Opioid-induced Respiratory Depression Research Articles

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 opioids 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 opioids is needed. Using in situ hybridization, we determined the distribution and co-expression 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), locus coeruleus (LC), Kölliker-Fuse nucleus (KF), and the lateral and medial parabrachial nuclei (LBPN and MPBN, respectively). Among Tacr1 mRNA-expressing cells, >50% co-expressed Oprm1 mRNA in the preBötC, NTS, NA, Bötzinger Complex (BötC), LC, raphe magnus nucleus, KF, LPBN, and MPBN, whereas among Vglut2 mRNA-expressing cells, >50% co-expressed Oprm1 mRNA in the preBötC, NTS, NA, BötC, LC, KF, LPBN, and MPBN. Taken together, our study provides a comprehensive map of the distribution and co-expression 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 opioids.

Exploring Serotonergic mechanisms in Opioid Induced Respiratory Depression

Opioids profoundly depress breathing which can be fatal in the case of overdose. Despite growing knowledge of the pontine and medullary respiratory control circuits that are inhibited by opioids, the circuit and cellular mechanisms of opioid induced respiratory depression are not fully understood. Serotonin neurons located in the caudal medullary raphe modulate breathing and possess mu opioid receptors. Therefore, we hypothesized that serotonin-producing raphe neurons contribute to opioid induced respiratory depression. To test this, we employed to experimental approaches: 1) arterially perfused in situ working heart brainstem preparations and 2) ex vivo acute brain slice electrophysiology to identify and characterize serotonin neuron inputs onto brainstem respiratory neurons. To specifically activate serotonin neurons, we used ePet-Cre::Ai32 mice which Cre-dependently express channelrhodopsin-2, a light-activated cation channel, in serotonin neurons. At the circuit level, using the in situ preparation, we found that activation of caudal medullary raphe serotonin neurons increased respiratory rate by decreasing inspiratory and expiratory duration. Fentanyl application blocked the respiratory effects induced by serotonin neuron activation which were subsequently restored using naloxone. These results suggest serotonin neurons in the caudal medullary raphe are inhibited by opioids. To characterize the serotonin-mediated mechanisms at the cellular level, we made acute brain slices containing dorsal raphe neurons and lateral parabrachial neurons from ePet-Cre::Ai32 mice. We verified that optical stimulation resulted in action potentials and serotonin release from dorsal raphe serotonin neurons. Optically evoked serotonin release caused 5HT1A receptor-mediated outward currents in dorsal raphe serotonin neurons. To locate and characterize serotonin neuron inputs onto lateral parabrachial neurons, we performed whole-cell voltage clamp recordings from lateral parabrachial neurons and delivered paired light pulses (10 ms duration, 50 ms interval). We observed optically evoked inhibitory post-synaptic currents (IPSCs) that were blocked by the GABA-A receptor antagonist gabazine (1 μM). Optically evoked IPSCs had long latency (> 5 ms) and high jitter (> 1 ms), indicating stimulation of serotonin terminals resulted in polysynaptic GABA release onto lateral parabrachial neurons. Future work will examine the influence of opioids on this raphe-parabrachial circuit. Uncovering the role of serotonin neurons in opioid induced respiratory depression may reveal targets for restoring breathing in the presence of opioids or other conditions where life-threatening apneas occur. This work was supported by the National Institutes of Health (NIDA) R01DA047978-05 grant to ESL. 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.

The effcacy of intranasal leptin for opioid induced respiratory depression depends on sex and obesity state

Opioid-induced respiratory depression (OIRD) is the primary cause of death associated with opioids and individuals with obesity are particularly susceptible due to comorbid obstructive sleep apnea (OSA). Repeated exposure to opioids, as in the case of pain management, results in diminished therapeutic effect and/or the need for higher doses to maintain the same effect. With limited means to address the negative impact of repeated exposure it is critical to develop drugs that prevent deaths induced by opioids without reducing beneficial analgesia. We have previously shown that intranasal (IN) leptin can reverse apneas, hypoventilation, and upper airway obstruction while enhancing analgesia following acute morphine administration in obese males. Here we hypothesize that OIRD as a result of chronic opioid use can be attenuated by administration of IN leptin while also maintaining analgesia in both lean mice and mice with diet-induced obesity (DIO) of both sexes. To test this hypothesis, an opioid tolerance protocol was developed and a model of OIRD in mice chronically receiving morphine and tolerant to morphine analgesia was established. Subsequently, sleep and breathing were recorded by barometric plethysmography in four experimental groups: obese male, obese female, lean male, and lean female following acute administration of IN leptin. Operant behavioral assays were used to determine the impact of IN leptin on the analgesic effcacy of morphine. Acute administration of IN leptin significantly attenuated OIRD in DIO male mice decreasing the apnea index by 58.9% and apnea time by 60.1%. In lean mice leptin was ineffective. Morphine caused a complete loss of temperature aversion which was not reduced by intranasal leptin indicating IN leptin does not decrease morphine analgesia. We conclude that IN leptin is ineffective in lean mice but prevents OIRD in obesity by increasing hypercapnic sensitivity when leptin resistance at the blood brain barrier is present without reducing analgesia. This work was supported by funding from the National Institutes of Health: R01NS112266 (AL), R01HL128970, R61HL156240, R41DA056239 (VYP), and T32HL110952 (MLS). 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.

Understanding the Role of Central Parasympathetic Activation in Opioid-Induced Respiratory Depression and Peripheral Airway Constriction

Opioid-induced respiratory depression (OIRD) is a primary cause of mortality resulting from opioid overdose. Numerous mechanisms have been identified as contributors to OIRD, such as the suppression of central respiratory rhythmogenesis. Our recent research revealed that opioids' ability to suppress breathing extends beyond the central suppression of rhythmic activity, notably leading to airway constriction, which can culminate in complete obstruction. The autonomic nervous system plays a pivotal role in regulating the tone of airway smooth muscles with the parasympathetic system being mainly responsible for bronchoconstriction, and the sympathetic system facilitating bronchodilation. In this study, we evaluated the hypothesis that exposure to fentanyl results in the disinhibition of parasympathetic motor output, leading to centrally mediated peripheral airway constriction. After administering fentanyl (500μg/kg i.p.), minute ventilation dropped by nearly 50%, primarily due to a decrease in breathing frequency. Transient airflow obstructions during the inspiratory phase were observed following fentanyl administration, as indicated by an increased latency between diaphragm contraction and the start of inspiratory flow. These airflow obstructions were fully reversed by the sympathomimetics salbutamol or epinephrine. To determine whether the transient obstructions were a result of vagal activation, another group of mice underwent vagotomy prior to fentanyl administration. The vagotomy effectively eliminated the occurrence of airflow obstructions following fentanyl administration. Additionally, using neuronal activity-based fos-dependent labeling and in-vitro patch-clamp recordings, we showed that fentanyl administration led to a pronounced activation of parasympathetic motor neurons within brainstem areas, including the dorsal motor nucleus of the vagus and the nucleus ambiguus. Collectively, our findings suggest that fentanyl induces transient obstructions to airflow that may be attributed to heightened central parasympathetic activity, which in turn drives peripheral airway constriction. P01 HL090554 (J.M.R.), R01 HL126523 (J.M.R.), R01 HL144801 (J.M.R.), R01 HL151389 (J.M.R.), F32 HL154558 (N.J.B.), R00HL145004 (N.A.B.) and R01HL166317 (N.A.B.). 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.

Optogenetic stimulation of Phox2b-expressing neurons in the respiratory parafacial region rescue fentanyl-induced respiratory depression

The primary cause of death from opioid overdose is opioid-induced respiratory depression (OIRD), which results in substantial suppression of respiratory rate, destabilization of breathing patterns, severe hypercapnia, and a heightened risk for life-threatening apnea. A crucial chemosensitive brainstem region, located in the rostral ventrolateral medullary reticular formation, contains a bilateral cluster of approximately 800 non-opioid receptor-expressing glutamatergic, non-catecholaminergic, Phox2b+ propriobulbar neurons. These neurons are stimulated by CO2 and acidification and play a vital role in regulating breathing to prevent respiratory acidosis. Under normal circumstances, opioid induced hypercapnia should stimulate these cells to restore ventilation and prevent disturbances in arterial blood gases. However, during OIRD, it remains unclear whether these neurons can effectively rescue breathing in the response to opioid induced hypercapnia. The present study aims to address this question by investigating whether the ability of these neurons to stimulate breathing is significantly altered during opioid-induced respiratory depression. Using optogenetic stimulation, we stimulated these Phox2b+ cells before and after fentanyl to test for whether their ability to stimulate ventilation is reduced during OIRD. As expected, fentanyl (500 μg/kg, ip) resulted in respiratory rate suppression and destabilization of breathing pattern. Before fentanyl administration optogenetic stimulation of Phox2b+ cells increased breathing activity in a pulse stimulation frequency dependent (5-20Hz) manner. Unexpectedly, following fentanyl administration, similar optogenetic stimulation of Phox2b+ cells resulted in a significantly greater frequency dependent (5-20Hz) increase in breathing activity compared to pre-fentanyl levels. Additionally, both hypercapnia (FiCO2 = 0.1) or hypoxia (FiO2 = = 0.1) produced an increase breathing activity in a similar manner in pre- and post-fentanyl conditions. The results suggest that fentanyl paradoxically increases the ability of Phox2b+ cells to stimulate breathing but shifts the steady-state relationship between ventilation and arterial blood gases, such that resting ventilation is reduced. FAPESP, NIH. 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.

Unraveling the Role of Enkephalin Signaling in Respiratory Control

Opioid-induced respiratory depression (OIRD) is the primary cause of death during opioid overdose characterized by a dramatic decrease in respiratory frequency and regularity. Opioid drugs cause neural depression in the ventral respiratory column (VRC) of the medulla via activation of mu-opioid receptors (MORs) that partially contribute to breathing cessation. Nonetheless, little is known about the role of endogenous opioid signaling in respiratory modulation. This study investigates the role of endogenous MORs ligands, enkephalins encoded by the Penk gene, in breathing control. To test whether enkephalin-expressing neurons of the preBӧtzinger Complex (preBӧtC) — the inspiratory rhythm-generating region of the VRC — are necessary for breathing rhythmogenesis, we permanently silenced the region’s Penk+ population via AAV1 injections encoding tetanus toxin light chain. Using whole-body plethysmography, we recorded the animals' respiratory performance within 14 days post-injection. During the second week of testing, we observed unexpected mortality in some experimental but not control animals; post-hoc analysis of breathing traces revealed the development of severe tachypnea in succumbed mice. These data suggest that Penk+ preBӧtC cells are integral for normal respiration. Still, these observations did not assess the specific contribution of enkephalin, as opposed to other types of signaling, to breathing stability. To directly dissect the effects of enkephalin on respiratory rhythm, we utilized optogenetics and pharmacological approaches in brainstem slice preparation from neonatal mice. Brief optogenetic activation of Penk+ neurons in the preBӧtC evoked population bursts while prolonged stimulation increased the rhythm frequency. However, the application of MOR antagonist Naloxone did not affect the network’s responses to light stimulations indicating the lack of MOR/enkephalin involvement in mediating these excitatory effects. High fidelity and temporal coordination of evoked bursts implicated glutamatergic transmission as the primary mechanism of excitation. Likewise, we were able to optogenetically drive respiratory rhythm in urethane-anesthetized spontaneously breathing adult mice by stimulating the preBӧtC. Further, there was a small but significant difference in breathing responses in the presence of Naloxone compared to control conditions. We hypothesized that longitudinal projections to the VRC that might be disrupted during slice preparation contributed enkephalin to the respiratory circuits in the whole-body preparation. We utilized recombinase-dependent reporter mice crosses and retrograde AAV tracers to identify brain-wide Penk inputs to the preBӧtC. Using conventional and light sheet fluorescence microscopy, we located regions in the pons, midbrain, and forebrain that send direct enkephalinergic projections to the VRC. Functional characterizations of these projections will potentially uncover state-dependent mechanisms of respiratory modulation via endogenous opioids. Untimely, this study will help elucidate the role of enkephalin signaling in breathing control and may establish therapeutic targets for preventing OIRD. R01HL166317, R00HL145004. 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.

Effects of high dose Fentanyl in combination with hypoxia or ketamine in adult female goats

The worsening opioid epidemic in the United States continues to claim >80,000 lives each year. Synthetic opioids such as fentanyl are highly useful in the clinical management of pain but at high doses are thought to cause death through opioid-induced respiratory depression (OIRD), impairment of the alveolar to arterial oxygen (A-a O2) gradient and though upper airway and respiratory pump muscles activation causing airway dysfunction and/or Wooden Chest Syndrome (WCS). These negative effects of high dose opioids may be exacerbated when individuals use additional drugs such as ketamine or by an existing hypoxia. We have shown previously that low (sub-lethal) doses of fentanyl (25-125 μg/kg; IV) cause transient apnea (<30 sec), a brief suppression of breathing frequency (FB; <5 min), increased tidal volume (VT), upper airway and pump muscle activity, and an increased A-a O2 gradient with an overall stimulatory effect on ventilation for up to 90 min post-injection (PMID: 37885800). Here we tested the hypothesis that the physiological effects of high doses of fentanyl will be exacerbated when combined with pre-treatment of either mild hypoxia (FIO2=0.12) or IV ketamine (10 mg/kg). Adult female goats (n=3) were surgically instrumented with electromyographic (EMG) wires in airway (genioglossus and thyropharyngeal) and respiratory pump (diaphragm, transverse abdominus and intercostal) muscles and the carotid arteries relocated subcutaneously and allowed 2 weeks for recovery. Arterial blood samples were obtained through a carotid catheter and all injections were via a catheter in the jugular. Following a 30-minute control period, goats were given IV saline (vehicle) or fentanyl (50–500 μg/kg). In most goats, fentanyl doses of 200-250 μg/kg cause immediate apnea up to 60 sec in duration and decreased FB (~40%) and PaO2 (~35 mmHg) while increasing PaCO2 (~70mmHg) along with an EMG activation and increased A-a O2 gradient. These effects tended to be less severe at a given dose when injections were performed during mild hypoxia (15 min; n=2) but were exacerbated by pretreatment with ketamine (n=1). These data suggest high doses of fentanyl in goats cause similar life-threatening features as in humans, and that these effects seem to be mitigated by hypoxic ventilatory stimulation but exacerbated by polypharmacy with ketamine. NIH DA050571. 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.

Examining the relationship between Locus coeruleus (LC) activity and breathing in response to chemical exposure

Objective: The control of breathing must continuously adapt in response to homeostatic changes. This is particularly important in the context of chemical exposure to substances such as opioids and anesthetic gases known to suppress the drive for breathing. While these agents suppress breathing through different modalities, how they affect neuromodulatory networks capable of influencing breathing remains unknown. This ongoing study aims to understand how exposure to the ultrapotent synthetic opioid (UPSO), fentanyl, and the anesthetic gas, isoflurane, affect the relationship between LC activity and breathing. Hypothesis: We hypothesize that fentanyl and isoflurane have divergent effects on the relationship between LC activity and breathing. Methods: Measurements were made using unrestrained whole-body plethysmography and fiber photometry in NET-cre positive mice expressing GCaMP8s while breathing room air (FiO2=21%) before and following the administration of either fentanyl (0.7 mg/kg i.p.) or exposure to isoflurane (1.5% inhaled). Post-hoc analyses were conducted using MATLAB. Results: Our analyses showed that awake mice (N=8) exhibited two types of LC activity. Type 1 LC activity coincided with high frequency respiratory transients (HFRTs); whereas Type 2 activity did not appear to coincide with changes in breathing. Both fentanyl (N=5) and isoflurane (N=3) suppressed breathing with a greater degree occurring with the UPSO. Furthermore, the frequency of LC activity increased during opioid-induced respiratory depression (OIRD) where both types of LC activity were evident. Isoflurane anesthetized mice showed decreased Type 1 LC activity and a reduction in the duration of Type 2 activity while breathing either room air or hypoxia (FiO2=10%). Conclusion: While isoflurane suppressed Type 1 LC activity in room air and hypoxia, fentanyl which caused a larger suppression in breathing, preserved Type 1 LC activity. These differential effects suggest that the contribution of LC activity to breathing fundamentally changes when exposed to either anesthesia or fentanyl, which may be relevant to understanding the physiological consequences of exposure to either agent. This work was supported by NIH: R01HL163965, R01DA057767. 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.

Effects of high, sub-lethal doses of fentanyl on respiratory functions in adult female goats

Since 1999, the opioid epidemic in the United States has claimed more than 300,000 lives, and data from more recent years indicate annual increases exceeding 80,000 fatalities. Synthetic opioids like fentanyl contribute to these opioid-related deaths through multiple physiologic effects including Opioid-induced respiratory depression (OIRD), impairment of the alveolar to arterial oxygen gradient (A-a), and rigidity of upper airway and pump muscles causing airway dysfunction, or Wooden Chest Syndrome (WCS). We have previously shown (PMID: 37885800) that sub-lethal doses of fentanyl (25-125 μg/kg; IV) cause in healthy adult goats a transient time and dose dependent effect on breathing frequency and tidal volume, WCS and A-a which varied greatly between goats. We hypothesize that high dose fentanyl will exacerbate the effects seen in sub-lethal doses in both a time and dose-dependent manner. Adult female goats (n=3) were surgically instrumented with electromyographic (EMG) wires in both the airway (genioglossus and thyropharyngeal) and respiratory pump muscles (diaphragm, transverse abdominus and diaphragm) and the carotid arteries were relocated to a subcutaneous location. Goats were allowed 2 weeks for recovery before the onset of studies. Arterial blood samples were obtained through carotid catheters and fentanyl injections were made through acute placement of jugular venous catheters. Following a 30-minute control period, we injected saline (vehicle) or high-dose fentanyl (250-500μg/kg). In a time dependent manner, high doses of IV fentanyl injections decreased breathing frequency (FB), increased expiratory time (TE) and increased tidal volume (VT). Arterial oxygen (PaO2) decreased substantially (~35 mmHg; and arterial CO2 (PaCO2) increased to as high as 70mmHg. From about 15 to 90 minutes after fentanyl injections, the overall effect on breathing and respiratory muscle activity was consistent with a stimulatory effect of fentanyl. These data suggest high dose fentanyl increases OIRD and exacerbate life-threatening effects that cause ventilatory suppression, hypoxemia, and hypercapnia. Funded by NIH DA050571. 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.

A Deep Dive into Opioid Antagonist Use for Opioid-Induced Respiratory Depression (OIRD)

A Deep Dive into Opioid Antagonist Use for Opioid-Induced Respiratory Depression (OIRD)

Evaluating the Risk Index for Serious Prescription Opioid-Induced Respiratory Depression or Overdose in Patients with Cancer

The Commercially Insured health Plan Risk Index for Overdose or Serious Opioid-induced Respiratory Depression (CIP-RIOSORD) is an evidence-based tool to determine serious opioid-induced respiratory depression (OIRD) or overdose risk. The CIP-RIOSORD total score determines a risk class and estimates the probability for an OIRD event within the next 6 months. We performed a single-center, retrospective analysis to determine CIP-RIOSORD baseline scores and the most common predictive factors in patients with cancer. Patients (n = 160) were split into new consultations (n = 83, Group 1) versus the first documented follow-up consultation (n = 77, Group 2). Most patients were Caucasian women with metastatic gastrointestinal cancer. CIP-RIOSORD scores for Group 1 patients were 14.8 ± 15.2 (mean ± SD, risk class 4). Group 2 patients had higher CIP-RIOSORD scores (16.6 ± 14.9, risk class 4). For Group 1, the most common CIP-RIOSORD predictive factors were use of a long-acting opioid formulation (n = 24, 29%) and daily oral morphine equivalent (OME) ≥100 (n = 20, 24%); for Group 2, predictive factors were use of an antidepressant (n = 34, 44%) and a long-acting opioid formulation (n = 27, 35%). Based on the CIP-RIOSORD, there is a 15% probability of experiencing a serious OIRD event or overdose within the next 6 months.

Obstructive Sleep Apnea and Risk of Postoperative Complications after Non-Cardiac Surgery.

Obstructive sleep apnea (OSA), a common sleep disorder, poses significant challenges in perioperative management due to its complexity and multifactorial nature. With a global prevalence of approximately 22.6%, OSA often remains undiagnosed, and increases the risk of cardiac and respiratory postoperative complications. Preoperative screening has become essential in many institutions to identify patients at increased risk, and experts recommend proceeding with surgery in the absence of severe symptoms, albeit with heightened postoperative monitoring. Anesthetic and sedative agents exacerbate upper airway collapsibility and depress central respiratory activity, complicating intraoperative management, especially with neuromuscular blockade use. Additionally, OSA patients are particularly prone to opioid-induced respiratory depression, given their increased sensitivity to opioids and heightened pain perception. Thus, regional anesthesia and multimodal analgesia are strongly advocated to reduce perioperative complication risks. Postoperative care for OSA patients necessitates vigilant monitoring and tailored management strategies, such as supplemental oxygen and Positive Airway Pressure therapy, to minimize cardiorespiratory complications. Health care institutions are increasingly focusing on enhanced monitoring and resource allocation for patient safety. However, the rising prevalence of OSA, heterogeneity in disease severity, and lack of evidence for the efficacy of costly perioperative measures pose challenges. The development of effective screening and monitoring algorithms, alongside reliable risk predictors, is crucial for identifying OSA patients needing extended postoperative care. This review emphasizes a multidimensional approach in managing OSA patients throughout the perioperative period, aiming to optimize patient outcomes and minimize adverse outcomes.

Prescription opioid dispensing patterns among patients with schizophrenia or bipolar disorder

BackgroundPatients with schizophrenia (SZ) or bipolar disorder (BD) may have increased risk of complications from prescribed opioids, including opioid-induced respiratory depression. We compared prescription opioid pain medication dispensing for patients with SZ or BD versus controls over 5 years to assess dispensing trends.MethodsThis retrospective, observational study analysed US claims data from the IBM® MarketScan® Commercial and Multi-State Medicaid databases for individuals aged 18–64 years with prevalent SZ or BD for years 2015–2019 compared with age- and sex-matched controls. Baseline characteristics, comorbidities, and medication use were assessed. Proportions of individuals dispensed prescription opioids chronically (ie, ≥70 days over a 90-day period or ≥ 6 prescriptions annually) or nonchronically (≥1 prescription, chronic definition not met) were assessed.ResultsIn 2019, the Commercial and Medicaid databases contained records for 4773 and 30,179 patients with SZ and 52,780 and 63,455 patients with BD, respectively. Patients with SZ or BD had a higher prevalence of comorbidities, including pain, versus controls in each analysis year. From 2015 to 2019, among commercially insured patients with SZ, chronic opioid-dispensing proportions decreased from 6.1% (controls: 2.7%) to 2.3% (controls: 1.2%) and, for patients with BD, from 11.4% (controls: 2.7%) to 6.4% (controls: 1.6%). Chronic opioid dispensing declined in Medicaid-covered patients with SZ from 15.0% (controls: 14.7%) to 6.7% (controls: 6.0%) and, for patients with BD, from 27.4% (controls: 12.0%) to 12.4% (controls: 4.7%). Among commercially insured patients with SZ, nonchronic opioid dispensing decreased from 15.5% (controls: 16.4%) to 10.7% (controls: 11.0%) and, for patients with BD, from 26.1% (controls: 17.5%) to 20.0% (controls: 12.2%). In Medicaid-covered patients with SZ, nonchronic opioid dispensing declined from 22.5% (controls: 24.4%) to 15.1% (controls: 12.7%) and, for patients with BD, from 32.3% (controls: 25.9%) to 24.6% (controls: 13.6%).ConclusionsThe proportions of individuals dispensed chronic or nonchronic opioid medications each year were similar between commercially and Medicaid-insured patients with SZ versus controls and were higher for patients with BD versus controls. From 2015 to 2019, the proportions of individuals who were dispensed prescription opioids chronically or nonchronically decreased for patients with SZ or BD and controls.

Gastrointestinal adverse effects associated with the use of intravenous oliceridine compared with intravenous hydromorphone or fentanyl in acute pain management utilizing adjusted indirect treatment comparison methods.

Background: In the absence of head-to-head comparative data from randomized controlled trials, indirect treatment comparisons (ITCs) may be used to compare the relative effects of treatments versus a common comparator (either placebo or active treatment). For acute pain management, the effects of oliceridine have been compared in clinical trials to morphine but not to fentanyl or hydromorphone. Aim: To assess the comparative safety (specifically differences in the incidence of nausea, vomiting and opioid-induced respiratory depression [OIRD]) between oliceridine and relevant comparators (fentanyl and hydromorphone) through ITC analysis. Methods: A systematic literature review identified randomized clinical trials with oliceridine versus morphine and morphine versus fentanyl or hydromorphone. The ITC utilized the common active comparator, morphine, for the analysis. Results: A total of six randomized controlled trials(oliceridine - 2; hydromorphone - 3; fentanyl - 1) were identified for data to be used in the ITC analyses. The oliceridine data were reported in two studies (plastic surgery and orthopedic surgery) and were also reported in a pooled analysis. The ITC focused on nausea and vomiting due to limited data for OIRD. When oliceridine was compared with hydromorphone in the ITC analysis, oliceridine significantly reduced the incidence of nausea and/or vomiting requiring antiemetics compared with hydromorphone (both orthopedic surgery and pooled data), while results in plastic surgery were not statistically significant. When oliceridine was compared with hydromorphone utilizing data from Hong, the ITC only showed a trend toward reduced risk of nausea and vomiting with oliceridine that was not statistically significant across all three comparisons (orthopedic surgery, plastic surgery and combined). An ITC comparing oliceridine with a study of fentanyl utilizing the oliceridine orthopedic surgery data and combined orthopedic and plastic surgery data showed a trend toward reduced risk that was not statistically significant. Conclusion: In ITC analyses, oliceridine significantly reduced the incidence of nausea and/or vomiting or the need for antiemetics in orthopedic surgery compared with hydromorphone and a non-significant trend toward reduced risk versus fentanyl.

Reversal of Opioid-Induced Respiratory Depression in Healthy Volunteers: Comparison of Intranasal Nalmefene and Intranasal Naloxone.

An open-label, randomized, crossover study in healthy volunteers compared the reversal of remifentanil-induced respiratory depression by intranasal (IN) naloxone hydrochloride (4 mg) to IN nalmefene (2.7 mg) (NCT04828005). Subjects were administered a hypercapnic gas mixture which produces an elevation in minute ventilation (MV), a result of the ventilatory response to hypercapnia. Subjects breathed a hypercapnic gas mixture through a tight-fitting mask for an initial period of 46 min prior to a series of mask "holidays" introduced to reduce subject discomfort and encourage study completion. Ten minutes after initiating the hypercapnic gas mixture, a remifentanil bolus was administered, and an infusion continued for the study duration. Subjects were administered either naloxone or nalmefene 15 min after initiating the remifentanil infusion and MV monitored for 21 min followed by a mask holiday. Both nalmefene and naloxone produced a time-dependent reversal of remifentanil-induced reductions in MV measured 2.5-20 min post administration. At the primary endpoint (5 min post administration), nalmefene increases in MV (5.75 L/min) were nearly twice that produced by naloxone (3.01 L/min) (P < .0009); the point estimate favors nalmefene, demonstrating non-inferiority and superiority. In this model of opioid-induced respiratory depression, nalmefene has a more rapid onset of action than naloxone, which required 20 min to achieve a comparable reversal of respiratory depression. Both nalmefene and naloxone were well tolerated by healthy volunteers. This rapid onset of action may prove particularly valuable in an era when over 90% of fatalities are linked to synthetic opioid overdose.

Fact vs. fiction: naloxone in the treatment of opioid-induced respiratory depression in the current era of synthetic opioids.

Opioid-induced respiratory depression (OIRD) deaths are ~80,000 a year in the US and are a major public health issue. Approximately 90% of fatal opioid-related deaths are due to synthetic opioids such as fentanyl, most of which is illicitly manufactured and distributed either on its own or as an adulterant to other drugs of abuse such as cocaine or methamphetamine. Other potent opioids such as nitazenes are also increasingly present in the illicit drug supply, and xylazine, a veterinary tranquilizer, is a prevalent additive to opioids and other drugs of abuse. Naloxone is the main treatment used to reverse OIRD and is available as nasal sprays, prefilled naloxone injection devices, and generic naloxone for injection. An overdose needs to be treated as soon as possible to avoid death, and synthetic opioids such as fentanyl are up to 50 times more potent than heroin, so the availability of new, higher-dose, 5-mg prefilled injection or 8-mg intranasal spray naloxone preparations are important additions for emergency treatment of OIRDs, especially by lay people in the community. Higher naloxone doses are expected to reverse a synthetic overdose more rapidly and the current formulations are ideal for use by untrained lay people in the community. There are potential concerns about severe withdrawal symptoms, or pulmonary edema from treatment with high-dose naloxone. However, from the perspective of first responders, the balance of risks would point to administration of naloxone at the dose required to combat the overdose where the risk of death is very high. The presence of xylazines as an adulterant complicates the treatment of OIRDs, as naloxone is probably ineffective, although it will reverse the respiratory depression due to the opioid. For these patients, hospitalization is particularly vital. Education about the benefits of naloxone remains important not only in informing people about how to treat emergency OIRDs but also how to obtain naloxone. A call to emergency services is also essential after administering naloxone because, although the patient may revive, they may overdose again later because of the short half-life of naloxone and the long-lasting potency of fentanyl and its analogs.

Low-Impact Ampakine CX1739 Exerts Pro-Cognitive Effects and Reverses Opiate-Induced Respiratory Depression in Rodents

AMPA-glutamate receptors (AMPARs) are expressed throughout the CNS and mediate the majority of fast excitatory synaptic transmission. Ampakines are orally available small molecules that bind allosterically to AMPARs and enhance excitatory currents elicited by the endogenous agonist glutamate. In preclinical studies, ampakines are effective in ameliorating symptoms in a battery of neurodegenerative and neuropsychiatric diseases in which excitatory transmission is compromised. However, the development of ampakines as medicines was slowed by the emergence of neurotoxicity and seizures in rodents due to some ampakines. Here, we describe the preclinical pharmacology of a novel ampakine, N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[c][1,2,5] oxadiazole-5-carboxamide (CX1739), that does not induce seizures in animals or humans at efficacious doses. CX1739 dose-dependently enhanced long-term potentiation in vivo in rats, a process thought to be a molecular substrate of learning and memory. Correspondingly, CX1739 dose-dependently enhanced performance in assays that probed multiple aspects of cognition—the novel object recognition test, the win shift radial arm maze, and the five-choice serial reaction time task in rats. CX1739 also abrogated amphetamine-induced locomotor activity, demonstrating that it may be given in conjunction with stimulants for pro-cognitive gains while mitigating the side effects of stimulant-based ADHD medications. CX1739 also rapidly reversed opioid-induced respiratory depression. While efficacy in these tests occurred at doses of 0.03–18 mg/kg, there were no adverse events detected in safety studies in rats up to 2000 mg/kg. These preclinical findings suggest that CX1739 can be translated safely into the clinical setting to potentially treat dementia, neuropsychiatric disorders, and the life-threatening complication of opiate-induced suppression of endogenous inspiratory breathing rhythms.

Serotonin therapies for opioid-induced disordered swallow and respiratory depression.

Opioids are well-known to cause respiratory depression, but despite clinical evidence of dysphagia, the effects of opioids on swallow excitability and motor pattern are unknown. We tested the effects of the clinically relevant opioid buprenorphine on pharyngeal swallow and respiratory drive in male and female rats. We also evaluated the utility of 5-HT1A agonists (8-OH-DPAT and buspirone) to improve swallowing and breathing following buprenorphine administration. Experiments were performed on 44 freely breathing Sprague-Dawley rats anesthetized with sodium pentobarbital. Bipolar fine wire electrodes were inserted into the mylohyoid, thyroarytenoid, posterior cricoarytenoid, thyropharyngeus, and diaphragm muscles to measure electromyographic (EMG) activity of swallowing and breathing. We evaluated the hypotheses that swallowing varies by stimulus, opioids depress swallowing and breathing, and that 5-HT1A agonists improve these depressions. Our results largely confirmed the following hypotheses: 1) swallow-related EMG activity was larger during swallows elicited by esophageal distension plus oral water infusion than by either stimulus alone. 2) Buprenorphine depressed swallow in both sexes, but females were more susceptible to total swallow suppression. 3) Female animals were also more vulnerable to opioid-induced respiratory depression. 4) 8-OH-DPAT rescued breathing following buprenorphine-induced respiratory arrest, and pretreatment with the partial 5-HT1A agonist buspirone prevented buprenorphine-induced respiratory arrest in female animals. 5) 8-OH-DPAT enhanced mylohyoid and thyropharyngeus EMG amplitude during swallow but did not restore excitability of the swallow pattern generator following total suppression by buprenorphine. Our results highlight sex-specific and behavior-specific effects of buprenorphine and provide preclinical evidence of a 5HT1A agonist for the treatment of respiratory depression and dysphagia.NEW & NOTEWORTHY This is the first study, to our knowledge, to evaluate sex-specific effects of opioid administration on pharyngeal swallow. We expand on a small but growing number of studies that report a lower threshold for opioid-induced respiratory depression in females compared with males, and we are the first to produce this effect with the partial μ-opioid-receptor agonist buprenorphine. This is the first demonstration, to our knowledge, that activation of 5-HT1A receptors can improve swallow and breathing outcomes following systemic buprenorphine administration.

Enantiomeric contributions to methamphetamine's bidirectional effects on basal and fentanyl-depressed respiration in mice

RationaleFentanyl remains the primary cause of fatal overdoses, and its co-use with methamphetamine (METH) is a growing concern. We previously demonstrated that racemic METH can either enhance or mitigate opioid-induced respiratory depression (OIRD) dependent upon whether a low or high dose is administered. The optical isomers of METH, dextromethamphetamine (d-METH) and levomethamphetamine (l-METH), differ substantially in their selectivity and potency to activate various monoamine (MA) receptors, and these pharmacological differences may underlie the bidirectional effects of the racemate. Since it is unknown which of METH's MA receptor mechanisms mediate these respiratory effects, examination of METH's pharmacologically distinct enantiomers may provide insight into treatment targets for OIRD. MethodsThe two optical isomers of METH, d-METH and l-METH, were tested in adult male mice to determine their effects on basal and fentanyl-depressed respiratory frequency, tidal volume, and minute ventilation (MVb; i.e., respiratory frequency x tidal volume) using whole-body plethysmography. ResultsWhen tested at dose ranges of 1.0–10 mg/kg, d-METH elevated MVb and l-METH decreased basal MVb. A dose of 30 mg/kg l-METH increased basal MVb. Under fentanyl-depressed conditions, the bidirectional effects of racemic METH were observed with d-METH treatment while l-METH significantly exacerbated OIRD at 1.0 and 3.0 mg/kg. Conclusionsd-METH and l-METH differentially contribute to the bidirectional respiratory modulation observed by the racemate, with d-METH exhibiting predominantly stimulatory effects and l-METH exhibiting primarily depressant effects depending on dose.

Use of noisy labels as weak learners to identify incompletely ascertainable outcomes: A Feasibility study with opioid-induced respiratory depression

ObjectiveAssigning outcome labels to large observational data sets in a timely and accurate manner, particularly when outcomes are rare or not directly ascertainable, remains a significant challenge within biomedical informatics. We examined whether noisy labels generated from subject matter experts’ heuristics using heterogenous data types within a data programming paradigm could provide outcomes labels to a large, observational data set. We chose the clinical condition of opioid-induced respiratory depression for our use case because it is rare, has no administrative codes to easily identify the condition, and typically requires at least some unstructured text to ascertain its presence. Materials and methodsUsing de-identified electronic health records of 52,861 post-operative encounters, we applied a data programming paradigm (implemented in the Snorkel software) for the development of a machine learning classifier for opioid-induced respiratory depression. Our approach included subject matter experts creating 14 labeling functions that served as noisy labels for developing a probabilistic Generative model. We used probabilistic labels from the Generative model as outcome labels for training a Discriminative model on the source data. We evaluated performance of the Discriminative model with a hold-out test set of 599 independently-reviewed patient records. ResultsThe final Discriminative classification model achieved an accuracy of 0.977, an F1 score of 0.417, a sensitivity of 1.0, and an AUC of 0.988 in the hold-out test set with a prevalence of 0.83% (5/599). DiscussionAll of the confirmed Cases were identified by the classifier. For rare outcomes, this finding is encouraging because it reduces the number of manual reviews needed by excluding visits/patients with low probabilities. ConclusionApplication of a data programming paradigm with expert-informed labeling functions might have utility for phenotyping clinical phenomena that are not easily ascertainable from highly-structured data.