Opioid-induced Respiratory Depression Research Articles

Mu-opioid receptors in tachykinin-1-positive cells mediate the respiratory and antinociceptive effects of the opioid fentanyl.

Opioid drugs are potent analgesics that carry the risk of respiratory side effects due to actions on μ-opioid receptors (MORs) in brainstem regions that control respiration. Substance P is encoded by the Tac1 gene and is expressed in neurons regulating breathing, nociception, and locomotion. Tac1-positive cells also express MORs in brainstem regions mediating opioid-induced respiratory depression. We determined the role of Tac1-positive cells in mediating the respiratory effects of opioid drugs. In situ hybridization was used to determine Oprm1 mRNA expression (gene encoding MORs) in Tac1-positive cells in regions regulating respiratory depression by opioid drugs. Conditional knockout mice lacking functional MORs in Tac1-positive cells were produced and the respiratory and locomotor responses to the opioid analgesic fentanyl were assessed using whole-body plethysmography. A tail immersion assay was used to assess the antinociceptive response to fentanyl. Oprm1 mRNA was highly expressed (>80%) in subpopulations of Tac1-positive cells in the preBötzinger Complex, nucleus tractus solitarius, and Kölliker-Fuse/lateral parabrachial region. Conditionally knocking out MORs in Tac1-positive cells abolished the effects of fentanyl on respiratory rate, relative tidal volume, and relative minute ventilation compared with control mice. Importantly, the antinociceptive response of fentanyl was eliminated in mice lacking functional MORs in Tac1-positive cells, whereas locomotor effects induced by fentanyl were preserved. Our findings suggest that Tac1-positive cells mediate the respiratory depressive and antinociceptive effects of the opioid fentanyl, providing important insights for the development of pain therapies with reduced risk of respiratory side effects.

PRODIGY score predicts respiratory depression in the post-anesthesia care unit: A post-hoc analysis.

Surgical patients who experience respiratory depressive episodes (RDEs) during their post-anesthesia care unit (PACU) admission are at a higher risk of developing subsequent respiratory complications in general care wards. A risk assessment tool for PACU RDEs has not been previously assessed. The PRediction of Opioid-induced respiratory Depression In patients monitored by capnoGraphY (PRODIGY) score is an assessment tool that uses baseline patient variables to categorize patients into low, intermediate, or high risk groups for RDEs in general care wards. This study assessed whether PRODIGY groups are associated with PACU RDEs. This analysis utilized data from a previous observational trial of PACU RDEs detected by capnography. PRODIGY scores were retrospectively calculated, and the number and duration of respiratory alerts were compared among PRODIGY groups. Twenty-six (29.9%) patients were classified as low risk, 29 (33.3%) as intermediate risk, and 32 (36.8%) as high risk. A total of 3,580 alerts were recorded in the PACU, 47% of which were apnea episodes lasting ≥ 10 seconds. The total number and duration of alerts were highest in high risk group patients (median 56 [IQR 12 - 87] alerts per patient vs 22 [9 - 37] in low risk and 26 [13 - 42] in intermediate risk patients, P = 0.035; 303 [123 - 885] seconds vs 177 [30 - 779] in low risk and 301 [168 - 703] in intermediate risk patients, P = 0.042). Poisson regression analysis indicated that the rate of RDEs in the high PRODIGY risk group was higher than in the intermediate (rate ratio estimate = 2.01 [95% CI 1.86 - 2.18], P < 0.001) and low (rate ratio estimate = 2.25 [95% confidence interval 2.07 - 2.45], P < 0.001) risk groups. This analysis suggests that the PRODIGY score may be useful in assessing the risk of PACU RDEs. Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT02707003.

Best perioperative practices in the management of obstructive sleep apnea patients undergoing ambulatory surgery.

This review is timely due to the increasing prevalence of obstructive sleep apnea (OSA) among patients undergoing ambulatory surgery, necessitating updated perioperative management strategies to improve outcomes and reduce complications. Recent studies emphasize the importance of risk stratification using tools like STOP-Bang, highlighting the association between high-risk OSA and increased perioperative complications. Intraoperative management strategies, including the preference for regional anesthesia and careful monitoring of neuromuscular blockade, have been shown to mitigate risks. Postoperative protocols, particularly continuous monitoring, are crucial in preventing opioid-induced respiratory depression. Effective management of OSA in ambulatory surgery requires a multidisciplinary approach, encompassing preoperative screening, tailored intraoperative techniques, and vigilant postoperative monitoring. Implementing guidelines and protocols can significantly enhance patient safety and outcomes.

Time Course of Reversal of Fentanyl-Induced Respiratory Depression in Healthy Subjects by Intramuscular Nalmefene and Intramuscular and Intranasal Naloxone.

The increase in opioid overdose deaths, particularly involving potent, long-acting synthetic opioids, has led to calls for stronger, longer-acting opioid-overdose-reversal agents. Using an opioid-induced respiratory depression model, we investigated the onset and time course of action of naloxone and a long-acting opioid antagonist, nalmefene, in reversing the effects of an ongoing intravenous fentanyl infusion over a period of up to 100 min. Healthy, moderately experienced opioid users received intramuscular (IM) nalmefene 1 mg, IM naloxone 2 mg, or intranasal (IN) naloxone 4 mg after fentanyl-induced respiratory depression was established based on reduction in respiratory minute volume (MV). Each participant received each opioid antagonist twice per a randomized crossover schedule. Reversal of respiratory depression, pharmacokinetics, and safety were investigated. Participants showed rapid increases in plasma opioid antagonist concentrations, and meaningful reversal of depressed MV tended to occur earlier with IM nalmefene and IM naloxone than with IN naloxone. Compared to naloxone, nalmefene provided extended exposure, and mean MV was maintained at a higher level. All participants experienced treatment-related adverse events, but none were severe, serious, or led to study drug discontinuation. This study provides evidence that IM nalmefene 1 mg achieves reversal of fentanyl-induced respiratory depression similar to or better than that achieved with standard-of-care naloxone treatments. No new safety concerns were raised for IM nalmefene at the tested dose. The pharmacokinetic and pharmacodynamic properties of IM nalmefene position it as an important treatment option in opioid overdose reversal, particularly given the increasing prevalence of overdoses involving potent, long-acting synthetic opioids.

Methocinnamox is a Potent and Long-Acting Antagonist that can Prevent and Reverse Opioid-Induced Respiratory Depression.

Methocinnamox is a Potent and Long-Acting Antagonist that can Prevent and Reverse Opioid-Induced Respiratory Depression.

Research and clinical implications of emerging evidence regarding patterns of postoperative opioid-induced respiratory depression.

The wider availability of continuous respiratory monitors and advanced data abstraction techniques has led to a substantial increase in understanding of postoperative opioid-induced respiratory depression (OIRD), particularly regarding its incidence, presentation, temporal distribution, and risk factors. Self-limited episodes of OIRD are relatively common, typically presenting as repetitive apneas beginning in the postoperative period and continuing through the first night after surgery. In contrast, life-threatening episodes of OIRD are rare and usually occur on the day of surgery. Traditional monitoring of patient vital signs may be insensitive in detecting OIRD, while healthcare staff may be more adept at recognizing the concurrent development of somnolence. Although obstructive sleep apnea is a known risk factor for OIRD, a more comprehensive phenotype is emerging-elderly patients with debility and substantial comorbidity. These advances have significant implications for managing postoperative OIRD. This review will focus on how these new insights into OIRD have highlighted knowledge gaps and created opportunities for future research and practice initiatives.

Overdose Detection Among High-Risk Opioid Users Via a Wearable Chest Sensor in a Supervised Injecting Facility: Protocol for an Observational Study.

Opioid overdose is a global health crisis, affecting over 27 million individuals worldwide, with more than 100,000 drug overdose deaths in the United States in 2022-2023. This protocol outlines the development of the PneumoWave chest biosensor, a wearable device being designed to detect respiratory depression in real time through chest motion measurement, intending to enhance early intervention and thereby reduce fatalities. The study aims to (1) differentiate opioid-induced respiratory depression (OIRD) from nonfatal opioid use patterns to develop and refine an overdose detection algorithm and (2) examine participants' acceptability of the chest biosensor. The study adopts an observational design over a 6-month period. The biosensor, a small device, will be worn by consenting participants during injecting events to capture chest motion data. Safe injecting facilities (SIF) in Melbourne, Victoria (site 1), and Sydney, New South Wales (site 2), which are legally sanctioned spaces where individuals can use preobtained illicit drugs under medical supervision. Each site is anticipated to recruit up to 100 participants who inject opioids and attend the SIF. Participants will wear the biosensor during supervised injecting events at both sites. The biosensor will attempt to capture data on an anticipated 40 adverse drug events. The biosensor's ability to detect OIRD will be compared to the staff-identified events that use standard protocols for managing overdoses. Measurements will include (1) chest wall movement measured by the biosensor, securely streamed to a cloud, and analyzed to refine an overdose detection algorithm and (2) acute events or potential overdose identified by site staff. Acceptability will be measured by a feedback questionnaire as many times as the participant is willing to throughout the study. As of April 2024, a total of 47 participants have been enrolled and data from 1145 injecting events have already been collected, including 10 overdose events. This consists of 17 females and 30 males with an average age of 45 years. Data analysis is ongoing. This protocol establishes a foundation for advancing wearable technology in opioid overdose prevention within SIFs. The study will provide chest wall movement data and associated overdose data that will be used to train an algorithm that allows the biosensor to detect an overdose. The study will contribute crucial insights into OIRD, emphasizing the biosensor's potential step forward in real-time intervention strategies. DERR1-10.2196/57367.

Managing opioids and mitigating opioid risks in patients with cancer: An environmental scan of the attitudes, confidence, and practices of ambulatory, community and hospital pharmacists practicing in Canada.

Canada is in the midst of an overdose crisis. The use of prescription opioids in Canada has increased steadily over the past two decades, with stark increases in opioid-induced respiratory depression and related deaths. Opioids are the mainstay of treatment for cancer-related pain. Patients with cancer are not immune to the risks associated with opioid use but are underrepresented in available literature outlining risk mitigation strategies. Pharmacists are ideally placed to employ opioid risk mitigation practices to support safe and effective opioid use for patients with cancer-related pain. However, the current attitudes, confidence, and safety practices of pharmacists around how to best support these patients are not known. This study was a descriptive environmental scan of pharmacists who provide direct patient care in Canada. An electronic questionnaire was built using the web based Opinio software. It was distributed via email by several provincial and national pharmacy organizations and online platforms. The questionnaire consisted of Likert-scale and open-ended questions and was open to participants for a 6-week period from February 12th to March 23rd, 2020. Analysis was conducted using descriptive statistics and qualitative content analysis. Eighty-one responses from pharmacists in nine provinces were included in the analysis. Respondents endorsed limited and varied practices when caring for patients receiving opioids for cancer-related pain. Further, they demonstrated wide ranging confidence and attitudes regarding opioid risk mitigation practices and beliefs. Less than 50% of pharmacists were aware of resources available for their patients with non-medical opioid use, and/or patients at high risk of opioid-induced respiratory depression. Education, resources, and communication were the most commonly reported perceived facilitators and barriers to resource use. Pharmacists in Canada report employing opioid risk mitigation practices with low and varied frequency when caring for patients receiving opioids for cancer-related pain. They endorsed varied confidence and limited awareness of available provider and patient resources. These findings may help inform the development of new education models and evidence-based guidelines. New education models and evidence-based guidelines will support pharmacists in their pharmaceutical care of this vulnerable patient population, ultimately aiming to improve patient outcomes.

Quantified Ataxic Breathing Can Detect Opioid-Induced Respiratory Depression Earlier in Normal Volunteers Infused with Remifentanil.

Ataxic breathing (AB) is a well-known manifestation of opioid effects in animals and humans, but is not routinely included in monitoring for opioid-induced respiratory depression (OIRD). We quantified AB in normal volunteers receiving increasing doses of remifentanil. We used a support vector machine (SVM) learning approach with features derived from a modified Poincaré plot. We tested the hypothesis that AB may be found when bradypnea and reduced mental status are not present. Twenty-six healthy volunteers (13 female) received escalating target effect-site concentrations of remifentanil with a low baseline dose of propofol to simulate typical breathing patterns in drowsy patients who had received parenteral opioids. We derived respiratory rate (RR) from respiratory inductance plethysmography, mental alertness from the Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S), and AB severity on a 0 to 4 scale (categories ranging from none to severe) from the SVM. The primary outcome measure was sensitivity and specificity for AB to detect OIRD. All respiratory measurements were obtained from unperturbed subjects during steady state in 121 assessments with complete data. The sensitivity of AB for detecting OIRD by the conventional method was 92% and specificity was 28%. As expected, 69 (72%) of the instances not diagnosed as OIRD using conventional measures were observed to have at least moderate AB. AB was frequently present in the absence of traditionally detected OIRD as defined by reduced mental alertness (MOAA/S score of <4) and bradypnea (RR <8 breaths/min). These results justify the need for future trials to explore replicability with other opioids and clinical utility of AB as an add-on measure in recognizing OIRD.

Screening and Perioperative Management of Obesity Hypoventilation Syndrome.

Obesity hypoventilation syndrome (OHS) can often be underdiagnosed or misdiagnosed and has been shown to pose significant risks in perioperative situations. Patients with OHS have a higher prevalence of baseline morbid conditions like hypertension, congestive heart failure (CHF), diabetes mellitus, atrial fibrillation, and pulmonary hypertension (PH), which contribute to adverse postoperative outcomes. The potential challenges include difficult intubation and loss of airway, postoperative respiratory failure, worsening heart failure, pulmonary hypertensive crisis, and opioid-induced respiratory depression (OIRD). It is, therefore, important to screen all obese patients for obstructive sleep apnea (OSA) and OHS before elective surgical procedures. The aim of this review is to discuss the preoperative screening and evaluation and safe anesthetic and up-to-date ventilatory management of this complex group of patients. This review also intends to increase the awareness of OHS in the adult population among hospitalists, surgeons, and cardiologists who may find themselves taking care of these patients in complex multidisciplinary settings.

Advances in attenuating opioid-induced respiratory depression: A narrative review.

Opioids exert analgesic effects by agonizing opioid receptors and activating signaling pathways coupled to receptors such as G-protein and/or β-arrestin. Concomitant respiratory depression (RD) is a common clinical problem, and improvement of RD is usually achieved with specific antagonists such as naloxone; however, naloxone antagonizes opioid analgesia and may produce more unknown adverse effects. In recent years, researchers have used various methods to isolate opioid receptor-mediated analgesia and RD, with the aim of preserving opioid analgesia while attenuating RD. At present, the focus is mainly on the development of new opioids with weak respiratory inhibition or the use of non-opioid drugs to stimulate breathing. This review reports recent advances in novel opioid agents, such as mixed opioid receptor agonists, peripheral selective opioid receptor agonists, opioid receptor splice variant agonists, biased opioid receptor agonists, and allosteric modulators of opioid receptors, as well as in non-opioid agents, such as AMPA receptor modulators, 5-hydroxytryptamine receptor agonists, phosphodiesterase-4 inhibitors, and nicotinic acetylcholine receptor agonists.

Fentanyl Overdose Causes Prolonged Cardiopulmonary Dysregulation in Male SKH1 Mice.

Fentanyl overdose is a survivable condition that commonly resolves without chronic overt changes in phenotype. While the acute physiological effects of fentanyl overdose, such as opioid-induced respiratory depression (OIRD) and Wooden Chest Syndrome, represent immediate risks of lethality, little is known about longer-term systemic or organ-level impacts for survivors. In this study, we investigated the effects of a single, bolus fentanyl overdose on components of the cardiopulmonary system up to one week post. SKH1 mice were administered subcutaneous fentanyl at the highest non-lethal dose (62 mg/kg), LD10 (110 mg/kg), or LD50 (135 mg/kg), before euthanasia at 40 min, 6 h, 24 h, or 7 d post-exposure. The cerebral cortex, heart, lungs, and plasma were assayed using an immune monitoring 48-plex panel. The results showed significantly dysregulated cytokine, chemokine, and growth factor concentrations compared to time-matched controls, principally in hearts, then lungs and plasma to a lesser extent, for the length of the study, with the cortex largely unaffected. Major significant analytes contributing to variance included eotaxin-1, IL-33, and betacellulin, which were generally downregulated across time. The results of this study suggest that cardiopulmonary toxicity may persist from a single fentanyl overdose and have wide implications for the endurance of the expanding population of survivors.

M6 - Proof of Concept of Regional Oximetry to Detect Opioid Induced Respiratory Depression, Signifying Possible Overdose

M6 - Proof of Concept of Regional Oximetry to Detect Opioid Induced Respiratory Depression, Signifying Possible Overdose

M18 - Targeting a Non-Opioid Signaling Pathway to Reverse Opioid-Induced Respiratory Depression

M18 - Targeting a Non-Opioid Signaling Pathway to Reverse Opioid-Induced Respiratory Depression

M2 - Pupillometer to Predict Postoperative Opioid-Induced Respiratory Depression in Children

M2 - Pupillometer to Predict Postoperative Opioid-Induced Respiratory Depression in Children

An Autonomous Implantable Device for the Prevention of Death from Opioid Overdose.

Opioid overdose accounts for nearly 75,000 deaths per year in the United States, representing a leading cause of mortality amongst the prime working age population (25-54 years). At overdose levels, opioid-induced respiratory depression becomes fatal without timely administration of the rescue drug naloxone. Currently, overdose survival relies entirely on bystander intervention, requiring a nearby person to discover and identify the overdosed individual, and have immediate access to naloxone to administer. Government efforts have focused on providing naloxone in abundance but do not address the equally critical component for overdose rescue: a willing and informed bystander. To address this unmet need, we developed the Naloximeter: a class of life-saving implantable devices that autonomously detect and treat overdose, with the ability to simultaneously contact first-responders. We present three Naloximeter platforms, for both fundamental research and clinical translation, all equipped with optical sensors, drug delivery mechanisms, and a supporting ecosystem of technology to counteract opioid-induced respiratory depression. In small and large animal studies, the Naloximeter rescues from otherwise fatal opioid overdose within minutes. This work introduces life-changing, clinically translatable technologies that broadly benefit a susceptible population recovering from opioid use disorder.

Continuous Capnography for Early Detection of Respiratory Compromise During Gastroenterological Procedural Sedation and Analgesia.

Gastroenterology nurses working across a variety of clinical settings are responsible for periprocedural monitoring during moderate to deep procedural sedation and analgesia (PSA) to identify signs of respiratory compromise and intervene to prevent cardiorespiratory events. Pulse oximetry is the standard of care for respiratory monitoring, but it may delay or fail to detect abnormal ventilation during PSA. Continuous capnography, which measures end-tidal CO2 as a marker of alveolar ventilation, has been endorsed by a number of clinical guidelines. Large clinical trials have demonstrated that the addition of continuous capnography to pulse oximetry during PSA for various gastroenterological procedures reduces the incidence of hypoxemia, severe hypoxemia, and apnea. Studies have shown that the cost of adding continuous capnography is offset by the reduction in adverse events and hospital length of stay. In the postanesthesia care unit, continuous capnography is being evaluated for monitoring opioid-induced respiratory depression and to guide artificial airway removal. Studies are also examining the utility of continuous capnography to predict the risk of opioid-induced respiratory depression among patients receiving opioids for primary analgesia. Continuous capnography monitoring has become an essential tool to detect early signs of respiratory compromise in patients receiving PSA during gastroenterological procedures. When combined with pulse oximetry, it can help reduce cardiorespiratory adverse events, improve patient outcomes and safety, and reduce health care costs.

Effectiveness of direct patient outreach with a narrative naloxone and overdose prevention video to patients prescribed long-term opioid therapy in the USA: the Naloxone Navigator randomised clinical trial

IntroductionPublic health efforts to reduce opioid overdose fatalities include educating people at risk and expanding access to naloxone, a medication that reverses opioid-induced respiratory depression. People receiving long-term opioid therapy...

The different doses of sufentanil combined with nalmefene in bronchoscopy: a systematic review and meta-analysis.

Bronchoscopy examination is a common clinical diagnostic method. However, due to its unique operational characteristics, the procedure often induces discomfort and pain in patients. The combined use of sufentanil and nalmefene offers advantages in effectively reversing opioid-induced respiratory depression without compromising analgesic effects. However, a comprehensive analysis report on the combined use of different doses of sufentanil and nalmefene in bronchoscopy examinations has not been reported. The aim of this subject is to investigate the application effects of different doses of sufentanil combined with nalmefene in bronchoscopy. Using computer-based and manual methods to retrieve relevant keywords, we searched the databases of PubMed, Embase, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang from inception to the present to find studies evaluating the application effects of different doses of sufentanil combined with nalmefene in bronchoscopy examinations. The quality of the included studies was assessed, and meta-analysis was conducted using RevMan 5.3 software. A total of six English-language articles, involving randomized controlled trials and reviews, and comprising 774 participants, were finally included. The control group used conventional therapy, whereas the intervention group used different doses of sufentanil combined with nalmefene. Meta-analysis results indicated that compared to conventional therapy, this approach significantly improved vital signs such as systolic blood pressure [SBP; mean difference (MD) =21.44, P<1×10-5] and diastolic blood pressure (DBP; MD =22.52, P<1×10-5), heart rate (HR; MD =25.16, P<1×10-5), and oxygen saturation (SpO2; MD =30.16, P<1×10-5). A total of 4 studies focused on sedative effects, and that of sufentanil combined with nalmefene was significantly superior to conventional therapy (P<1×10-5). Analysis of adverse events showed that the combined therapy had better outcomes in terms of hypertension and tachycardia incidence compared to the control group (P<0.001, P<1×10-5), and Riker sedation-agitation scale (SAS score) was significantly reduced (P<0.05). However, there were no significant differences in other adverse events (P>0.05). Subgroup analysis showed fewer adverse reactions at 0.4 µg/kg sufentanil concentration compared to 0.2 and 0.8 µg/kg, with only hypertension differing significantly. In clinical practice, considering the use of sufentanil combined with nalmefene can improve patients' experience during bronchoscopy examinations. However, it should be noted that this approach may not be suitable for all patients, and clinicians need to choose appropriate analgesic and sedative methods for bronchoscopy examinations based on patients' conditions and individual differences. Furthermore, it is important to recognize that this study has some limitations and further research is needed to evaluate the efficacy and safety of this approach in other types of endoscopic examinations, as well as to compare the effects and safety of different drug combinations.

Identification and biophysical characterization of a novel domain-swapped camelid antibody specific for fentanyl

Opioid use disorders (OUD) and overdoses are ever-evolving public health threats that continue to grow in incidence and prevalence in the United States and abroad. Current treatments consist of opioid receptor agonists and antagonists, which are safe and effective but still suffer from some limitations. Murine and humanized monoclonal antibodies (mAb) have emerged as an alternative and complementary strategy to reverse and prevent opioid-induced respiratory depression. To explore antibody applications beyond traditional heavy-light chain mAbs, we identified and biophysically characterized a novel single-domain antibody specific for fentanyl from a camelid variable-heavy-heavy (VHH) domain phage display library. Structural data suggested that VHH binding to fentanyl was facilitated by a unique domain-swapped dimerization mechanism, which accompanied a rearrangement of complementarity-determining region loops leading to the formation of a fentanyl-binding pocket. Structure-guided mutagenesis further identified an amino acid substitution that improved the affinity and relaxed the requirement for dimerization of the VHH in fentanyl binding. Our studies demonstrate VHH engagement of an opioid and inform on how to further engineer a VHH for enhanced stability and efficacy, laying the groundwork for exploring the invivo applications of VHH-based biologics against OUD and overdose.