Fentanyl-induced Respiratory Depression Research Articles

Covalently Loaded Naloxone Nanoparticles as a Long-Acting Medical Countermeasure to Opioid Poisoning.

The mu opioid receptor antagonist naloxone has been a vital, long-standing countermeasure in the ongoing battle against opioid use disorders (OUD) and toxicity. However, due to its distinctive short elimination half-life, naloxone has shown diminished efficacy in cases of synthetic opioid poisoning as larger or repeated doses of the antidote have been required to achieve adequate reversal of severe respiratory depression and prevent episodes of renarcotization. This report describes the synthesis, characterization, and in vivo evaluation of a novel, nanoparticle-based naloxone formulation that provides extended protection against the toxic effects of the powerful synthetic opioid fentanyl. The strategy was predicated on a modified two-step protocol involving the synthesis and subsequent nanoprecipitation of a poly(lactic-co-glycolic acid) polymer scaffold bearing a covalently linked naloxone chain end (drug loading ∼7% w/w). Pharmacokinetic evaluation of the resulting covalently loaded naloxone nanoparticles (cNLX-NP) revealed an elimination half-life that was 34 times longer than high dose free naloxone (10 mg/kg) in male Sprague-Dawley rats. This enhancement was further demonstrated by cNLX-NP in subsequent in vivo studies affording protection against fentanyl-induced respiratory depression and antinociception for up to 48 h following a single intramuscular injection. These discoveries support further investigation of cNLX-NP as a potential therapeutic to reverse overdose and prevent renarcotization from fentanyl and its potent analogs.

Anti‐fentanyl Vaccines and Monoclonal Antibodies are Effective in Prevention and Reversal of Fentanyl‐induced Overdose in Rats

The incidence of drug overdose deaths in the United States is an alarming public health threat that has accelerated during the COVID-19 pandemic, with over 80,000 deaths recorded in 2020. A substantial portion of this increase is attributable to the widespread access to fentanyl and other synthetic opioids, either used alone or encountered as adulterants in heroin or psychostimulants such as cocaine or methamphetamine. Vaccines and monoclonal antibodies (mAb) offer prophylactic and therapeutic interventions against opioid overdose by binding to the target opioids in serum, and reducing drug distribution to the brain. Here, the efficacy of anti-fentanyl vaccines and mAb for prevention and reversal of fentanyl-induced overdose was investigated in rats. Rats were immunized with a candidate vaccine consisting of a fentanyl-based hapten (F) conjugated to a diphtheria toxin carrier protein (CRM), or with a control vaccine. Rats were challenged subcutaneously with doses of 0.25 mg/kg fentanyl every 15 minutes to a cumulative dose of 2.25mg/kg, or until cardiac and/or respiratory arrest occurred. Prophylactic immunization with F-CRM was effective in counteracting fentanyl-induced respiratory depression, bradycardia, and antinociception; and reduced the incidence of mortality compared to control. Additionally, a murine anti-fentanyl mAb was isolated from mice immunized against fentanyl. Purified mAb had previously shown pre-exposure efficacy in protecting mice and rats from fentanyl challenges. To evaluate the efficacy of mAb in reversing fentanyl overdose post-exposure, rats were dosed with 0.1-0.5 mg/kg fentanyl, and 15 minutes later received 40 mg/kg mAb, 0.1 mg/kg naloxone, or both intravenously. Within 15 minutes, treatment with mAb reduced fentanyl-induced respiratory depression and bradycardia, and compared favorably to naloxone in terms of the degree and rate of onset of protection. One week later, rats retained mAb-induced protection from the effects of additional doses of fentanyl, as confirmed by a 10-fold reduction of the distribution of fentanyl to the brain compared to control. These results support translation of vaccines and mAb as medical interventions to prevent and reverse opioid overdose related to fentanyl and its analogs.

The Role of Somatostatin‐Expressing Cells in Opioid‐Induced Respiratory Depression

Introduction Opioids have the ability to cause respiratory depression, a severe decline in respiratory rate that can be lethal with overdose. While key brainstem respiratory regions have been shown to play a role in respiratory depression by opioids, the cells involved remain unknown. One region of interest is the preBötzinger Complex, a site that mediates respiratory depression and contains a subgroup of somatostatin (SST)-expressing cells that are required to maintain normal breathing. We aimed to determine the role of SST-expressing cells in respiratory depression by opioids. We hypothesized that deletion of mu-opioid receptors (MORs) in SST-expressing cells will prevent opioid-induced respiratory depression. Methods We developed transgenic knockout mice that lack MORs in SST-expressing cells (SST-MOR-/-) using Cre-lox recombination. SST-Cre+/+ mice (Ssttm2.1(cre)Zjh/J) were bred with Oprm1fl/fl mice (Oprm1tm1.1Cgrf/KffJ) to produce SST-MOR-/- mice. We used in situ hybridization to determine whether MOR mRNAs are co-expressed with SST mRNA in the brainstem of control (wild-type, SST-MOR+/+) and SST-MOR-/- mice. To determine the effect of removing MORs from SST-expressing cells, respiratory depression by intraperitoneal injection of fentanyl (0.3mg/kg) was quantified in control (wild-type, SST-MOR+/+) and SST-MOR-/- mice. Respiratory rate was recorded using whole-body plethysmography. Results MORs were expressed in several brainstem regions regulating breathing such as the preBötzinger Complex, the Bötzinger Complex, the nucleus ambiguus, the Kölliker-Fuse nucleus, the locus coeruleus and the nucleus tractus solitarius, while SST and MORs were co-expressed primarily in the preBötzinger Complex. Knockout of MORs in SST-expressing cells was confirmed by microscopy. Intraperitoneal injection of fentanyl (0.3mg/kg) induced a similar, significant respiratory rate depression in both wild-type (p<0.001, n=14) and SST-MOR-/- (p<0.001, n=12) mice. Conclusions SST and MORs are co-expressed in the preBötzinger Complex while MORs are expressed in other key brainstem respiratory sites. Preliminary data suggests that MORs in SST-expressing cells are not required for fentanyl-induced respiratory depression. Our previous work showed that arousal state can affect the severity of respiratory depression by opioids. For this reason, we are currently investigating the impact of arousal state (active versus inactive) on opioid-induced respiratory depression in control and SST-MOR-/- mice. We are also looking at the role of SST-expressing cells in respiratory depression by other opioid drugs such as morphine.

Fentanyl-Induced Respiratory Depression: A Narrative Review on the Possible Single-Nucleotide Polymorphism.

Opioid-related respiratory depression is a serious clinical problem as it can cause multiple deaths and anoxic brain injury. Genetic variations influence the safety and clinical efficacy of fentanyl. Pharmacogenetic studies help in identifying single-nucleotide polymorphisms (SNPs) associated with fentanyl causing respiratory depression and aid clinician in personalized pain medicine. This narrative review gives an insight of the common SNPs associated with fentanyl.

Tandospirone Reverses Fentanyl-Induced Respiratory Depression While Increasing its Analgesic Effects in Rodents

Tandospirone Reverses Fentanyl-Induced Respiratory Depression While Increasing its Analgesic Effects in Rodents

Cannabinoid CB2 Receptor Activation Attenuates Fentanyl-Induced Respiratory Depression.

Introduction: Overdose fatalities associated with the opioid epidemic are predictably attributable to drug-induced respiratory depression. In terms of illicit opioid abuse, fentanyl is the synthetic opioid responsible for the largest number of overdose deaths. There is, therefore, an urgent need to identify safe and effective therapeutics that can attenuate fentanyl-induced respiratory depression. Identification of effective alternate analgesic strategies that lessen the respiratory depression associated with narcotics would also help improve current strategies for pain management. Our laboratory recently reported that the G protein-biased CB2 cannabinoid receptor agonist LY2828360 suppressed chemotherapy-induced neuropathic nociception and attenuated both morphine tolerance and physical dependence in paclitaxel-treated mice. However, the impact of LY2828360 on other undesirable side effects of opioids, such as opioid-induced respiratory depression, remains unknown. Materials and Methods: We used whole-body plethysmography to assess the impact of the CB2 cannabinoid agonist LY2828360 on fentanyl-induced respiratory depression using wild-type (WT) and CB2 knockout (CB2KO) mice. Results: Fentanyl reduced minute ventilation and respiratory frequency without altering tidal volume in both WT and CB2KO mice. In WT mice, the high dose of fentanyl (0.2 mg/kg intraperitoneal [i.p.]) produced a greater suppression of respiratory parameters compared with the low dose of fentanyl (0.1 mg/kg i.p.). Coadministration of a behaviorally active dose of LY2828360 (3 mg/kg i.p.) with fentanyl (0.2 mg/kg i.p.) attenuated fentanyl-induced respiratory depression in WT mice. Notably, LY2828360 (3 mg/kg i.p.) did not attenuate fentanyl-induced respiratory depression in CB2KO mice, consistent with mediation by CB2 receptors. Moreover, LY2828360 (3 mg/kg i.p.) alone lacked intrinsic effects on respiratory parameters in either WT or CB2KO mice. Conclusion: The combination of a CB2 agonist with fentanyl may represent a safer adjunctive therapeutic strategy compared with a narcotic analgesic alone by attenuating the development of opioid-induced respiratory depression. Moreover, the CB2 agonist, administered alone, did not alter respiration. Our findings suggest that the CB2 cannabinoid agonist LY2828360 may provide CB2-mediated protection against fentanyl-induced respiratory depression, a detrimental and unwanted side effect of opioid use and abuse.

Monoclonal Antibodies Counteract Opioid-Induced Behavioral and Toxic Effects in Mice and Rats

Monoclonal antibodies (mAbs) and vaccines have been proposed as medical countermeasures to treat opioid use disorder (OUD) and prevent opioid overdose. In contrast to current pharmacotherapies (e.g., methadone, buprenorphine, naltrexone, and naloxone) for OUD and overdose, which target brain opioid receptors, mAbs and vaccine-generated polyclonal antibodies sequester the target opioid in the serum and reduce drug distribution to the brain. Furthermore, mAbs offer several potential clinical benefits over approved medications, such as longer serum half-life, higher selectivity, reduced side effects, and no abuse liability. Using magnetic enrichment to isolate opioid-specific B cell lymphocytes prior to fusion with myeloma partners, this study identified a series of murine hybridoma cell lines expressing mAbs with high affinity for opioids of clinical interest, including oxycodone, heroin and its active metabolites, and fentanyl. In mice, passive immunization with lead mAbs against oxycodone, heroin, and fentanyl reduced drug-induced antinociception and the distribution of the target opioid to the brain. In mice and rats, mAb pretreatment reduced fentanyl-induced respiratory depression and bradycardia, two risk factors for opioid-related overdose fatality. Overall, these results support use of mAbs to counteract toxic effects of opioids and other chemical threats. SIGNIFICANCE STATEMENT: The incidence of fatal overdoses due to the widespread access to heroin, prescription opioids, and fentanyl suggests that current Food and Drug Administration-approved countermeasures are not sufficient to mitigate the opioid epidemic. Monoclonal antibodies (mAbs) may provide acute protection from overdose by binding to circulating opioids in serum. Use of mAbs prophylactically, or after exposure in combination with naloxone, may reduce hospitalization and increase survival.

Calabadion 1 selectively reverses respiratory and central nervous system effects of fentanyl in a rat model

BackgroundWe hypothesised that Calabadion 1, an acyclic cucurbit[n]uril molecular container, reverses fentanyl-induced respiratory depression and dysfunction of the CNS. MethodsExperiments were conducted in male Sprague-Dawley rats. A constant-rate i.v. infusion of fentanyl (12.5 or 25 μg kg−1 over 15 min) was administered followed by an i.v. bolus of Calabadion 1 (0.5–200 mg kg−1) or placebo. The primary outcome was reversal of ventilatory and respiratory depression, assessed by pneumotachography and arterial blood gas analysis, respectively. Key secondary outcomes were effects on fentanyl-induced central nervous dysfunction quantified by righting reflex, balance beam test, and electromyography (EMG). ResultsCalabadion 1 reversed fentanyl-induced respiratory depression across the endpoints minute ventilation, pH, and Paco2 (P=0.001). Compared with placebo, Calabadion 1 dose dependently (P for trend <0.001) reversed fentanyl-induced hypoventilation {81.9 [5.1] (mean [standard error of the mean]) vs 45.5 [12.4] ml min−1; P<0.001}, acidosis (pH 7.43 [0.01] vs 7.28 [0.04]; P=0.005), and hypercarbia (Paco2 43.4 [1.6] vs 63.4 [8.1] mm Hg; P=0.018). The effective Calabadion 1 doses required to reverse respiratory depression by 50% and 90% (ED50Res and ED90Res) were 1.7 and 15.6 mg kg−1, respectively. Higher effective doses were needed for recovery of righting reflex (ED50CNS: 9.6 mg kg−1; ED90CNS: 86.1 mg kg−1), which was accelerated by Calabadion 1 (4.6 [0.3] vs 9.0 [0.7] min; P<0.001). Calabadion 1 also significantly accelerated recovery of full functional mobility and reversal of muscle rigidity. ConclusionsCalabadion 1 selectively and dose dependently reversed the respiratory system and CNS side-effects of fentanyl.

Solving the Opioid Crisis: Respiratory Depression by Opioids as Critical End Point

Solving the Opioid Crisis: Respiratory Depression by Opioids as Critical End Point

Inhibition of protein kinase A and GIRK channel reverses fentanyl-induced respiratory depression

Opioid-induced respiratory depression is a major obstacle to improving the clinical management of moderate to severe chronic pain. Opioids inhibit neuronal activity via various pathways, including calcium channels, adenylyl cyclase, and potassium channels. Currently, the underlying molecular pathway of opioid-induced respiratory depression is only partially understood. This study aimed to investigate the mechanisms of opioid-induced respiratory depression in vivo by examining the effects of different pharmacological agents on fentanyl-induced respiratory depression. Respiratory parameters were detected using whole body plethysmography in conscious rats. We show that pre-treatment with the protein kinase A (PKA) inhibitor H89 reversed the fentanyl-related effects on respiratory rate, inspiratory time, and expiratory time. Pre-treatment with the G protein-gated inwardly rectifying potassium (GIRK) channel blocker Tertiapin-Q dose-dependently reversed the fentanyl-related effects on respiratory rate and inspiratory time. A phosphodiesterase 4 (PDE4) inhibitor and cyclic adenosine monophosphate (cAMP) analogs did not affect fentanyl-induced respiratory depression. These findings suggest that PKA and GIRK may be involved in fentanyl-induced respiratory depression and could represent useful therapeutic targets for the treatment of fentanyl-induced ventilatory depression.

P-Glycoprotein on Blood-Brain Barrier Plays a Vital Role in Fentanyl Brain Exposure and Respiratory Toxicity in Rats.

Fentanyl is a rapid-acting, short duration opioid analgesic agent. In recent years, increased prescription and illicit use of fentanyl drugs have led to major safety concerns and a growing death toll. However, the causes of fentanyl-induced fatal adverse effects have not been thoroughly researched. This study investigated P-glycoprotein (P-gp) modulated blood-brain barrier penetration of fentanyl and its resulting toxicity in vitro and in vivo. ATPase assays were performed together with bi-directional transport assays using Caco-2 cells in the presence and absence of tariquidar, a P-gp inhibitor, to confirm the P-gp substrate property of fentanyl. In vivo determinations of brain pharmacokinetic profile, duration of loss of righting reflex, and respiratory function were further conducted following intravenous administration of low and high doses of fentanyl with and without tariquidar in rats. Fentanyl significantly increased the ATPase activity of P-gp membrane. The efflux ratio of fentanyl on Caco-2 cells was >2, which was remarkably reduced when co-incubated with tariquidar. Using concomitant tariquidar with fentanyl (40 μg/kg) in rats, the unbound brain-to-plasma concentration ratio in rats increased 2.9- fold. The duration of loss of righting reflex was significantly extended, and fentanyl-induced respiratory depression was aggravated. At high fentanyl doses (80 µg/kg), inhibition of P-gp resulted in severe respiratory toxicity in the rats and even death. Collectively, these results gave strong evidence that P-gp plays a vital role in fentanyl blood-brain barrier penetration and the resulting toxicity. Fentanyl requires close monitoring in clinic when administered concomitantly with P-gp inhibitors.

Fentanyl-Induced Brain Hypoxia Triggers Brain Hyperglycemia and Biphasic Changes in Brain Temperature.

Fentanyl is a potent synthetic opioid used extensively in humans for general anesthesia and analgesia. Fentanyl has emerged as a recreational drug, often in combination with heroin, and can result in lethality during overdose. Fentanyl is well characterized as an anesthetic, but the basic physiological effects of fentanyl in the brain when taken as a drug of abuse are largely unknown. We used high-speed amperometry in freely moving rats to examine the effects of intravenous fentanyl at doses within the range of possible human intake (3-40 μg/kg) on oxygen and glucose levels in nucleus accumbens (NAc). Fentanyl induced a rapid, dose-dependent decrease in NAc oxygen followed by a more delayed and prolonged increase in NAc glucose. Fentanyl induced similar oxygen decreases in the basolateral amygdala, indicating that brain hypoxia could be a generalized phenomenon. We used oxygen recordings in the subcutaneous space to confirm that fentanyl-induced brain hypoxia results from decreases in blood oxygen levels caused by drug-induced respiratory depression. Temperature recordings in the NAc, muscle, and skin showed that fentanyl induces biphasic changes in brain temperature, with an initial decrease that results primarily from peripheral vasodilation, and a subsequent increase driven by metabolic brain activation. The initial vasodilation appears caused by respiratory depression-induced hypoxia and a subsequent rise in CO2 that drives fentanyl-induced increases in NAc glucose. Together, these data suggest that fentanyl-induced respiratory depression triggers brain hypoxia and subsequent hyperglycemia, both of which precede slower changes in brain temperature and metabolic brain activity.

5-HT1A receptor agonist Befiradol reduces fentanyl-induced respiratory depression, analgesia, and sedation in rats.

There is an unmet clinical need to develop a pharmacological therapy to counter opioid-induced respiratory depression without interfering with analgesia or behavior. Several studies have demonstrated that 5-HT1A receptor agonists alleviate opioid-induced respiratory depression in rodent models. However, there are conflicting reports regarding their effects on analgesia due in part to varied agonist receptor selectivity and presence of anesthesia. Therefore the authors performed a study in rats with befiradol (F13640 and NLX-112), a highly selective 5-HT1A receptor agonist without anesthesia. Respiratory neural discharge was measured using in vitro preparations. Plethysmographic recording, nociception testing, and righting reflex were used to examine respiratory ventilation, analgesia, and sedation, respectively. Befiradol (0.2 mg/kg, n = 6) reduced fentanyl-induced respiratory depression (53.7 ± 5.7% of control minute ventilation 4 min after befiradol vs. saline 18.7 ± 2.2% of control, n = 9; P < 0.001), duration of analgesia (90.4 ± 11.6 min vs. saline 130.5 ± 7.8 min; P = 0.011), duration of sedation (39.8 ± 4 min vs. saline 58 ± 4.4 min; P = 0.013); and induced baseline hyperventilation, hyperalgesia, and "behavioral syndrome" in nonsedated rats. Further, the befiradol-induced alleviation of opioid-induced respiratory depression involves sites or mechanisms not functioning in vitro brainstem-spinal cord and medullary slice preparations. The reversal of opioid-induced respiratory depression and sedation by befiradol in adult rats was robust, whereas involved mechanisms are unclear. However, there were adverse concomitant decreases in fentanyl-induced analgesia and altered baseline ventilation, nociception, and behavior.

Postoperative Apnea Induced by Fentanyl and Other Multiple Respiratory-Modulating Factors

Purpose: Opioids are concerned as a major cause of postoperative respiratory depression. In the immediate postoperative period, however, other factors can produce instability of breathing such as pain, agitation, and residual effects of anesthetics. Such factors might be overlooked masked by the fear for opioid-induced respiratory depression. We report a case who presented apnea immediately after emergence from anesthesia that we considered was produced by an interaction among such factors accompanied with fentanyl-induced respiratory depression. Clinical Features: A 31-year-old woman underwent ovarian cystectomy under general anesthesia with continuous infusions of propofol and remifentanil, and bolus doses of fentanyl. Transversus abdominis plane blocks with ropivacaine were given upon completion of surgery. She complained of severe wound pain and was agitated at the emergence from anesthesia. Fentanyl 50 μg was administered intravenously. In several minutes, she developed apnea, unconsciousness, and difficulty of mechanical ventilation via a face mask. The estimated effect site concentration at the onset of the episode (2.9 ng&middotml-1) was approximately the same (3.0 ng&middotml-1) as after 30 min when she regained consciousness and spontaneous breathing. It indicated that not only direct inhibition of the respiratory center by fentanyl but also other stimulatory and inhibitory factors contributed to respiratory arrest. Conclusion: In the immediate postoperative period, transient factors, such as pain, mental instability and anesthetic residues, which are indirectly-related with breathing, can interact each other and with opioids. The interaction would induce apnea through mechanisms combined among direct inhibition of the respiratory center, and modulation of chemical and cortical controls of breathing.

Negative Pressure Pulmonary Edema Following Naloxone Administration in a Patient With Fentanyl-induced Respiratory Depression

Naloxone is commonly used to reverse narcotic intoxication. However, its use is not entirely free of hazards. For instance, pulmonary edema (PE) has been reported to arise with the mechanism of over-sympathetic discharge caused by release of cat-echolamine or central neurogenetic responses to narcotic reversal. Here, we report a healthy young patient who, after undergoing an uneventful uvulopalatopharyngo-plasty for obstructive sleep apnea hypopnea syndrome, developed PE following administration of naloxone. Fentanyl-induced respiratory depression was found during anesthesia emergence and thus naloxone was indicated for reversal. Unfortunately, upper airway obstruction-induced negative pressure PE occurred following naloxone administration. From this case, we suggest that a patent airway should be ascertained before naloxone administration for treating narcotic-induced respiratory depression.

Obesity, obstructive sleep apnoea, and diabetes mellitus: anaesthetic implications

Obesity is an epidemic in much of the Western World. The extent of this problem, combined with the increasing preference for ambulatory surgical procedures, has produced a difficult situation for many anaesthesiologists. Even the simplest anaesthetic procedures can become very complicated and potentially difficult in this population. Although there are numerous complications associated with obesity, perhaps obstructive sleep apnoea (OSA) and diabetes mellitus are among the more significant. Patients with OSA are often not ideal candidates for certain day-case procedures, but many outpatient procedures can be performed on patients with OSA as long as attention is paid to anaesthetic technique. Diabetic patients are prone to numerous complications in the perioperative period, including cardiac problems, but with careful management, they are able to undergo day-case surgical procedures safely.

Polymorphism of the μ-Opioid Receptor Gene (OPRM1 118A&gt;G) Affects Fentanyl-Induced Analgesia During Anesthesia and Recovery

There is much variation in the response of both individuals and different ethnic populations to opioids, with genetic differences being responsible for interindividual variation. The micro-opioid receptor single nucleotide polymorphism (rs number 1799971) at nucleotide position 118 (OPRM1 118A>G) affects the analgesic response to opioids. This study aimed to investigate the association between the OPRM1 118A>G polymorphism and the effects of fentanyl-induced analgesia, respiratory depression, and anesthetic recovery responses in a population of Han Chinese patients. The study was a case series in a hospital setting, with 1 year of study and 1 year of follow-up. A total of 189 patients (92 males and 97 females; American Society of Anesthesiologists Physical Status I or II, Glasgow Coma Scale = 15) who were scheduled for laparoscopic abdominal surgery received intravenous midazolam (Versed) 0.08-0.01 mg/kg and fentanyl (Duragesic) 5.0 microg/kg. The main outcome measure was the degree of postoperative pain, as assessed using the Visual Analog Scale (VAS). VAS scores were recorded 5, 15, 30, 45, and 60 minutes after a fentanyl bolus injection in the post-anesthesia care unit (PACU). The minute expiratory volume, end-tidal carbon dioxide concentration (EtCO(2)) and respiratory rate (RR) were measured continuously. The incidence of fentanyl-induced respiratory depression (RR <8/min and EtCO(2) >45 mmHg) was recorded at its appearance and treated with respiratory assistance. Blood gas analysis was done 15, 30, 45, and 60 minutes after extubation. These parameters were correlated with genotyping results of genomic DNA extracted from whole blood. Patients with the OPRM1 118 AG or GG genotypes had significantly higher VAS pain scores 15 and 30 minutes after a fentanyl bolus injection in the PACU than AA genotype patients (p < 0.05). A small but statistically significant difference was observed between the 118 AA and 118 AG/GG genotypes with regard to the carbon dioxide arterial pressure (PaCO(2)) at 15 and 30 minutes from the fentanyl bolus injection after extubation (p < 0.05); however, no clinically significant difference in the frequency of respiratory depression was seen. Homozygous 118 GG genotype patients had a significantly shorter time to awakening (p = 0.018) and extubation (p = 0.024) than patients with the 118 AA genotype. When the 118 GG and 118 AG genotypes were combined for analysis, a significantly shorter time to awakening (p = 0.011) and extubation (p = 0.010), compared with the 118 AA genotype, was also seen. The OPRM1 118A>G polymorphism lessens the analgesic response to fentanyl and the time to awakening and extubation but has no clinically significant effect on the incidence of respiratory depression.

Ampakine CX717 Protects against Fentanyl-induced Respiratory Depression and Lethal Apnea in Rats

The use of fentanyl as a potent analgesic is contradicted by marked respiratory depression among a subpopulation of patients. The commonly used approach of reversing fentanyl-induced respiratory depression with mu-opiate receptor antagonists such as naloxone has the undesirable effect of blocking analgesia. Here, the authors report a clinically feasible pharmacological solution for countering fentanyl-induced respiratory depression via a mechanism that does not interfere with analgesia. Specifically, to determine if the ampakine CX717, which has been proven metabolically stable and safe for human use, can prevent and rescue from severe fentanyl-induced apnea. Plethsymographic recordings were performed from young and adult rats. Varying doses of fentanyl were administered either intraperitoneally or intravenously to induce moderate to life-threatening apneas. CX717 was administered either before or after fentanyl administration. In addition, phrenic nerve recordings were performed from in situ working heart brainstem preparations from juvenile rats. Preadministration of CX717 markedly attenuated fentanyl-induced respiratory depression. Postadministration of CX717 rescued animals from a lethal dose of fentanyl. Significantly, CX717 countered fentanyl-induced depression of respiratory frequency without suppressing analgesia. The effective dose of CX717 was in the range deemed safe on the basis of clinical trials examining its efficacy for cognitive disorders. In situ, fentanyl-induced depression in respiratory frequency and amplitude was alleviated by CX717. CX717 is an agent that enhances the safety of using opiate drugs while preserving the analgesic effects. This advancement could significantly improve pain management in a variety of clinical settings.

Ampakine therapy to counter fentanyl-induced respiratory depression

Opioid analgesics are the most widely used and effective pharmacological agents for the treatment of acute, postoperative and chronic pain. However, activation of opiate receptors leads to significant depression of respiratory frequency in a subpopulation of patients. Here we test the hypothesis that the AMPAKINE CX717 is effective for alleviating fentanyl-induced respiratory depression without interfering with analgesia. Ampakines are a relatively new class of compounds that are in Phase II clinical trials as potential treatments for cognitive disorders and the enhancement of memory and attentiveness. They function by allosterically binding to amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPA)-type glutamate receptors and modulating the kinetics of channel closing, transmitter dissociation and desensitization. AMPA receptor mediated conductances play a central role in controlling respiratory rhythmogenesis and drive to motoneurons. Here, we demonstrate that CX717 counters fentanyl-induced respiratory depression without significantly altering analgesia and sedation, or noticeably affecting the animals' behavior. Collectively, the preclinical data demonstrate the significant potential for the use of ampakines in respiratory medicine.

5-Hydroxytryptamine 1A/7 and 4α Receptors Differentially Prevent Opioid-Induced Inhibition of Brain Stem Cardiorespiratory Function

Opioids evoke respiratory depression, bradycardia, and reduced respiratory sinus arrhythmia, whereas serotonin (5-HT) agonists stimulate respiration and cardiorespiratory interactions. This study tested whether serotonin agonists can prevent the inhibitory effects of opioids on cardiorespiratory function. Spontaneous and rhythmic inspiratory-related activity and gamma-aminobutyric acid (GABA) neurotransmission to premotor parasympathetic cardioinhibitory neurons in the nucleus ambiguus were recorded simultaneously in an in vitro thick slice preparation. The mu-opioid agonist fentanyl inhibited respiratory frequency. The 5-hydroxytryptamine 1A/7 receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin increased respiratory frequency by itself and also prevented the fentanyl-induced respiratory depression. The 5-hydroxytryptamine 4alpha agonist BIMU-8 did not by itself change inspiratory activity but prevented the mu-opioid-mediated respiratory depression. Both spontaneous and inspiratory-evoked GABAergic neurotransmission to cardiac vagal neurons were inhibited by fentanyl. 8-Hydroxy-2-(di-n-propylamino)tetralin inhibited spontaneous but not inspiratory-evoked GABAergic activity to parasympathetic cardiac neurons. However, 8-hydroxy-2-(di-n-propylamino)tetralin differentially altered the opioid-mediated depression of inspiratory-evoked GABAergic activity but did not change the opioid-induced reduction in spontaneous GABAergic neurotransmission. In contrast, BIMU-8 did not alter GABAergic neurotransmission to cardiac vagal neurons by itself but prevented the fentanyl depression of both spontaneous and inspiratory-elicited GABAergic neurotransmission to cardiac vagal neurons. In the presence of tetrodotoxin, the inhibition of GABAergic inhibitory postsynaptic currents with fentanyl is prevented by coapplication of BIMU-8, indicating that BIMU-8 acts at presynaptic GABAergic terminals to prevent fentanyl-induced depression. These results suggest that activation of 5-hydroxytryptamine receptors, particularly 5-hydroxytryptamine 4alpha agonists, may be a useful therapeutic approach in preventing opioid-evoked cardiorespiratory depression.