Reversal Of Opioid-induced Respiratory Depression Research Articles

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.

Systematic Review of Naloxone Dosing and Adverse Events in the Emergency Department

BackgroundExperts recommend using the lowest effective dose of naloxone to balance the reversal of opioid-induced respiratory depression and avoid precipitated opioid withdrawal, however, there is no established dosing standards within the emergency department (ED). ObjectivesThe aim of this review was to determine current naloxone dosing practice in the ED and their association with adverse events. MethodsWe conducted a systematic review by searching PubMed, Cochrane, Embase, and EBSCO from 2000–2021. Articles containing patient-level data for initial ED dose and patient outcome had data abstracted by two independent reviewers. Patients were divided into subgroups depending on the initial dose of i.v. naloxone: low dose ([LD], < 0.4 mg), standard dose ([SD], 0.4–2 mg), or high dose ([HD], > 2 mg). Our outcomes were the dose range administered and adverse events per dose. We compared groups using chi-squared difference of proportions or Fisher's exact test. ResultsThe review included 13 articles with 209 patients in the results analysis: 111 patients in LD (0.04–0.1 mg), 95 in SD (0.4–2 mg), and 3 in HD (4–12 mg). At least one adverse event was reported in 37 SD patients (38.9%), compared with 14 in LD (12.6%, p < 0.0001) and 2 in HD (100.0%, p = 0.16). At least one additional dose was administered to 53 SD patients (55.8%), compared with 55 in LD (49.5%, p < 0.0001), and 3 in HD (100.0%, p = 0.48). ConclusionsLower doses of naloxone in the ED may help reduce related adverse events without increasing the need for additional doses. Future studies should evaluate the effectiveness of lower doses of naloxone to reverse opioid-induced respiratory depression without causing precipitated opioid withdrawal.

Are thyrotropin-releasing hormone (TRH) and analog taltirelin viable reversal agents of opioid-induced respiratory depression?

Opioid‐induced respiratory depression (OIRD) is a potentially life‐threatening complication of opioid consumption. Apart from naloxone, an opioid antagonist that has various disadvantages, a possible reversal strategy is treatment of OIRD with the hypothalamic hormone and neuromodulator thyrotropin‐releasing hormone (TRH). In this review, we performed a search in electronic databases and retrieved 52 papers on the effect of TRH and TRH‐analogs on respiration and their efficacy in the reversal of OIRD in awake and anesthetized mammals, including humans. Animal studies show that TRH and its analog taltirelin stimulate breathing via an effect at the preBötzinger complex, an important respiratory rhythm generator within the brainstem respiratory network. An additional respiratory excitatory effect may be related to TRH’s analeptic effect. In awake and anesthetized rodents, TRH and taltirelin improved morphine‐ and sufentanil‐induced respiratory depression, by causing rapid shallow breathing. This pattern of breathing increases the work of breathing, dead space ventilation, atelectasis, and hypoxia. In awake and anesthetized humans, a continuous infusion of intravenous TRH with doses up to 8 mg, did not reverse sufentanil‐ or remifentanil‐induced respiratory depression. This is related to poor penetration of TRH into the brain compartment but also other causes are discussed. No human data on taltirelin are available. In conclusion, data from animals and human indicate that TRH is not a viable reversal agent of OIRD in awake or anesthetized humans. Further human studies on the efficacy and safety of TRH’s more potent and longer lasting analog taltirelin are needed as this agent seems to be a more promising reversal drug.

Mechanisms of opioid-induced respiratory depression.

Opioid-induced respiratory depression (OIRD), the primary cause of opioid-induced death, is the neural depression of respiratory drive which, together with a decreased level of consciousness and obstructive sleep apnea, cause ventilatory insufficiency. Variability of responses to opioids and individual differences in physiological and neurological states (e.g., anesthesia, sleep-disordered breathing, concurrent drug administration) add to the risk. Multiple sites can independently exert a depressive effect on breathing, making it unclear which sites are necessary for the induction of OIRD. The generatorof inspiratoryrhythm is the preBötzinger complex (preBötC) in the ventrolateral medulla. Other important brainstem respiratory centres includethe pontine Kölliker-Fuse and adjacent parabrachial nuclei (KF/PBN) in the dorsal lateral pons, and the dorsal respiratory group in the medulla. Deletion of μ opioid receptors from neurons showed that the preBötC and KF/PBN contribute to OIRD with the KF as a respiratory modulator and the preBötC as inspiratory rhythm generator. Glutamatergic neurons expressing NK-1R and somatostatin involved in the autonomic function of breathing, and modulatory signal pathways involvingGIRK and KCNQ potassium channels, remain poorly understood. Reversal of OIRD has relied heavily on naloxone which also reverses analgesia but mismatches between the half-lives of naloxone and opioids can make it difficult to clinically safely avoid OIRD. Maternal opioid use, which is rising, increases apneas and destabilizes neonatal breathing but opioid effects on maternal and neonatal respiratory circuits in neonatal abstinence syndrome (NAS) are not well understood. Methadone, administered to alleviate symptoms of NAS in humans, desensitizes rats to RD.

Advances in Reversal Strategies of Opioid-induced Respiratory Toxicity.

Opioids may produce life-threatening respiratory depression and death from their actions at the opioid receptors within the brainstem respiratory neuronal network. Since there is an increasing number of conditions where the administration of the opioid receptor antagonist naloxone is inadequate or undesired, there is an increased interest in the development of novel reversal and prevention strategies aimed at providing efficacy close to that of the opioid receptor antagonist naloxone but with fewer of its drawbacks such as its short duration of action and lesser ability to reverse high-affinity opioids, such as carfentanil, or drug combinations. To give an overview of this highly relevant topic, the authors systematically discuss predominantly experimental pharmacotherapies, published in the last 5 yr, aimed at reversal of opioid-induced respiratory depression as alternatives to naloxone. The respiratory stimulants are discussed based on their characteristics and mechanism of action: nonopioid controlled substances (e.g., amphetamine, cannabinoids, ketamine), hormones (thyrotropin releasing hormone, oxytocin), nicotinic acetylcholine receptor agonists, ampakines, serotonin receptor agonists, antioxidants, miscellaneous peptides, potassium channel blockers acting at the carotid bodies (doxapram, ENA001), sequestration techniques (scrubber molecules, immunopharmacotherapy), and opioids (partial agonists/antagonists). The authors argue that none of these often still experimental therapies are sufficiently tested with respect to efficacy and safety, and many of the agents presented have a lesser efficacy at deeper levels of respiratory depression, i.e., inability to overcome apnea, or have ample side effects. The authors suggest development of reversal strategies that combine respiratory stimulants with naloxone. Furthermore, they encourage collaborations between research groups to expedite development of viable reversal strategies of potent synthetic opioid-induced respiratory depression.

Abstract 14444: A Novel Role for the Hypothalamic Paraventricular Nucleus in Resuscitation From Opioid-Induced Respiratory Depression by Fentanyl in the Rat

Introduction: Opioid receptor antagonists, like naloxone, reverses opioid-induced respiratory depression (OIRD). We recently found that systemic oxytocin reverses fentanyl OIRD in rats. Naloxone triggers a surge in oxytocin release from the hypothalamic paraventricular nucleus (PVN) in anesthetized rats. Hypothesis: Given that naloxone induces PVN oxytocin release, we hypothesized that the PVN, an unrecognized brain region for opioid overdose reversal, is capable of respiratory resuscitation following fentanyl OIRD. Methods: Naloxone (5 mg/kg, i.v.) was given to conscious rats with indwelling venous cannulae. Blood samples were extracted at 5 min post-naloxone to measure plasma oxytocin by ELISA. Under anesthesia, phrenic nerve activity was recorded in vagotomized, paralyzed, and artificially ventilated rats to quantify inspiratory drive following fentanyl (60 nmol/kg, i.v.) and assess OIRD reversal potential following unilateral PVN nanoinjection of naloxone (3 nmol/kg, 50 nL) or vehicle (50 nL). In spontaneously breathing mice with channelrhodopsin expressed exclusively in oxytocin neurons, expired CO 2 was used to monitor rhythmic ventilation and to quantify bradypnea during OIRD. Following fentanyl, blue light (473 nm, 12 mW) pulses (10 ms, 20 Hz) or dummy pulses were delivered to the PVN using a 5 s On/1 s Off pattern for 3 min. Results: Systemic naloxone resulted in a surge in plasma oxytocin compared to vehicle in the conscious rat. Naloxone in PVN both reversed and prevented OIRD by systemic fentanyl in the rat. Photostimulation of PVN oxytocin neurons prevented lethal effects of fentanyl OIRD, whereas dummy pulses failed to prevent lethal respiratory arrest in the mouse. Conclusions: Here, we confirm that naloxone stimulates oxytocin neurons of the PVN and results in a surge of plasma oxytocin. PVN opioid receptor antagonism and photoactivation of PVN oxytocin neurons are individually capable of reversing OIRD. Findings also indicate that PVN oxytocin neurons, previously unrecognized in reversal of OIRD, are a novel target for resuscitation agents.

Dose-dependent Respiratory Depression by Remifentanil in the Rabbit Parabrachial Nucleus/Kölliker-Fuse Complex and Pre-Bötzinger Complex.

Recent studies showed partial reversal of opioid-induced respiratory depression in the pre-Bötzinger complex and the parabrachial nucleus/Kölliker-Fuse complex. The hypothesis for this study was that opioid antagonism in the parabrachial nucleus/Kölliker-Fuse complex plus pre-Bötzinger complex completely reverses respiratory depression from clinically relevant opioid concentrations. Experiments were performed in 48 adult, artificially ventilated, decerebrate rabbits. The authors decreased baseline respiratory rate ~50% with intravenous, "analgesic" remifentanil infusion or produced apnea with remifentanil boluses and investigated the reversal with naloxone microinjections (1 mM, 700 nl) into the Kölliker-Fuse nucleus, parabrachial nucleus, and pre-Bötzinger complex. In another group of animals, naloxone was injected only into the pre-Bötzinger complex to determine whether prior parabrachial nucleus/Kölliker-Fuse complex injection impacted the naloxone effect. Last, the µ-opioid receptor agonist [d-Ala,2N-MePhe,4Gly-ol]-enkephalin (100 μM, 700 nl) was injected into the parabrachial nucleus/Kölliker-Fuse complex. The data are presented as medians (25 to 75%). Remifentanil infusion reduced the respiratory rate from 36 (31 to 40) to 16 (15 to 21) breaths/min. Naloxone microinjections into the bilateral Kölliker-Fuse nucleus, parabrachial nucleus, and pre-Bötzinger complex increased the rate to 17 (16 to 22, n = 19, P = 0.005), 23 (19 to 29, n = 19, P < 0.001), and 25 (22 to 28) breaths/min (n = 11, P < 0.001), respectively. Naloxone injection into the parabrachial nucleus/Kölliker-Fuse complex prevented apnea in 12 of 17 animals, increasing the respiratory rate to 10 (0 to 12) breaths/min (P < 0.001); subsequent pre-Bötzinger complex injection prevented apnea in all animals (13 [10 to 19] breaths/min, n = 12, P = 0.002). Naloxone injection into the pre-Bötzinger complex alone increased the respiratory rate to 21 (15 to 26) breaths/min during analgesic concentrations (n = 10, P = 0.008) but not during apnea (0 [0 to 0] breaths/min, n = 9, P = 0.500). [d-Ala,2N-MePhe,4Gly-ol]-enkephalin injection into the parabrachial nucleus/Kölliker-Fuse complex decreased respiratory rate to 3 (2 to 6) breaths/min. Opioid reversal in the parabrachial nucleus/Kölliker-Fuse complex plus pre-Bötzinger complex only partially reversed respiratory depression from analgesic and even less from "apneic" opioid doses. The lack of recovery pointed to opioid-induced depression of respiratory drive that determines the activity of these areas.

Intracerebroventricular Neuropeptide FF Diminishes the Number of Apneas and Cardiovascular Effects Produced by Opioid Receptors’ Activation

The opioid-induced analgesia is associated with a number of side effects such as addiction, tolerance and respiratory depression. The involvement of neuropeptide FF (NPFF) in modulation of pain perception, opioid-induced tolerance and dependence was well documented in contrast to respiratory depression. Therefore, the aim of the present study was to examine the potency of NPFF to block post-opioid respiratory depression, one of the main adverse effects of opioid therapy. Urethane-chloralose anaesthetized Wistar rats were injected either intravenously (iv) or intracerebroventricularly (icv) with various doses of NPFF prior to iv endomorphin-1 (EM-1) administration. Iv NPFF diminished the number of EM-1-induced apneas without affecting their length and without influence on the EM-1 induced blood pressure decline. Icv pretreatment with NPFF abolished the occurrence of post-EM-1 apneas and reduced also the maximal drop in blood pressure and heart rate. These effects were completely blocked by the NPFF receptor antagonist RF9, which was given as a mixture with NPFF before systemic EM-1 administration. In conclusion, our results showed that centrally administered neuropeptide FF is effective in preventing apnea evoked by stimulation of μ-opioid receptors and the effect was due to activation of central NPFF receptors. Our finding indicates a potential target for reversal of opioid-induced respiratory depression.

Pharmacokinetic study of Sudaxine in dog plasma using novel LC-MS/MS method.

Sudaxine is a novel respiratory stimulant that increases ventilatory drive via NO+ -thiolate signaling and is under development for reversal of opioid-induced respiratory depression and other critical care indications. This study investigates the pharmacokinetic characteristics after intravenous administration of Sudaxine by using a simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. A sensitive LC-MS/MS method was validated to determine the concentration of Sudaxine in beagle dog plasma after intravenous administration of Sudaxine at (3, 10, 30, and 100mg/kg). Blood samples (1mL) were collected at designated time points and SDX concentration was measured for pharmacokinetic study. The calibration curve was linear within the range of 50-5,000 ng/mL with the lower limit of quantification at 50 ng/mL. The CTmax for all doses was reached at 10minutes (Tmax ). Over the dose range studied, average concentration - time curves and systemic exposure (CTmax and AUC0-t ) increased to Sudaxine dose. The terminal half-life of Sudaxine in dogs ranged from 10 to 30minutes and about 17.3±1.0% of Sudaxine was protein-bound in dog plasma. We developed a novel LC-MS/MS method of Sudaxine detection and quantification and determined its pharmacokinetic profiles after intravenous administration in canine subjects. Sudaxine followed first-order kinetics with rapid dose-dependent clearance rates and short half-life making it an ideal candidate for use in a critical care setting with intramuscular or IV administration.

Patterns of naloxone use in hospitalized patients

ABSTRACTObjectives: Naloxone is indicated for reversal of opioid-induced respiratory depression. The objective of this study is to evaluate patterns of naloxone use in hospitalized patients.Methods: Retrospective chart review at the University of California, San Diego Health. Subjects included adults ≥18 years old who were admitted to and received naloxone in the medical-surgical, telemetry, intermediate care, or obstetrics/gynecology units from May 1st, 2014 to April 30th, 2015. The primary endpoint was to determine the percentage of naloxone administrations that resulted in an improvement in sedation. Secondary endpoints included the percentage of naloxone administrations that reversed respiratory depression and any association of naloxone use with opioid routes of administration, other concomitant central nervous system depressants, or disease states. Data were analyzed using descriptive and contingency statistics.Results: 124 episodes of naloxone were identified during the study period. 62% of naloxone administrations resulted in an improved level of consciousness. In contrast to this, only 30 (24.2%) episodes of naloxone administration met the criteria for respiratory depression. Of these 30 episodes, naloxone reversed respiratory depression in 25 (83.3%) of them. The most frequent opioid routes of administration were short-acting oral (53.2%) and IV opioids (44.4%). Of the concomitant medications, gabapentin (28.2%) was the most frequently associated sedating medication.Conclusion: In our study, naloxone was more often used for reversal of sedation than for respiratory depression. Gabapentin may pose a risk factor for oversedation when combined with opioids, leading to increased naloxone use. Further studies are needed to explore these patterns.

Reversal of opioid-induced respiratory depression by BK-channel blocker GAL021: A pharmacokinetic-pharmacodynamic modeling study in healthy volunteers.

Opioid-induced respiratory depression (OIRD) is a serious and potentially life-threatening complication of opioid overdose, abuse, and misuse. An option to avert OIRD is to treat patients on strong opioids with respiratory stimulants that do not interact with the opioid system and consequently do not compromise opioid analgesic efficacy. The BK-channel blocker GAL021 is a respiratory stimulant acting at K(+) -channels expressed on type 1 carotid body cells. The authors performed a population pharmacokinetic-pharmacodynamic (PKPD) analysis on the ability of GAL021 to reverse alfentanil-induced respiratory depression in 12 male volunteers using an isohypercapnic experimental design. The analysis showed that (1) GAL021 interacts in a multiplicative fashion with alfentanil and GAL021, which predicts that GAL021 efficacy is reduced at low ventilation levels; (2) GAL021 has a rapid onset/offset with a blood-effect site equilibration half-life not different from zero; and (3) GAL021 displays ceiling in its efficacy to reverse OIRD.

Comparative Usability Study of a Novel Auto-Injector and an Intranasal System for Naloxone Delivery.

IntroductionThe standard of care for reversal of opioid-induced respiratory depression associated with opioid overdose is injectable naloxone. This study compared the usability of two naloxone delivery devices, a naloxone auto-injector (NAI) and a naloxone intranasal delivery system (NXN), in the administration of naloxone during a simulated opioid overdose emergency. NAI (EVZIO®; kaleo, Inc., Richmond, VA, USA) is a Food and Drug Administration approved single-use pre-filled auto-injector containing 0.4 mg of naloxone.MethodsStudy participants were randomly assigned to administer naloxone using NAI and NXN, sequentially. The primary endpoint was successful administration of a simulated dose of naloxone into a mannequin during a simulated opioid emergency, both before and after receiving training. Secondary endpoints included using the NAI or NXN in accordance with the instructions-for-use and the comparative measurement of successful completion time of administration for both NAI and NXN.ResultsA total of 42 healthy participants aged 18–65 years were enrolled in the study. The proportion of participants able to successfully administer a simulated dose of naloxone was significantly greater for NAI compared to NXN both before (90.5% vs. 0.0%, respectively, P < 0.0001) and after (100% vs. 57.1%, respectively, P < 0.0001) participant training. The proportion of participants able to administer a simulated dose of naloxone in accordance with the instructions-for-use was also significantly greater for NAI compared to NXN before (85.7% vs. 0.0%, respectively, P < 0.0001) and after (100% vs. 0.0%, respectively, P < 0.0001) participant training. The average time to task completion for administration attempt before training was 0.9 ± 0.25 min for NAI versus 6.0 ± 4.76 min for NXN and after training was 0.5 ± 0.15 min for NAI versus 2.0 ± 2.15 min for NXN.ConclusionLaypersons experienced substantially greater success administering a simulated dose of naloxone, both before and after training, using NAI versus NXN during a simulated opioid overdose emergency. No participants correctly used NXN without training.Electronic supplementary materialThe online version of this article (doi:10.1007/s40122-015-0035-9) contains supplementary material, which is available to authorized users.

Two Studies on Reversal of Opioid-Induced Respiratory Depression by BK-Channel Blocker GAL021 in Human Volunteers

Roozekrans, Margot*; van der Schrier, Rutger*; Okkerse, Pieter†; Hay, Justin†; McLeod, James F.‡; Dahan, Albert* Author Information

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.

BK Channel Blocker Rapidly Reverses OIRD

A pharmacokinetic/pharmacodynamic (PK/PD) modeling study on the effect of the BK channel blocker GAL021 found that it produced rapid reversal of opioid-induced respiratory depression (OIRD) in a population of healthy male volunteers. This article discusses a study assessing whether GAL21 stimulates breathing in OIRD and evaluated its safety in a proof-of-concept, double-blind crossover study on isohypercapnic ventilation and a subsequent double-blind exploratory study on poikilocapnic ventilation and nonrespiratory end points.

Two studies on reversal of opioid-induced respiratory depression by BK-channel blocker GAL021 in human volunteers.

Opioid-induced respiratory depression is potentially lethal. GAL021 is a calcium-activated potassium (BKCa) channel blocker that causes reversal of opioid-induced respiratory depression in animals due to a stimulatory effect on ventilation at the carotid bodies. To assess in humans whether GAL021 stimulates breathing in established opioid-induced respiratory depression and to evaluate its safety, a proof-of-concept double-blind randomized controlled crossover study on isohypercapnic ventilation (study 1) and subsequent double-blind exploratory study on poikilocapnic ventilation and nonrespiratory end points (study 2) was performed. In study 1, intravenous low- and high-dose GAL021 and placebo were administrated on top of low- and high-dose alfentanil-induced respiratory depression in 12 healthy male volunteers on two separate occasions. In study 2, the effect of GAL021/placebo on poikilocapnic ventilation, analgesia, and sedation were explored in eight male volunteers. Data are mean difference between GAL021 and placebo (95% CI). Study 1: Under isohypercapnic conditions, a separation between GAL021 and placebo on minute ventilation was observed by 6.1 (3.6 to 8.6) l/min (P < 0.01) and 3.6 (1.5 to 5.7) l/min (P < 0.01) at low-dose alfentanil plus high-dose GAL021 and high-dose-alfentanil plus high-dose GAL021, respectively. Study 2: Similar observations were made on poikilocapnic ventilation and arterial pCO2. GAL021 had no effect on alfentanil-induced sedation, antinociception and no safety issues or hemodynamic effects became apparent. GAL021 produces respiratory stimulatory effects during opioid-induced respiratory depression with containment of opioid-analgesia and without any further increase of sedation. Further studies are needed to confirm these preliminary data.

Methylxanthine reversal of opioid-induced respiratory depression in the neonatal rat: Mechanism and location of action

Methylxanthines like caffeine and theophylline have long been used to treat apnea of prematurity. Despite their success in stimulating neonatal breathing, their mechanism of action remains poorly understood. Methylxanthines can act as both non-specific adenosine receptor antagonists and inhibitors of cAMP-dependent phosphodiesterases, sarcoplasmic/endoplasmic reticulum calcium ATPases or receptor-coupled anion channels, depending on the dose used. Though there is evidence for methylxanthine action at the level of the carotid body, the consensus is that methylxanthines stimulate the respiratory centers of the brainstem. Here we used the in situ neonatal rat working heart-brainstem preparation and the ex vivo neonatal rat carotid body preparation to test the hypothesis that methylxanthines act at the level of the carotid body. We conclude that although the neonatal carotid body has active adenosine receptors, the effects of methylxanthine therapy are likely mediated centrally, predominantly via inhibition of cAMP-dependent phosphodiesterase-4.

Rebuttal from Gaspard Montandon and Richard Horner

We agree with Lalley et al. (2014) that various brainstem sites may contribute to opioid-induced respiratory depression. Our focus here, however, is on respiratory rate depression by systemically administered drugs acting on μ-opioid receptors. Of all the potential neural sites where systemically administered μ-opioids could act, Lalley et al. suggest that the parabrachial/Kolliker–Fuse complex may be critically mediating respiratory rate depression. First, if pontine nuclei were responsible for rate suppression, then depression should not be observed in the absence of the pons. Still, respiratory slowing occurs in preparations where transections are performed caudal to the pons (Takita et al. 1997; Gray et al. 1999). Also, the blocking of μ-opioid receptors alone in pontine regions has a stimulatory effect on respiratory rate that can be misinterpreted as a reversal of opioid-induced respiratory depression (Phillips et al. 2012; Prkic et al. 2012). Using microdialysis tools to locally manipulate cells, we showed that the preBotC is highly sensitive to μ-opioid receptor agonists and mediates respiratory rate depression by systematically administered μ-opioids (Montandon et al. 2011). One caveat raised when using local drug application is that drug concentration in tissue is unknown as diffusion depends on the molecule, concentration and route of perfusion. To circumvent these issues, we designed strategies to assess how effective drug perfusion is. First, we simulated drug diffusion ex situ and found that after 2 h of perfusion less than 18% of the delivered concentration was present beside the probe membrane and 5% was found at a 1 mm distance (Grace et al. 2014), which invalidates the notion that drugs diffuse beyond the preBotC and affect other respiratory nuclei. Secondly, perfusion close to the preBotC was more potent in causing rate depression or its reversal than perfusion further away (Montandon et al. 2011). Also, if the μ-opioid receptor antagonist naloxone was affecting other nuclei, it should also block the impact of systemic μ-opioids on genioglossus muscle activity since the hypoglossal premotor/motor neurons are close to the preBotC. It did not, however, and we previously revealed separate medullary sites for hypoglossal motor suppression (Hajiha et al. 2009; Montandon et al. 2011). In conclusion, we dispute the belief that the preBotC plays an indirect role in opioid-induced respiratory rate depression. Other sites may indeed mediate other components of respiratory depression, such as reduced respiratory drive transmission and upper airway dysfunction, but based on the evidence discussed (Montandon et al. 2011), we restate that the preBotC plays a critical role in mediating opioid-induced respiratory rate depression.

Opioid Antagonists

Opioid Antagonists

Practice guidelines for the prevention, detection, and management of respiratory depression associated with neuraxial opioid administration.

Practice guidelines for the prevention, detection, and management of respiratory depression associated with neuraxial opioid administration.