics, supporting its continued evaluation as a potential analgesic for chronic or neuropathic pain.

Aim: Corneal confocal microscopy (CCM) is a non-invasive ophthalmic imaging technique for evaluating the corneal microstructure, particularly the subepithelial nerve plexus. This dense, dynamic plexus contains small nerve fibers from the ophthalmic branch of the trigeminal nerve. This study aimed to evaluate corneal nerve alterations in individuals with migraine, including its subtypes and visual hypersensitivity (measured with the Leiden visual sensitivity scale (L-VISS), a validated nine-item questionnaire). Methods: In total, 55 migraine participants were included, including 26 with episodic migraine and 29 with chronic migraine, as well as 55 age- and sex-matched controls. All subjects underwent CCM, and automated corneal nerve fiber density (ACNFD), length (ACNFL) and branch density (ACNBD) were assessed using the Rostock Cornea Module (Heidelberg Retina Tomograph III). Data were compared with age- and sex-matched healthy volunteers. Results: Reduced ACNFD, ACNFL and ACNBD were found in migraine participants compared to controls (all p < 0.001). No difference was found between episodic migraine and chronic migraine, and regression analysis showed no significant effect for (inter)ictal visual hypersensitivity. Conclusions: These findings support the utility of CCM as a sensitive tool for detecting nerve fiber pathology in migraine and highlight its potential in further understanding migraine pathophysiology. The observed nerve changes, present irrespective of migraine frequency status or visual hypersensitivity, suggest a broader role for peripheral nerve dysfunction in migraine beyond sensory hypersensitivity symptoms.

Opioids are known to constrict pupils, and mobile phone-based self-administered eye scanning (MPSES) offers a potential method for monitoring opioid use in real-world settings. A clinical trial with 12 volunteers measured pupil size using MPSES under different light conditions (approx. 50 or approx. 500 lux) in the lab and over a week at home. Each participant made approximately 21 home tests, 12 in the lab without oxycodone and 16 in the lab after oxycodone intake. At the second visit the participants received a single dose of 20 mg oxycodone, and their pupil size was monitored hourly for 5 h. The pupil size after oxycodone intake was compared to drug-naïve tests performed at the lab and at home. Logistic regression models were built using measured pupil size and light conditions measured by the phone during each test, and a dichotomous variable indicating tests before or after oxycodone dosing as the outcome. The model demonstrated high classification accuracy (AUC = 0.94), with 82% true positives, 9% false positives, 91% true negatives and 18% false negatives. Misclassifications were largely due to difficulties measuring pupil size in individuals with corneal arcus, causing most of the false positive findings, and other interindividual differences. This shows that MPSES, including monitoring of ambient light conditions, can effectively detect opioid use within the 50–500 lux range. Our study paves the way for using MPSES to detect opioid use.

Background: Neuromuscular blocking agents inhibit the peripheral chemoreflex. This study examined the effect of 2 and 4 mg/kg sugammadex compared to spontaneous recovery of neuromuscular block on the recovery of the acute hypoxic ventilatory response (AHVR). Methods: This was a two-experiment, randomized, controlled trial in healthy volunteers. Participants received a continuous infusion of rocuronium, to achieve stable symptoms of neuromuscular block in the head and neck region (symptomatic neuromuscular block). Thereafter, neuromuscular block was allowed to recover spontaneously in the first experiment, while in experiment 2, volunteers were randomized to receive 2 mg/kg or 4 mg/kg sugammadex for reversal. The depth of neuromuscular block was assessed with electromyography at the adductor pollicis muscle. AHVR was measured at baseline, during stable neuromuscular block, and at 0, 20, and 40 min after recovery. Results: A total of 37 volunteers were enrolled; data from 27 volunteers were eligible for analysis. AHVR was reduced by 32% (mean difference vs. baseline, –0.22 l · %⁻¹ · min⁻¹; 95% CI, –0.32 to –0.12) during symptomatic neuromuscular block (mean train-of-four ratio, 0.42 ± 0.22;). At the disappearance of all symptoms, AHVR remained on average depressed by 23% (mean difference, –0.16 l · %⁻¹ · min⁻¹; 95% CI, –0.28 to –0.04). In 57% of volunteers after spontaneous recovery versus 28% after sugammadex reversal, AHVR did not return to baseline values during the measurement period. In addition, the magnitude of residual AHVR depression was greater after spontaneous recovery compared to reversal with sugammadex. However, on average AHVR was not significantly different from baseline at 20 and 40 min after recovery in any group. Conclusions: The AHVR after reversal of a minimal neuromuscular block with sugammadex did not significantly differ with spontaneous recovery of neuromuscular block. However, fewer patients had residual depression of AHVR when sugammadex was used. In all groups, a considerable proportion of patients had residual depression of the AHVR 40 min after recovery.

Background: Admission to a hospital can be a very stressful and anxiety-provoking experience, as patients face many unknowns that can compromise their physical and psychological well-being. Patient-centered care necessitates that health care organizations and professionals actively comprehend patients’ experiences and values, for which effective training in communication skills is essential. Objective: This study will contribute to this field of research by evaluating a blended therapeutic communication training program. Methods: The training consists of online e-learning that provides insights into important concepts of therapeutic communication, followed by a virtual reality patient-embodied experience shown to help nurses feel what it is like to be a patient themselves during a 1-day didactic training with experiential small groups. Theory on therapeutic communication is taught, focusing on how to use rapid rapport techniques and hypnotic and suggestive language to facilitate empathy. This is combined with practical exercises, ensuring an active learning process. By integrating these diverse blended learning training methods, the program aims to enhance nurses’ communication skills, ultimately improving patient care. Applying the Kirkpatrick model for training evaluation, this prospective study will use a convergent mixed methods study design, integrating both qualitative and quantitative data. Qualitative data will include fieldwork, as well as individual and focus group interviews with the participating nurses. Quantitative data will include questionnaires that include the first two levels of the Kirkpatrick model and that are validated for this purpose. Inclusion started in April 2024, and the therapeutic communication training was scheduled for the first half of 2024. Results: On February 8, 2024, we received permission from the authorizing body (Institutional Science Committee and NWMO Committee) to start our study. Data collection started in April 2024 and was completed by the end of 2024. Conclusions: This study will systematically evaluate the effectiveness of therapeutic communication training in the acute admission ward for patients who require emergency treatment. The results will yield insights into the feasibility and acceptance of the implementation of therapeutic communication training among nurses in an acute admission ward in the Netherlands. International Registered Report Identifier (IRRID): DERR1-10.2196/65795