Respiratory Tolerance Research Articles

CHARACTERIZATION OF HUMAN FUNCTIONING IN INDIVIDUALS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) BASED ON THE INTERNATIONAL CLASSIFICATION OF FUNCTIONING, DISABILITY AND HEALTH (ICF): A BROAD REVIEW OF CLINICAL STUDIES

Chronic obstructive pulmonary disease (COPD) is complex condition affecting millions worldwide, characterized by persistent symptoms such as dyspnea, cough, and sputum production due to abnormalities in the airways and/or alveoli. These symptoms significantly impact patients' quality of life, affecting respiratory and muscular functions, as well as emotional and social aspects. The study is a scoping review of clinical trials using the ICF to describe the functionality of individuals with COPD. Fourteen studies were analyzed, highlighting variability in functionality parameters, with emphasis on body functions, activities and participation, environmental factors, and body structures. The Comprehensive ICF Core Set for COPD was widely used in 68.75% of the reviewed articles, demonstrating the comprehensiveness and utility of this tool in assessing patients' health conditions. The most frequently cited functions included respiratory, mobility, and exercise tolerance functions, indicating their significance in the context of COPD. Additionally, emotional aspects and cardiovascular functions were also highlighted as important for understanding patient functionality. These findings underscore the importance of continuous and multidimensional monitoring COPD patients supporting stakeholders on their approaches to develop public health policies aimed at enhancing quality of life for these individuals. This comprehensive approach aids in the effective management of COPD, bearing its multi-faceted effects on individual's lives.

Functional and Disability Outcomes in NSCLC Patients Post-Lobectomy Undergoing Pulmonary Rehabilitation: A Biopsychosocial Approach.

Worldwide, lung cancer remains the predominant cause of cancer cases and deaths and poses significant health challenges, with surgical resection being a key treatment. Post-surgery, patients often experience functional impairments. This study aimed to develop a comprehensive ICF version for assessing the functional profile and disability in lung cancer patients post-thoracic surgery undergoing pulmonary rehabilitation using the ICF and WHODAS 2.0 tool. We analyzed the correlation between the ICF Core Set and WHODAS 2.0 data to understand the impact on daily functioning. This study included 50 patients (23 F, 27 M) from the Clinic of Thoracic Surgery and Respiratory Rehabilitation in Lodz. Essential ICF codes were determined using the Delphi method, and assessments were conducted on the third day post-operation. Statistical analyses included various tests with α = 0.05. The results showed no impairments in voice functions (b310), respiration rates (b4400), and diaphragm functions (b4451), but there were significant issues with chest pain (b28011), respiratory muscle functions (b445), exercise tolerance (b455), and muscle endurance (b740). In Activities and Participation and Environmental Factors, most codes were not problematic, except for employment (d845, d850) and atmospheric pressure (e2252). Significant correlations were found between mobility limitations (d410, d460) and self-care (d510, d540) with the WHODAS 2.0 results. The comprehensive ICF Core Set effectively described the functional profile of post-surgery patients, confirming its utility and highlighting the impact of disability on daily functioning.

Bivalent and bitopic ligands of the opioid receptors: The prospects of a dual approach.

Opioid receptors belonging to the class A G-protein coupled receptors (GPCRs) are the targets of choice in the treatment of acute and chronic pain. However, their on-target side effects such as respiratory depression, tolerance and addiction have led to the advent of the 'opioid crisis'. In the search for safer analgesics, bivalent and more recently, bitopic ligands have emerged as valuable tool compounds to probe these receptors. The activity of bivalent and bitopic ligands rely greatly on the allosteric nature of the GPCRs. Bivalent ligands consist of two pharmacophores, each binding to the individual orthosteric binding site (OBS) of the monomers within a dimer. Bitopic or dualsteric ligands bridge the gap between the OBS and the spatially distinct, less conserved allosteric binding site (ABS) through the simultaneous occupation of these two sites. Bivalent and bitopic ligands stabilize distinct conformations of the receptors which ultimately translates into unique signalling and pharmacological profiles. Some of the interesting properties shown by these ligands include improved affinity and/or efficacy, subtype and/or functional selectivity and reduced side effects. This review aims at providing an overview of some of the bivalent and bitopic ligands of the opioid receptors and, their pharmacology in the hope of inspiring the design and discovery of the next generation of opioid analgesics.

Editorial to “Improvement in respiratory function and exercise tolerance following video‐assisted thoracoscopic diaphragm plication for symptomatic iatrogenic persistent diaphragm paralysis after radiofrequency catheter ablation”—An essential respiratory physiology every electrophysiologist should know‐

Editorial to “Improvement in respiratory function and exercise tolerance following video‐assisted thoracoscopic diaphragm plication for symptomatic iatrogenic persistent diaphragm paralysis after radiofrequency catheter ablation”—An essential <scp>respiratory physiology</scp> every <scp>electrophysiologist</scp> should know‐

The impact of repeat opioid use (ROU) on fentanyl-induced respiratory depression

Objective: Repeat opioid use (ROU) is a primary driver for the ongoing opioid epidemic, and while a substantial understanding exists for the impact of ROU on behavioral neurophysiology, the consequences of ROU on respiratory-related physiology including opioid-induced respiratory depression (OIRD) remain poorly understood. Hypothesis: ROU leads to respiratory tolerance to fentanyl that is characterized by the blunting of respiratory depression and improvement of O2 consumption (VO2). Methods: We utilized a pre-clinical rodent model. Breathing was measured via whole body-plethysmography in freely behaving adult mice (P&gt;90) prior to and immediately following fentanyl administration. A single dose of fentanyl (0.7 mg/kg, i.p.) was given for up to 6 consecutive days. In a subset of experiments, O2 consumption was measured simultaneously using whole-body plethysmography. Results: We identified two distinct respiratory phenotypes in response to OIRD following ROU. Type 1 phenotype (n=18) adapted over time where breathing during OIRD is greater on day 5 versus day 1. In contrast, the Type 2 phenotype (n=5) showed no such adaptation, with unchanged or worsened breathing by day 5. In a subset of animals (n=12) the relationship between breathing (i.e. minute ventilation (Ve)) and oxygen consumption (VO2) was examined before and following ROU. Under baseline conditions the Ve to VO2 relationship positively correlated on day 1 and 5. During OIRD on day 1 this correlation became negative, but began to normalize by day 5, resembling the baseline relationship. These phenomena also coincided with an increase in the ventilatory drive observed at the whole-animal level and in the isolated preBötzinger complex following ROU. Conclusions: ROU leads to two distinct respiratory phenotypes in response to OIRD, where the majority of subjects show a blunted respiratory depression. Additionally, ROU improves the relationship between breathing and oxygen consumption and enhances inspiratory drive in the presence of fentanyl. These findings suggest that fentanyl-induced hypoxia experienced by repeat opioid users vastly differ from naïve users. Such differences may contribute to the unpredictable occurrence of overdose amongst repeat users. This work was supported by NIH: R01 HL163965 and DA057767. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Improvement in respiratory function and exercise tolerance following video‐assisted thoracoscopic diaphragm plication for symptomatic iatrogenic persistent diaphragm paralysis after radiofrequency catheter ablation

Improvement in respiratory function and exercise tolerance following video‐assisted thoracoscopic diaphragm plication for symptomatic iatrogenic persistent diaphragm paralysis after radiofrequency catheter ablation

Impact of breathing exercises in patients who had open heart operation on respiratory function and exercise tolerance

Objective: This study aims to determine the effect of deep breathing and coughing exercise training before surgery on respiratory functions and exercise tolerance in patients with open-heart surgery in the postoperative period. Background: The decrease in respiratory functions and activity tolerance of patients after open heart surgeries reveals the need to improve this situation with effective interventions. Methods: The quasi-experimental study was conducted with 80 patients undergoing open-heart surgery. Data were collected using the patient information form and the patient follow-up form. The patients were taught deep breathing and coughing exercises before the open-heart surgery and were supported in exercising regularly before and after the surgery. The patients' respiratory functions and exercise tolerance were measured and recorded via the patient follow-up form. Results: It was determined that the respiratory capacity, distance, time, and walking speed of the patients in the experimental group during the postoperative period were significantly higher than the control group. Conclusion: Substantially, deep breathing and coughing exercise training administered before surgery to patients undergoing open heart surgery improved respiratory functions and exercise tolerance in the postoperative period. It is recommended that nurses working in open-heart surgery clinics should plan deep breathing and coughing exercise training in the preoperative period and administer them regularly to the patients. Implications for research, policy, and practice: Patients who will undergo open heart surgery should be trained by nurses in the preoperative period. Nurses should teach these patients deep breathing and coughing exercises. In the postoperative period, it should be checked regularly whether the patients do exercises or not. What is already known about the topic? It is important to teach and practice breathing exercises in patients who will have open heart surgery. Respiratory training given by nurses in the preoperative period contributes to the management of the postoperative process. What this paper adds: This article demonstrates the importance of preoperative education for patients undergoing open heart surgery. In this study, it is shown that open heart surgery has a negative effect on the respiratory capacity and exercise tolerance of the patients. In addition, in this study, it is shown that the respiratory capacity and exercise tolerance of the patients who were taught preoperative breathing exercises and who performed the exercises in the postoperative period increased in the postoperative period.

Examination of changes in the breathing intolerance index to determine the respiratory support needs of very low birth weight infants.

The breathing intolerance index (BITI) is used to evaluate respiratory muscle tolerance. The higher the ratio of the inspiratory time to the total breathing time and the ratio of the tidal volume to the vital capacity, the more easily the respiratory muscles become fatigued. The BITI is high with chronic respiratory failure, and values of 0.15 or more indicate the need for assisted ventilation. This study aimed to examine the changes in the BITI of very low birth weight infants (VLBWIs) and determine whether it is possible to use the BITI as an objective indicator of the timing of noninvasive respiratory support (NRS) withdrawal. VLBWIs admitted to our neonatal intensive care unit between July 2020 and July 2022 under NRS at 36 weeks' postmenstrual age (PMA). If the BITI was less than 0.15, then we attempted to determine whether NRS could be withdrawn. Sixteen infants with a median gestational age and birth weight of 30.9 weeks and 1249 g, respectively, were eligible. The median PMA at the time of the first examination was 36.6 weeks. The BITI of two VLBWIs was less than 0.15. For 11 of the other VLBWIs, the BITI decreased over time to less than 0.15 at 39 weeks' PMA. After confirming that the BITI was less than 0.15, weaning from NRS was attempted. Weaning from NRS was possible except one VLBWI. The BITI can help evaluate respiratory tolerance and could be an objective indicator of the timing of NRS withdrawal.

Implications for respiratory muscle training in patients with stroke-associated pneumonia: a meta-analysis

Purpose To evaluate the effect of respiratory muscle training on improving lung function in patients with stroke-associated pneumonia. Materials and methods A systematic retrieval was conducted using the databases of the Cochrane Library, PubMed, the Web of Science, Embase, ProQuest, and others. Studies involving patients who received respiratory muscle training with/without a breathing trainer and those who adopted routine post-stroke rehabilitation training were included in the systematic review. The statistical analysis was performed using RevMan 5.3 software. Results Fourteen studies were included involving 850 patients with stroke. According to the results of the meta-analysis, compared with the control group, there were statistically significant differences in forced vital capacity (FVC) measurements (mean difference (MD) = 0.93, p < 0.0001) and improvement values for FEV1/FVC (MD = 0.65, p < 0.00001) in the experimental group. The FEV1 value was higher in the experimental group than in the control group (MD = 5.89, p < 0.0001). Furthermore, respiratory muscle training was superior to routine rehabilitation training for improving the PImax of patients with stroke (MD = 9.20, p < 0.0001). The patients had better respiratory tolerance after respiratory muscle training intervention (MD = 73.40, p < 0.0001). Conclusions The implementation of respiratory muscle training can improve FVC and FEV lung function indicators, inspiratory muscle strength and the 6-min walk test results in patients with stroke.

Impact of daily cyclic enteral nutrition versus standard continuous enteral nutrition in critically ill patients: a study protocol for a randomised controlled trial in three intensive care units in France (DC-SCENIC)

IntroductionCurrent guidelines on clinical nutrition of ventilated patients in the intensive care unit (ICU) recommend initiating continuous enteral nutrition within 48 hours of ICU admission when feasible. However, discontinuous feeding...

A Balancing Act: Learning from the Past to Build a Future-Focused Opioid Strategy.

The harmful side effects of opioid drugs such as respiratory depression, tolerance, dependence, and abuse potential have limited the therapeutic utility of opioids for their entire clinical history. However, no previous attempt to develop effective pain drugs that substantially ameliorate these effects has succeeded, and the current opioid epidemic affirms that they are a greater hindrance to the field of pain management than ever. Recent attempts at new opioid development have sought to reduce these side effects by minimizing engagement of the regulatory protein arrestin-3 at the mu-opioid receptor, but there is significant controversy around this approach. Here, we discuss the ongoing effort to develop safer opioids and its relevant historical context. We propose a new model that reconciles results previously assumed to be in direct conflict to explain how different signaling profiles at the mu-opioid receptor contribute to opioid tolerance and dependence. Our goal is for this framework to inform the search for a new generation of lower liability opioid analgesics.

Effectiveness of Inspiratory Muscle Training among Chronic Obstructive Pulmonary Disease Patients: A Systematic Review

Inspiratory muscle training (IMT) has been shown to be effective for some types of illnesses or conditions, including respiratory problems, cardiac disorders, and neuromuscular disorders. Reduced exercise capacity and health-related quality of life, weakness of respiratory muscles, and complaints of dyspnea are all frequent among COPD patients. This study aimed to investigate whether the use of IMT can alter the consequences of COPD in patients and provide an updated understanding of the effects of IMT in COPD patients. The specific objectives of the study were to evaluate the effectiveness of IMT on respiratory muscle strength, exercise tolerance, dyspnea, and health-related quality of life in COPD patients. Included databases were the Physiotherapy Evidence Database (PEDro), Google Scholar, and PubMed. A preliminary selection of papers was produced using inclusion/exclusion criteria. Subsequently, a final selection was made based on the quality of the studies assessed using the PEDro scale. For the realization of this systematic review, seven studies were involved. According to the evidence gathered from the literature review, IMT therapy has been shown to improve respiratory muscle strength, exercise tolerance, perception of dyspnea, and health-related quality of life in COPD patients. It is necessary to conduct studies using high-quality, evidence-based data to draw more definitive conclusions about the effectiveness of IMT in COPD patients. Future research should examine whether these improvements are applicable to all COPD patient groups. Additionally, it should explore the long-term effectiveness of these therapeutic improvements and determine which IMT treatment protocol provides the most significant clinical benefits.

Changes in diaphragm thickness and 6-min walking distance improvement after inspiratory muscle training in patients with chronic obstructive pulmonary disease: Clinical trial

AimInspiratory muscle training (IMT) improves respiratory muscle function and exercise tolerance in patients with chronic obstructive pulmonary disease (COPD), but the detailed mechanism is unclear. The purpose of this study is to elucidate the mechanism of functional improvement by IMT from P0.1, an index of respiratory central output, and thickness of diaphragm (Tdi), a noninvasive and reliable ultrasound examination. MethodsThis clinical trial study enrolled 13 elderly patients with COPD. IMT was performed using the POWER breathe® Medic Plus breathing trainer in combination with each participant's outpatient rehabilitation regimen. Starting at 20% of the maximal inspiratory pressure (PImax) and increasing to 50%, the participants performed 30 IMT repetitions twice a day for 2 months. P0.1 is the value of airway-occlusion pressure at 0.1 s after the start of inspiratory flow, and Tdi was measured at rest and maximal breathing. ResultsPImax and 6-min walking distance(6MWD) significantly increased after training. Tdi at resting inspiration and expiration, and maximal inspiration also significantly increased after training. In addition, the Borg Scale scores for dyspnea and leg fatigue and the respiratory rate of the 1-min recovery period after the 6MWD significantly decreased. There was no significant difference in P0.1. ConclusionsThese results suggest that the effects of IMT may be attributed to the improved peripheral factors rather than to the central factors in elderly COPD patients.

A novel method for assessment of airway opening pressure without the need for low-flow insufflation

BackgroundAirway opening pressure (AOP) detection and measurement are essential for assessing respiratory mechanics and adapting ventilation. We propose a novel approach for AOP assessment during volume assist control ventilation at a usual constant-flow rate of 60 L/min.ObjectivesTo validate the conductive pressure (Pcond) method, which compare the Pcond—defined on the airway pressure waveform as the difference between the airway pressure level at which an abrupt change in slope occurs at the beginning of insufflation and PEEP—to resistive pressure for AOP detection and measurement, and to compare its respiratory and hemodynamic tolerance to the standard low-flow insufflation method.MethodsThe proof-of-concept of the Pcond method was assessed on mechanical (lung simulator) and physiological (cadavers) bench models. Its diagnostic performance was evaluated in 213 patients, using the standard low-flow insufflation method as a reference. In 45 patients, the respiratory and hemodynamic tolerance of the Pcond method was compared with the standard low-flow method.Measurements and main resultsBench assessments validated the Pcond method proof-of-concept. Sensitivity and specificity of the Pcond method for AOP detection were 93% and 91%, respectively. AOP obtained by Pcond and standard low-flow methods strongly correlated (r = 0.84, p < 0.001). Changes in SpO2 were significantly lower during Pcond than during standard method (p < 0.001).ConclusionDetermination of Pcond during constant-flow assist control ventilation may permit to easily and safely detect and measure AOP.

Aerobic exercise simultaneous with non-invasive ventilation reduces the length of stay in intensive care in patients with heart failure: a randomised clinical trial

Introduction Early cardiac rehabilitation using non-invasive ventilation (NIV) and aerobic exercise may reduce the length of hospital stay in patients with heart failure (HF), however, there is still no evidence of this effect on patients in the intensive care unit (ICU). Objectives to investigate the effects of aerobic exercise (AE) performed simultaneously with non-invasive ventilation (NIV) on the length of intensive care stay (LICUS) in patients diagnosed with decompensated heart failure (HF) admitted to the intensive care units (ICU). Methods Twenty-eight patients admitted to the intensive care unit (ICU) because of decompensation of HF were randomised into two groups: the intervention group (AE + NIV), and a control group. The intervention group’s treatment strategy involved simultaneous AE with NIV daily. The control group performed non-simultaneous AE and NIV daily during their ICU stay. The primary outcome was LICUS. The secondary outcomes were the length of hospital stay, peripheral and respiratory muscle strength, functional status, functional classification, and exercise tolerance. Results The mean LICUS was shorter in AE + NIV than in the control group (6.3 ± 4.7 days vs 8.3 ± 3.6 days, respectively; p = 0.015). Secondary outcomes were similar between groups, except for exercise hemodynamics, which was improved in AE + NIV, as showed by the decreased diastolic blood pressure immediately after the exercise tolerance test. Conclusion The use of AE simultaneous with NIV reduced the LICUS of patients admitted to the ICU because of decompensated HF. This innovative approach is a promising tool for accelerating ICU discharge during the in-hospital rehabilitation of patients with HF.

Investigating the differences in nutritional status between successfully weaned and unsuccessfully weaned respirator patients

Long-term respirator users admitted to intensive care units need to be transferred to a respiratory care center (RCC) for weaning. It may cause malnutrition in critical care patients, which may manifest as a reduction in respiratory muscle mass, lower ventilatory capacity, and decreased respiratory tolerance. This study aimed to assess that if the patients’ nutritional status were improved, it could help RCC patients to wean from respirators. All participants were recruited from the RCC of a medical foundation in the city and Taipei Tzu Chi Hospital. The indicators include serum albumin level, respirator detachment index, maximum inspiratory pressure (PImax), rapid shallow breathing index, and body composition measurements. We recorded the length of hospital stay, mortality, and RCW (respiratory care ward) referral rate for these participants and analyzed the differences in relevant research indicators between those who were and weren’t weaned off. 43 of 62 patients were weaned from respirators, while 19 failed. The resuscitation rate was 54.8%. Patients with respirator weaning had a lower number of RCC admission days (23.1 ± 11.1 days) than respirator-dependent patients (35.6 ± 7.8 days, P < 0.05). The PImax of successfully weaned patients had a greater reduction (− 27.09 ± 9.7 cmH2O) than unsuccessful ones (− 21.4 ± 10.2 cmH2O, P < 0.05). The Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of successfully weaned patients (15.8 ± 5.0) were lower than those who were not (20.4 ± 8.4, P < 0.05). There was no significant difference in serum albumin levels between the two groups. In the successfully weaned patients, the serum albumin concentration was increased from 2.2 ± 0.3 to 2.5 ± 0.4 mg/dL, P < 0.05. Improved nutritional status can help RCC patients to wean from respirators.

Modulation of opioid overdose susceptibility due to context-dependent tolerance

The US is in the midst of an opioid epidemic, which is primarily being driven by repeat opioid use (ROU). The primary cause of opioid overdose is opioid-induced respiratory depression (OIRD). It has been shown that the risk of overdosing, and subsequently death, can change depending on the environment in which the user takes the drug. This phenomenon is called context-dependent tolerance. However, how OIRD changes depending on the location of drug delivery is not known. The objective of this pilot study is to investigate context-dependent respiratory tolerance to OIRD and overdose. We repeatedly paired an injection of fentanyl (0.7 mg/kg/day i.p.) with a distinctive environmental context (fentanyl-paired (FP) environment) and saline with another distinctive context (saline-paired (SP) environment) in adult mice for five days while monitoring breathing via unrestrained whole-body plethysmography. The ROU protocol was followed by two test days where fentanyl was administered in both environments and breathing was measured. We found that minute ventilation was greater during OIRD in the FP environment as compared to the SP environment (n=4). In the second set of mice (n=6?), we tested overdose susceptibility following ROU by administering a high dose of fentanyl (5mg/kg) in both contexts. In contrast to the FP environment where no mice overdosed (n=0/6), n=4/6 mice overdosed in the SP environment. These data suggest a greater susceptibility to OIRD and overdose when in an environment not previously paired with fentanyl administration. This context-dependent effect on OIRD may be a significant psychophysiological factor driving opioid-related deaths in the ongoing opioid epidemic. NIH: R01NS107421; R01HL163965; R01DA057767. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Investigating the role of the Locus Coeruleus in context-dependent respiratory tolerance to opioids

Pairing an environmental context with repeat opioid use (ROU) can result in increased tolerance to the effects of the opioid. This context-dependent tolerance has been extensively studied with respect to the analgesic effects of opioids, yet a knowledge gap exists in understanding whether there is context-dependent tolerance that develops in opioid induced respiratory depression (OIRD). While activity in the Locus Coeruleus (LC), the primary noradrenergic center of the brain, is involved in cue-reward related behaviors, it also enhances breathing in response to changes in blood gas homeostasis. The objective of this study is to investigate the role of the LC in context-dependent respiratory tolerance. Adult mice expressing GCaMP in the noradrenergic cells of the LC underwent a ROU protocol consisting of an initial five-day period of context pairing where each mouse was administered fentanyl (0.7mg·kg-1·day-1; i.p.) in a distinctive fentanyl-paired context (FP), and saline was administered in different distinctive saline-paired (SP) context. Following context pairing, each mouse was administered fentanyl in both the FP and SP, while LC activity and breathing were simultaneously assessed using fiber photometry and unrestrained whole body plethysmography, respectively. Independent of context, fentanyl administration caused LC activity to increase and become rhythmic during OIRD (n=6). In the FP, however, the OIRD nadir occurred 10 min after fentanyl in all subjects (n=6/6); whereas the OIRD nadir in the SP occurred 5 min after fentanyl administration in the majority of subjects (n=5/6). The difference in time to OIRD nadir corresponded to a greater amount of LC activity in the FP prior to fentanyl (n=5 of 6, p=0.03) and during OIRD (n=5 of 6, p=0.021). These results implicate the potential involvement of LC activity and increased central noradrenergic status in producing context-dependent tolerance delaying the OIRD nadir. Our findings may be leveraged to better predict and/or mitigate overdose-related deaths associated with ROU. NIH: R01NS107421; R01HL163965; R01DA057767 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Virtual screening of zinc compounds similar to NSAIDS with better pharmacodynamic and pharmacokinetic profiles

BACKGROUND: Pain is a common symptom that is managed in both outpatients and inpatients. There are many side effects associated with opioids such as respiratory depression, constipation, hyperalgesia, and tolerance. Non- steroidal anti-inflammatory drugs cause gastrointestinal tract (GIT) irritation and may be a risk factor for developing peptic ulcer disease. This study aimed to generate active analgesic agents from known analgesics, determine the docking scores of these agents to their receptors, determine the pharmacokinetic properties of these agents, and evaluate their toxicity profiles. METHODS: PubChem was used to download smiles for ibuprofen, aspirin and celecoxib. Avogadro optimized the ligands. The smiles were copied to SwissSimilarity and were used as query compounds to generate zinc compounds. DrugBank and Protein Data Bank were used to download cyclooxygenase 1 and 2. Molecular docking was done using Chimera and Autodock Vina. Smiles for both query compounds and generated zinc compounds were pasted onto the Protox II webserver and SwissADME for toxicity and pharmacokinetics properties determination. The data was presented in tabular forms with textual descriptions of the contents in the tables. RESULTS: Aspirin, ibuprofen and celecoxib’s zinc compounds were generated and the first 20 compounds were docked to COX-1 and COX-2 enzymes. Seven, one, and four of the docked compounds showed better binding energies to COX-2 than COX-1. The zinc compounds were analyzed for toxicity profiles. ZINC01680731 and ZINC33823423 were predicted to have LD50 of 1240 mg/kg as compared to aspirin’s 250mg/kg. Ibuprofen and ZINC39120409 showed LD50 of 299mg/kg and they were hepatoactive. Celecoxib and four of its zinc compounds showed LD50 of 1400mg/kg. All compounds had high GIT absorption and they conformed with Lipinski rule of five. CONCLUSIONS: ZINC01680731 0.994 and ZINC00600558 0.988 were identified as the best compounds as they showed better binding affinities, toxicities and pharmacokinetics properties compared to standard compounds.

Non-opioid antinociceptive drugs : risk of respiratory depression and death related with concomitant use of gabapentinoids in addition to opioids

Introduction : Respiratory depression and opioid-related death are reported when opioids are associated with gabapentinoids. Metanalyses of randomized clinical trials investigating efficacy and safety of such association failed to assess these risks because of the lack of data. The aim of this systematic review was to investigate the risk of respiratory depression or death during this combination in the scientific literature, including case reports or series, observational studies and clinical trials. Area covered : PubMed®, Web of Science®, Embase® and Google Scholar® were searched from their inception to December 2021, for original articles in English, French and German. Data synthesis was done on a narrative approach by type of articles. Expert opinion : The review included 25 articles (4 case reports, 2 cross-sectional, 3 case-control and 14 cohort studies, 2 clinical trials). Respiratory depression or opioid-related death and co-exposure to gabapentinoids were associated in perioperative setting/chronic pain (odds ratios around 1.3) and in opioid maintenance treatment (hazard ratio 3.4). These findings are in agreement with experimental studies showing that a single dose of gabapentinoid may reverse opioid respiratory tolerance. Because the combination gabapentinoids-opioids is highly prevalent in all clinical context, all healthcare professionals and patients must be aware of this risk.