Respiratory Depressant Effects 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.

Elucidating the harm potential of brorphine analogues as new synthetic opioids: Synthesis, in vitro, and in vivo characterization

The emergence of new synthetic opioids (NSOs) has added complexity to recreational opioid markets worldwide. While NSOs with diverse chemical structures have emerged, brorphine currently remains the only NSO with a piperidine benzimidazolone scaffold. However, the emergence of new generations of NSOs, including brorphine analogues, can be anticipated. This study explored the pharmaco-toxicological, opioid-like effect profile of brorphine alongside its non-brominated analogue (orphine) and three other halogenated analogues (fluorphine, chlorphine, iodorphine). In vitro, radioligand binding assays in rat brain tissue indicated that all analogues bind to the μ-opioid receptor (MOR) with nM affinity. While analogues with smaller-sized substituents showed the highest MOR affinity, further in vitro characterization via two cell-based (HEK 293T) MOR activation (β-arrestin 2 and mini-Gαi recruitment) assays indicated that chlorphine, brorphine, and iodorphine were generally the most active MOR agonists. None of the compounds showed significant in vitro biased agonism compared to hydromorphone. In vivo, we investigated the effects of intraperitoneal (IP) administration of the benzimidazolones (0.01–15 mg/kg) on mechanical and thermal antinociception in male CD-1 mice. Chlorphine and brorphine overall induced the highest levels of antinociception. Furthermore, the effects on respiratory changes induced by a fixed dose (15 mg/kg IP) of the compounds were investigated using non-invasive plethysmography. Fluorphine-, chlorphine-, and brorphine-induced respiratory depressant effects were the most pronounced. For some compounds, pretreatment with naloxone (6 mg/kg IP) could not reverse respiratory depression. Taken together, brorphine-like piperidine benzimidazolones are opioid agonists that have the potential to cause substantial harm to users should they emerge as NSOs.This article is part of the Special Issue on "Novel Synthetic Opioids (NSOs)".

Dexmedetomidine as a total intravenous anesthetic in pediatric patients undergoing cleft lip and palate surgery: a case series

BackgroundSurgery for pediatric cleft lip and palate repair often utilizes high-dose opioids and inhaled anesthesia, thereby causing postoperative complications such as desaturation and/or severe agitation after anesthesia. These complications are detrimental to the child and medical personnel and cause tremendous psychologic stress to parents. Our aim is to decrease these complications through dexmedetomidine, an alpha-2 receptor agonist with anxiolytic, sympatholytic, and analgetic properties. Devoid of respiratory depressant effect, it allows patients to maintain effective ventilation and reduce agitation, postoperatively. Its unique anesthetic property may shed light on providing safe anesthesia and gentle emergence to this young, vulnerable population.Case presentationA total of 21 patients of Sundanese ethnicity, aged 3 months to 8 years (9 males and 12 females), underwent cleft lip or cleft palate surgery using total intravenous dexmedetomidine. Anesthesia was induced using sevoflurane, fentanyl, and propofol, and airway was secured. Intravenous dexmedetomidine 1.5 μg/kg was administered within 10 minutes, and a maintenance dose of 1.5 μg/kg/hour was continued as the sole anesthetic maintenance agent thereafter. Hemodynamics and anesthetic depth using Patient State Index (SEDLine™ monitor, Masimo Corporation, Irvine, CA, USA) were monitored carefully throughout the surgical procedure. Dexmedetomidine did not cause any hemodynamic derangements or postoperative complications in any of our patients. We found agitation in 9.5% (2/21) of patients.ConclusionDexmedetomidine can be used as a total intravenous anesthetic agent to maintain anesthesia and provide gentle emergence to infants and young children undergoing cleft lip and palate repair.

Combined General Anaesthesia with Retrolaminar Block for Breast Cancer Surgery in Pompe’s Disease

Pompe’s disease is a rare metabolic disease that results in progressive muscle weakness which culminates in respiratory failure in the late onset type. Patients with Pompe’s disease are at high risk of cardiac and respiratory complications under general anaesthesia owing to their premorbid cardiac and respiratory impairments, as well as the respiratory depressant effects of anaesthetic and analgesic agents. We present a high-risk case of a patient with late onset Pompe’s disease complicated by severe restrictive lung disease scheduled for breast cancer surgery under general anaesthesia with a single shot retrolaminar nerve block for analgesia.

Respiratory Depressant Effects of Fentanyl in Combination With Synthetic Cannabinoid Receptor Agonists: A Potential Mechanism for “Narcan-Resistant” Overdose

Respiratory Depressant Effects of Fentanyl in Combination With Synthetic Cannabinoid Receptor Agonists: A Potential Mechanism for “Narcan-Resistant” Overdose

Anatomical distribution of µ-opioid receptors, neurokinin-1 receptors, and vesicular glutamate transporter 2 in the mouse brainstem respiratory network.

µ-Opioid receptors (MORs) are responsible for mediating both the analgesic and respiratory effects of opioid drugs. By binding to MORs in brainstem regions involved in controlling breathing, opioids produce respiratory depressive effects characterized by slow and shallow breathing, with potential cardiorespiratory arrest and death during overdose. To better understand the mechanisms underlying opioid-induced respiratory depression, thorough knowledge of the regions and cellular subpopulations that may be vulnerable to modulation by opioid drugs is needed. Using in situ hybridization, we determined the distribution and coexpression of Oprm1 (gene encoding MORs) mRNA with glutamatergic (Vglut2) and neurokinin-1 receptor (Tacr1) mRNA in medullary and pontine regions involved in breathing control and modulation. We found that >50% of cells expressed Oprm1 mRNA in the preBötzinger complex (preBötC), nucleus tractus solitarius (NTS), nucleus ambiguus (NA), postinspiratory complex (PiCo), locus coeruleus (LC), Kölliker-Fuse nucleus (KF), and the lateral and medial parabrachial nuclei (LBPN and MPBN, respectively). Among Tacr1 mRNA-expressing cells, >50% coexpressed Oprm1 mRNA in the preBötC, NTS, NA, Bötzinger complex (BötC), PiCo, LC, raphe magnus nucleus, KF, LPBN, and MPBN, whereas among Vglut2 mRNA-expressing cells, >50% coexpressed Oprm1 mRNA in the preBötC, NTS, NA, BötC, PiCo, LC, KF, LPBN, and MPBN. Taken together, our study provides a comprehensive map of the distribution and coexpression of Oprm1, Tacr1, and Vglut2 mRNA in brainstem regions that control and modulate breathing and identifies Tacr1 and Vglut2 mRNA-expressing cells as subpopulations with potential vulnerability to modulation by opioid drugs.NEW & NOTEWORTHY Opioid drugs can cause serious respiratory side-effects by binding to µ-opioid receptors (MORs) in brainstem regions that control breathing. To better understand the regions and their cellular subpopulations that may be vulnerable to modulation by opioids, we provide a comprehensive map of Oprm1 (gene encoding MORs) mRNA expression throughout brainstem regions that control and modulate breathing. Notably, we identify glutamatergic and neurokinin-1 receptor-expressing cells as potentially vulnerable to modulation by opioid drugs and worthy of further investigation using targeted approaches.

Safe Management of Adverse Effects Associated with Prescription Opioids in the Palliative Care Population: A Narrative Review.

In the palliative care population, prescription opioids are often considered viable pain relief options. However, in this complex patient population, the adverse effects of opioid medications should be identified and managed without delay. Common adverse effects can include constipation, nausea, somnolence, dizziness, vomiting, and pruritus. Less common adverse effects can include potentially lethal respiratory depression and cardiovascular effects. Critical aspects of safe opioid prescribing are recognition of side effects and knowledge of effective management strategies; prompt management is necessary for uninterrupted pain relief. Most complications are managed with general approaches such as dose reduction, opioid rotation, alternate routes of administration, and symptomatic management. The only opioid-induced complication for which US Food and Drug Administration-approved treatments currently exist is constipation. Treating laxative-refractory opioid-induced constipation (OIC) with peripherally acting mu-opioid receptor antagonists (PAMORAs), which block gastrointestinal opioid receptors, can restore gastrointestinal motility and fluid secretion. This narrative review discusses key complications of prescription opioid treatment and their management in the palliative care setting.

Comparison of nalbuphine and morphine as intrathecal adjuvant to 0.5% bupivacaine for post-operative analgesia in lower abdominal surgeries – A randomized and control study

Background: The use of a higher volume of 0.5% bupivacaine, however, is associated with hemodynamic instability. Adjuvants such as morphine and other opioids are added in with the local anesthetic to reduce this adverse effect and extend the duration of sensory block, hence extending the length of analgesia. However, opiates are associated with a high risk of respiratory depression and other side effects. Nalbuphine has been used to counteract these adverse effects. Thus, we decided to compare the analgesic effect of intrathecal (IT) nalbuphine with IT morphine. Aims and Objectives: The aim of the study was to compare IT morphine with nalbuphine as adjuvant to a spinal anesthetic agent. The primary objective was to compare between the time of onset of sensory and motor blockade and the post-operative analgesic duration between the two adjuvants, while hemodynamic variables and side effects were studied as secondary variables. Materials and Methods: This randomized controlled study was conducted after Ethical Committee approval for a period of 1 year on 100 patients who fulfilled the inclusion criteria. They were randomized into two groups to receive sub-arachnoid block: Group A: 3 mL of 0.5% Hyperbaric Bupivacaine and 0.2 mg morphine and Group B:3 mL of 0.5% Hyperbaric Bupivacaine and 0.5 mg nalbuphine. The following parameters were monitored – Height, Weight, blood pressure, American Society of Anesthesiologists grading, time of onset, maximum duration and regression of Motor and sensory blocks, and total duration of analgesia. Results: The onset of sensory blockade was comparable in both groups while the onset of motor blockade was significantly longer in the morphine group (P≤0.001). The duration of analgesia in the morphine group was longer as compared to nalbuphine group and was statistically significant (P<0.05). The incidence of side effects was 26% in the morphine group and 6% in the nalbuphine group, which was statistically significant (P<0.05). Fourteen patients in the morphine group had pruritus and four patients in the nalbuphine group experienced nausea. Conclusion: IT nalbuphine with 0.5% bupivacaine produces rapid onset of anesthesia and early post-operative analgesia with minimal side effects, but the total analgesic duration was more with IT morphine.

Evaluating the rate of reversal of fentanyl-induced respiratory depression using a novel long-acting naloxone nanoparticle, cNLX-NP.

Fentanyl and fentanyl analogs (F/FA) have become increasingly common adulterants in counterfeit prescription pills and illicit street drug mixtures due to their ease of synthesis and exceedingly high potency. The ongoing epidemic of fatal overdoses fueled by F/FA continues to highlight the need for longer-acting therapies than naloxone (NLX), the current gold-standard for reversing opioid overdoses, which shows limited efficacy to prevent renarcotization associated with F/FA toxicity. A novel opioid reversal agent based on covalent naloxone nanoparticles (cNLX-NP) has been shown to blunt fentanyl-induced respiratory depression out to 48 hr, demonstrating its potential therapeutic utility. The purpose of this study was to characterize how rapidly cNLX-NP reverses fentanyl-induced respiratory effects as well as the duration of its protective effects. Sprague Dawley male rats (n=6/group) were tested on an oximeter for baseline percent arterial oxygen saturation (%SaO2) challenged with 0.1 mg/kg SC fentanyl and 15min later given 10 mg/kg IM doses of NLX, nalmefene (NLMF), or cNLX-NP and continuously monitored via oximetry for 10 minutes. One week later the experiment was repeated using a 1:1 mixture of NLX:cNLX-NP as the reversal agent in the rats that previously received NLX alone. While both NLX and NLMF rapidly reversed %SaO2 to baseline within 1min, rats that received cNLX-NP did not return to >90% SaO2 levels until 9min after administration. Similarly, heart and breath rates returned to baseline within 1min of treatment with NLX and NLMF but did not return to baseline until 10 minutes after cNLX-NP administration. In contrast, NLX:cNLX-NP reversed all fentanyl-induced respiratory depressive effects within one minute. While cNLX-NP alone may not sufficiently reverse F/FA overdose in a timely manner, mixing free NLX with cNLX-NP can provide a mechanism to both rapidly reverse fentanyl-related effects and maintain extended protection against synthetic opioid toxicity. These data support further development of cNLX-NP as a fast-acting and long-lasting antidote to treat F/FA-induced respiratory depression and overdose, and potentially prevent renarcotization in humans.

Anesthetic Management with Intubation in Awake Patient with Ludwig's Angina Using Dexmedetomidine and Ketamine: A Case Report

Introduction: Ludwig's Angina (LA) is a bacterial infection of the submandibular space that can cause airway obstruction. Prompt surgical treatment and antimicrobial therapy are crucial. Airway evaluation is important to identify risk factors for difficult intubation and anatomical distortion that may require awake endotracheal intubation. Case presentation: A 22-year-old female presented to the emergency department with left submandibular pain, edema, increased skin temperature, and erythema with a history of grade III caries of 6 months evolution without treatment. Physical examination revealed extension to the left lateral neck region and mild respiratory distress. Classified as ASA grade III, the patient underwent awake intubation using dexmedetomidine (DXM) and ketamine (KET), followed by balanced general anesthesia for the surgical procedure. Clinical discussion: The patient's condition predicted high difficult airway, therefore awake intubation was performed to maintain spontaneous ventilation and reduce cardiac arrest risk. In this case, DXM was used to avoid anxiety and respiratory depression, while KET was employed for its analgesic, bronchodilator, and tachycardic effects. Conclusion: Ketamine and dexmedetomidine allow adequate spontaneous ventilatory mechanics, without respiratory depressant effect. Further research is needed to find more anesthetic drugs that can be used for intubation without suppressing autonomic ventilation, and to develop guidelines to prevent respiratory depressant effects in patients with LA.

EFFECTS OF INTRAVENOUS LIDOCAINE VERSUS DEXMEDETOMIDINE ON ATTENUATION OF COUGH DURING TRACHEAL EXTUBATION AFTER ELECTIVE SURGERY: A COMPARATIVE DOUBLE-BLIND STUDY

Objective: The objective of the study is to compare the effects of intravenous lidocaine and dexmedetomidine in attenuating cough during tracheal extubation after elective surgery. Methods: Study conducted on 100 patients aged 18–65 years at Mahatma Gandhi University of Medical Sciences and Technology from August 2020 to July 2021. Patients with elective surgeries under general anesthesia with endotracheal intubation, age 18–65 years, both the sexes, American Society of Anesthesiologists, grade I and II were included in the study. Results: Both lidocaine and dexmedetomidine are equally effective in cough attenuation on tracheal extubation. The hemodynamic stability was much better with dexmedetomidine compared to lidocaine at all times. Lidocaine group patients were ready to discharge from post-anesthesia care unit statistically earlier than the dexmedetomidine group. Conclusion: Both lidocaine and dexmedetomidine are safe and reliable drugs which provide very effective attenuation of cough during tracheal extubation without any respiratory depressant effect.

Intraoperative low-dose ketamine infusion for postoperative pain relief in laparoscopic surgeries – A randomised, double blind controlled clinical trial

Abstract Background: Patients undergoing laparoscopic surgery often experience moderate-to-severe postoperative pain. The use of opioids for postoperative pain relief often results in respiratory depression and other adverse effects. Hence, we studied the effect of ketamine infusion administered at a low dose intraoperatively on postoperative pain relief. Materials and Methods: Fifty-two patients belonging to American Society of Anesthesia (ASA) I/ASA II, scheduled for laparoscopic surgery were randomized into two groups (n = 26). Group A received 0.2 mg/kg bolus of ketamine before the skin incision followed by an infusion of 0.1 mg/kg/h throughout the period of surgery. Group B received an equal volume of saline bolus and infusion. Postoperative pain was assessed (Numerical Rating Scale [NRS] scale) every 30 min till 6 h. The time taken for first rescue analgesia, the total amount of opioid used, and degree of sedation postoperatively were also compared. Pain scores between the groups were compared using the Chi-square test. Results: Pain scores (NRS scores) over various time intervals postoperatively were significantly reduced in the ketamine group (P < 0.001). The overall cumulative opioid consumption was significantly lower in the ketamine group compared to the placebo (69.29 ± 23.35 mg vs. 107.88 ± 35.21 mg, respectively, P = 0.008). There was also a significant difference in time to first rescue analgesia between the ketamine and placebo groups (2.60 ± 1.87 h vs. 0.43 ± 0.85 h, respectively, P = 0.001). Conclusion: Intraoperative low-dose ketamine infusion as an adjuvant significantly decreased postoperative pain with a reduced total dose of opioid consumption and a delayed time to first rescue analgesic.

Opioid sensitivity in treated and untreated obstructive sleep apnoea: a prospective cohort study

BackgroundOpioid administration to patients with obstructive sleep apnoea (OSA) is controversial because they are believed to be more sensitive to opioids. However, objective data on opioid effects in OSA are lacking. We tested the hypothesis that subjects with untreated OSA have increased sensitivity to opioids compared with subjects without OSA, or with OSA treated with continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BIPAP). MethodsThis was a single-centre, prospective cohort study in subjects without OSA (n=20), with untreated OSA (n=33), or with treated OSA (n=21). OSA diagnosis was verified using type III (in-home) polysomnography. Subjects received a stepped-dose remifentanil infusion (target effect-site concentrations of 0.5, 1, 2, 3, 4 ng ml−1). Primary outcome was miosis (pupil area fractional change), the most sensitive opioid effect. Secondary outcomes were ventilatory rate, end-expired CO2, sedation, and thermal analgesia. ResultsThere were no differences in miosis between untreated OSA subjects (mean=0.51, 95% confidence interval [CI] 0.41–0.61) and subjects without OSA (mean=0.49, 95% CI 0.36–0.62) (mean difference=0.02, 95% CI −0.18 to 0.22); between treated OSA subjects (mean=0.56, 95% CI 0.43–0.68) and subjects without OSA (difference=0.07, 95% CI −0.16 to 0.29); or between untreated OSA and treated OSA (difference=−0.05, 95% CI −0.25 to 0.16). There were no significant differences between subjects without OSA, untreated OSA, and treated OSA in ventilatory rate, end-expired CO2, sedation, or thermal analgesia responses to remifentanil. There was no relationship between OSA severity and magnitude of opioid effects. ConclusionsNeither obstructive sleep apnoea nor obstructive sleep apnoea treatment affected sensitivity to the miotic, sedative, analgesic, or respiratory depressant effects of the opioid remifentanil in awake adults. These results challenge conventional notions of opioid effects in obstructive sleep apnoea. Clinical trial registrationNCT02898792 (clinicaltrials.gov).

An Examination of the Complex Pharmacological Properties of the Non-Selective Opioid Modulator Buprenorphine.

The goal of this review is to provide a recent examination of the pharmacodynamics as well as pharmacokinetics, misuse potential, toxicology, and prenatal consequences of buprenorphine. Buprenorphine is currently a Schedule III opioid in the US used for opioid-use disorder (OUD) and as an analgesic. Buprenorphine has high affinity for the mu-opioid receptor (MOR), delta (DOR), and kappa (KOR) and intermediate affinity for the nociceptin (NOR). Buprenorphine's active metabolite, norbuprenorphine, crosses the blood-brain barrier, is a potent metabolite that attenuates the analgesic effects of buprenorphine due to binding to NOR, and is responsible for the respiratory depressant effects. The area under the concentration curves are very similar for buprenorphine and norbuprenorphine, which indicates that it is important to consider this metabolite. Crowding sourcing has identified a buprenorphine street value (USD 3.95/mg), indicating some non-medical use. There have also been eleven-thousand reports involving buprenorphine and minors (age < 19) at US poison control centers. Prenatal exposure to clinically relevant dosages in rats produces reductions in myelin and increases in depression-like behavior. In conclusion, the pharmacology of this OUD pharmacotherapy including the consequences of prenatal buprenorphine exposure in humans and experimental animals should continue to be carefully evaluated.

Patient Safety during Propofol Sedation before and after Implementation of Capnography Monitoring.

Endoscopic procedures are routinely applied to cancer screening programs and surveillance. The preferred technique is usually deep sedation with propofol being a convenient agent allowing for a quicker patient recovery while maintaining a similar safety profile compared to traditional agents. However, adverse events, including respiratory depression and consequent undesirable cardiovascular side effects, may occur. The goal of this work is to evaluate the patient safety impact of adding capnography during endoscopic procedures under deep propofol sedation. Data were retrospectively collected from patients undergoing deep, procedural sedation for gastrointestinal (GI) endoscopy in October 2019 to January 2021 in a single Turkish university hospital. Included in the analysis were all adult patients classified by the American Society of Anesthesiologists (ASA) as I-IV, who were scheduled for GI endoscopy utilizing propofol alone or in combination. Data on 1840 patients were collected, of whom 1610 (730 pre- and 880 post-capnography implemention) met inclusion criteria. The primary outcome was a change in the composite incidence of mild oxygen desaturation (SpO2 75-90% for <60 s), severe oxygen desaturation (SpO2 < 75% anytime or <90% for >60 s), bradycardia (<60 ppm), and tachycardia (>25% from baseline). Without capnography, on average, 7.5 events of the primary endpoint were observed per 100 procedures and 2.9 with additional capnography monitoring (p < 0.001). A significant reduction was observed for mild oxygen desaturation, with a resulting odds ratio of 0.25 (95% CI 0.14 to 0.46). ASA I patients had the highest difference in combined incidence of any oxygen desaturation of 5.85% in the pre-capnography group and 0.64% in the post-capnography group. Although procedural sedation using propofol is not associated with severe adverse events, the incidence of composite adverse events could be reduced with the addition of capnography monitoring.

Dexmedetomidine Versus Remifentanil Monitored Anesthesia Care During Endothelial Keratoplasty: A Retrospective Study

Purpose: Descemet's membrane endothelial keratoplasty (DMEK) is usually performed under topical or locoregional anesthesia; a sedation is often required. Several drugs are administered but undesirable side effects limit the use of each medication. Dexmedetomidine (DEX), a sedative-analgesic, has minimal respiratory depressant effects, and its use in DMEK surgery has not been reported. This study compares the use of DEX versus Remifentanil (REMI) during DMEK. Methods: Retrospective, observational, single-center study. Forty-two patients received sedation with DEX or REMI. Heart rate, blood pressure, oxygen saturation were always recorded during the procedure. The degree of sedation was evaluated using the Ramsay sedation scale; preoperative evaluation of anxiety disorders was carried out with the Hospital Anxiety and Depression Scale, while patients' and surgeon's satisfaction was evaluated using the 7-point Likert-like verbal rating scale. Results: Baseline demographic and clinical characteristics, as well as the baseline anxiety trait were similar for the 2 groups. Patients and surgeons reported higher satisfaction scores with DEX compared to patients receiving REMI (P &lt; 0.01; P &lt; 0.001). The intraoperative Ramsay score was 3 in 62% of patients in Group DEX and 23% in Group REMI; conversely, it was 2 in 38% of DEX Group and 77% in REMI Group (P &lt; 0.02). No statistical difference in the hemodynamic and respiratory parameters between the 2 groups was recorded. Conclusions: With similar stability of hemodynamic and respiratory parameters, Dexmedetomedine provided a deeper sedation than REMI without respiratory depression, resulting in better surgical performance in terms of the patients' and the surgeon's satisfaction, thus suggesting a possible role for sedation during DMEK surgery.

Assessment of the potential of novel and classical opioids to induce respiratory depression in mice.

Opioid-induced respiratory depression limits the use of μ-opioid receptor agonists in clinical settings and is the main cause of opioid overdose fatalities. The relative potential of different opioid agonists to induce respiratory depression at doses exceeding those producing analgesia is understudied despite its relevance to assessments of opioid safety. Here we evaluated the respiratory depressant and anti-nociceptive effects of three novel opioids and relate these measurements to their in vitro efficacy. Respiration was measured in awake, freely moving male CD-1 mice using whole body plethysmography. Anti-nociception was measured using the hot plate test. Morphine, oliceridine and tianeptine were administered intraperitoneally, whereas methadone, oxycodone and SR-17018 were administered orally. Receptor activation and arrestin-3 recruitment were measured in HEK293 cells using BRET assays. Across the dose ranges examined, all opioids studied depressed respiration in a dose-dependent manner, with similar effects at the highest doses, and with tianeptine and oliceridine showing reduced duration of effect, when compared with morphine, oxycodone, methadone and SR-17018. When administered at doses that induced similar respiratory depression, all opioids induced similar anti-nociception, with tianeptine and oliceridine again showing reduced duration of effect. These data were consistent with the in vitro agonist activity of the tested compounds. In addition to providing effective anti-nociception, the novel opioids, oliceridine, tianeptine and SR-17018 depress respiration in male mice. However, the different potencies and kinetics of effect between these novel opioids may be relevant to their therapeutic application in different clinical settings.

Evaluating the Pharmacokinetics of Fentanyl in the Brain Extracellular Fluid, Saliva, Urine, and Plasma of Newborns from Transplacental Exposure from Parturient Mothers Dosed with Epidural Fentanyl Utilizing PBPK Modeling.

Fentanyl can mitigate the mother and newborn complications resulting from labor pain. However, fentanyl shows a narrow therapeutic index between its respiratory depressive and analgesic effects. Thus, prenatally acquired high fentanyl levels in the newborn brain extracellular fluid (bECF) may induce respiratory depression which requires therapeutic drug monitoring (TDM). TDM using saliva and urine in newborns can reduce the possibility of infections and distress associated with TDM using blood. The objective of this study was to develop aphysiologically based pharmacokinetic (PBPK) modelto predict fentanyl concentrations in different newborn tissues due to intrauterine exposure. A fentanyl PBPK model in adults after intravenous and epidural administration was built, validated, and scaled to pregnancy and newborn populations. The dose that the newborn received transplacentally at birth was calculated using the pregnancy model. Then, the newborn bECF, saliva, plasma, and urine concentrations after such a dose were predicted using the newborn PBPK model. After a maternal epidural dose of fentanyl245 µg, the predicted newborn plasma and bECF levels were below the toxicity thresholds. Furthermore, the salivary threshold levels in newborns for fentanyl analgesic and respiratory depression effects were estimated to be 0.39 and 14.7-18.2 ng/ml, respectively. The salivary TDM of fentanyl in newborns can be useful in newborns exposed to intrauterine exposure from parturient females dosed with epidural fentanyl. However, newborn-specific values of µ-opioid receptors IC50 for respiratory depression are needed.

Analysis of the efficacy of subclinical doses of esketamine in combination with propofol in non-intubated general anesthesia procedures - a systematic review and meta-analysis

BackgroundThe number of non-intubated general anesthesia outside the operating room is growing as the increasing demand for comfort treatment. Non-intubated general anesthesia outside the operating room requires rapid onset of anesthesia, smoothness, quick recovery, and few postoperative complications. Traditional anesthetic regimens (propofol alone or propofol and opioids/dezocine/midazolam, etc.) have severe respiratory and circulatory depression and many systemic adverse effects. In this paper, we compare the effectiveness and safety of propofol and subclinical doses of esketamine with other traditional regimens applied to non-intubated general anesthesia through a systematic review and meta-analysis.MethodsWe searched PubMed, Embase, Cochrane Library, Web of Science, CNKI, Wanfang, VIP, and Sinomed databases for the period from January 2000 to October 2022. We rigorously screened the literature according to predefined inclusion and exclusion criteria, while risk assessment of the studies was performed using The Cochrane Collaboration’s tool, and statistical analysis of the data was performed using RevMan 5.4 software. The main outcome indicators we evaluated were the various hemodynamic parameters and incidence of various adverse effects between the experimental and control groups after induction of anesthesia.ResultsAfter a rigorous screening process, a total of 14 papers were included in the final meta-analysis. After risk bias assessment, three of the papers were judged as low risk and the others were judged as having moderate to high risk. Forest plots were drawn for a total of 16 indicators. Meta-analysis showed statistically significant differences in HR’ WMD 3.27 (0.66, 5.87), MAP’ WMD 9.68 (6.13, 13.24), SBP’ WMD 5.42 (2.11, 8.73), DBP’ WMD 4.02 (1.15, 6.88), propofol dose’ SMD -1.39 (-2.45, -0.33), hypotension’ RR 0.30 (0.20, 0.45), bradycardia’ RR 0.33 (0.14, 0.77), hypoxemia or apnea’ RR 0.45 (0.23, 0.89), injection pain’ RR 0.28 (0.13, 0.60), intraoperative choking’ RR 0.62 (0.50, 0.77), intraoperative body movements’ RR 0.48 (0.29, 0.81) and overall incidence of adverse reactions’ RR 0.52 (0.39, 0.70).The indicators that were not statistically different were time to wake up’ WMD − 0.55 (-1.29, 0.19), nausea and vomiting 0.84’ RR (0.43, 1.67), headache and dizziness’ RR 1.57 (0.98, 2.50) and neuropsychiatric reaction’ RR 1.05 (0.28, 3.93). The funnel plot showed that the vast majority of studies fell within the funnel interval, but the symmetry was relatively poor.ConclusionIn non-intubated general anesthesia, the combination of subclinical doses of esketamine and propofol did reduce circulatory and respiratory depression, injection pain, and other adverse effects, while the incidence of esketamine’s own side effects such as neuropsychiatric reactions did not increase, and the combination of the two did not cause the occurrence of new and more serious adverse reactions, and the combination of the two was safe and effective.Trial registrationPROSPREO registration number: CRD 42022368966.

Fentanyl concentrations in ligated femoral blood in the presence and absence of NPS benzodiazepine drugs. A review of over 1250 benzo-dope / fentanyl toxicity cases in Alberta, Canada

The drug combination referred to as ‘benzo dope’ has become prevalent in recent years, with an increasing number of fentanyl-related deaths reporting the concomitant presence of one or more benzodiazepine drug, such as etizolam, flualprazolam and flubromazepam. The central nervous system (CNS) depressant effects of these benzodiazepine drugs can exacerbate respiratory and CNS depressant effects resulting from the use/misuse of potent opioids such as fentanyl. This combined and enhanced drug-induced toxicity can pose a significant threat to life. Over a three-year period (2020–2022), the Office of the Chief Medical Examiner, Edmonton, Alberta, Canada issued 2812 case reports with fentanyl detected; of these cases, approximately 45% (1261) were positive for at least one benzodiazepine drug. This study presents concentrations of both fentanyl and benzodiazepine drugs in post mortem blood collected from a visualized, ligated femoral vein. The study demonstrates that the blood concentration of fentanyl in benzo-dope case reports is considerably higher than in cases where no benzodiazepine drug was detected.The median concentration of fentanyl in femoral blood for cases that also contained a benzodiazepine drug was 12.4 ng/mL (2020), 11.9 ng/mL (2021) and 14.0 ng/mL (2022). The median concentration of fentanyl in femoral blood for cases that did not contain a benzodiazepine drug was 8.5 ng/mL (2020), 7.0 ng/mL (2021) and 7.2 ng/mL (2022). The percent differences between the groups were similar with those observed from quantitative analysis of drug powders from unrelated police seizures in Alberta, Canada, suggesting the observed differences in blood fentanyl concentration may be due to the use of a drug substance with a higher concentration of fentanyl.Furthermore, the reported concentration of the benzodiazepine drug(s) is low, such that the role/contribution, if any, that this drug may have played in the decedents’ death should be questioned and carefully considered by the certifying medical examiner/coroner.