Opiate-induced Respiratory Depression Research Articles

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.

Opioids and obstructive sleep apnea.

Freire C, Sennes LU, Polotsky VY. Opioids and obstructive sleep apnea. J Clin Sleep Med. 2022;18(2):647-652.

Two Paths to Competency Validation: A Pilot for Use of Exemplars and Simulation for Validating Nurses' Responses to Patients with Opiate-Induced Respiratory Depression.

To determine nurses' ability to intervene appropriately in cases of opiate-induced respiratory depression, educators piloted two competency validation options. Nurses could choose to write an exemplar or perform in a simulation. A comparison of how nurses prepared for the methods and how educators validated their competency is described. Although unofficial staff and leadership responses to the competency methods were positive, further exploration is needed to evaluate the effectiveness of the strategies in improving nurses' care practices and patient outcomes.

Design, Synthesis and Biological Evaluation of Brain-Targeted Thiamine Disulfide Prodrugs of Ampakine Compound LCX001

Ampakine compounds have been shown to reverse opiate-induced respiratory depression by activation of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. However, their pharmacological exploitations are hindered by low blood-brain barrier (BBB) permeability and limited brain distribution. Here, we explored whether thiamine disulfide prodrugs with the ability of “lock-in” can be used to solve these problems. A series of thiamine disulfide prodrugs 7a–7f of ampakine compound LCX001 was synthesized and evaluated. The trials in vitro showed that prodrugs 7e, 7d, 7f possessed a certain stability in plasma and quickly decomposed in brain homogenate by the disulfide reductase. In vivo, prodrug 7e decreased the peripheral distribution of LCX001 and significantly increased brain distribution of LCX001 after i.v. administration. This compound showed 2.23- and 3.29-fold greater increases in the AUC0-t and MRT0-t of LCX001 in brain, respectively, than did LCX001 itself. A preliminary pharmacodynamic study indicated that the required molar dose of prodrug 7e was only one eighth that of LCX001 required to achieve the same effect in mice. These findings provide an important reference to evaluate the clinical outlook of ampakine compounds.

Identification and Characterization of GAL-021 as a Novel Breathing Control Modulator.

The authors describe the preclinical pharmacological properties of GAL-021, a novel peripheral chemoreceptor modulator. The ventilatory effects of GAL-021 were characterized using tracheal pneumotachometry (n = 4 to 6), plethysmography (n = 5 to 6), arterial blood gas analyses (n = 6 to 11), and nasal capnography (n = 3 to 4) in naive animals and those subjected to morphine-induced respiratory depression. Morphine analgesia in rats was evaluated by tail-flick test (n = 6). Carotid body involvement in GAL-021 ventilatory effects was assessed by comparing responses in intact and carotid sinus nerve-transected rats. Hemodynamic effects of GAL-021 were evaluated in urethane-anesthetized rats (n = 7). The pharmacological profile of GAL-021 in vitro was investigated using radioligand binding, enzyme inhibition, and cellular electrophysiology assays. GAL-021 given intravenously stimulated ventilation and/or attenuated opiate-induced respiratory depression in rats, mice, and nonhuman primates, without decreasing morphine analgesia in rats. GAL-021 did not alter mean arterial pressure but produced a modest increase in heart rate. Ventilatory stimulation in rats was attenuated by carotid sinus nerve transection. GAL-021 inhibited KCa1.1 in GH3 cells, and the evoked ventilatory stimulation was attenuated in Slo1 mice lacking the pore-forming α-subunit of the KCa1.1 channel. GAL-021 behaved as a breathing control modulator in rodents and nonhuman primates and diminished opioid-induced respiratory depression without compromising opioid analgesia. It acted predominantly at the carotid body, in part by inhibiting KCa1.1 channels. Its preclinical profile qualified the compound to enter clinical trials to assess effects on breathing control disorders such as drug (opioid)-induced respiratory depression and sleep apnea.

Tianeptine prevents respiratory depression without affecting analgesic effect of opiates in conscious rats

Respiratory depression remains an important clinical problem that limits the use of opiate analgesia. Activation of AMPA glutamate receptors has been shown to reverse fentanyl-induced respiratory changes. Here, we explored whether tianeptine, a drug known for its ability to phosphorylate AMPA receptors, can be used to prevent opiate-induced respiratory depression. A model of respiratory depression in conscious rats was produced by administration of morphine (10mg/kg, i.p.). Rats were pre-treated with test compounds or control solutions 5min prior to administration of morphine. Respiratory activity was measured using whole-body plethysmography. In conscious animals, tianeptine (2 and 10mg/kg, ip) and DP-201 (2-(4-((3-chloro-6-methyl-5,5-dioxido-6,11-dihydrodibenzo[c,f][1,2] thiazepin-11-yl)amino)butoxy)acetic acid; tianeptine analogue; 2mg/kg, ip) triggered significant (~30%) increases in baseline respiratory activity and prevented morphine-induced respiratory depression. These effects were similar to those produced by an ampakine CX-546 (15mg/kg, ip). The antinociceptive effect of morphine (hot plate test) was unaffected by tianeptine pre-treatment. In conclusion, the results of the experiments conducted in conscious rats demonstrate that systemic administration of tianeptine increases respiratory output and prevents morphine-induced respiratory depression without interfering with the antinociceptive effect of opiates.

Take-home emergency naloxone to prevent heroin overdose deaths after prison release: rationale and practicalities for the N-ALIVE randomized trial.

The naloxone investigation (N-ALIVE) randomized trial commenced in the UK in May 2012, with the preliminary phase involving 5,600 prisoners on release. The trial is investigating whether heroin overdose deaths post-prison release can be prevented by prior provision of a take-home emergency supply of naloxone. Heroin contributes disproportionately to drug deaths through opiate-induced respiratory depression. Take-home emergency naloxone is a novel preventive measure for which there have been encouraging preliminary reports from community schemes. Overdoses are usually witnessed, and drug users themselves and also family members are a vast intervention workforce who are willing to intervene, but whose responses are currently often inefficient or wrong. Approximately 10% of provided emergency naloxone is thought to be used in subsequent emergency resuscitation but, as yet, there have been no definitive studies. The period following release from prison is a time of extraordinarily high mortality, with heroin overdose deaths increased more than sevenfold in the first fortnight after release. Of prisoners with a previous history of heroin injecting who are released from prison, 1 in 200 will die of a heroin overdose within the first 4 weeks. There are major scientific and logistical challenges to assessing the impact of take-home naloxone. Even in recently released prisoners, heroin overdose death is a relatively rare event: hence, large numbers of prisoners need to enter the trial to assess whether take-home naloxone significantly reduces the overdose death rate. The commencement of pilot phase of the N-ALIVE trial is a significant step forward, with prisoners being randomly assigned either to treatment-as-usual or to treatment-as-usual plus a supply of take-home emergency naloxone. The subsequent full N-ALIVE trial (contingent on a successful pilot) will involve 56,000 prisoners on release, and will give a definitive conclusion on lives saved in real-world application. Advocates call for implementation, while naysayers raise concerns. The issue does not need more public debate; it needs good science.

Respiratory depression in rats induced by alcohol and barbiturate and rescue by ampakine CX717

Barbiturate use in conjunction with alcohol can result in severe respiratory depression and overdose deaths. The mechanisms underlying the additive/synergistic actions were unresolved. Current management of ethanol-barbiturate-induced apnea is limited to ventilatory and circulatory support coupled with drug elimination. Based on recent preclinical and clinical studies of opiate-induced respiratory depression, we hypothesized that ampakine compounds may provide a treatment for other types of drug-induced respiratory depression. The actions of alcohol, pentobarbital, bicuculline, and the ampakine CX717, alone and in combination, were measured via 1) ventral root recordings from newborn rat brain stem-spinal cord preparations and 2) plethysmographic recordings from unrestrained newborn and adult rats. We found that ethanol caused a modest suppression of respiratory drive in vitro (50 mM) and in vivo (2 g/kg ip). Pentobarbital induced an ∼50% reduction in respiratory frequency in vitro (50 μM) and in vivo (28 mg/kg for pups and 56 mg/kg for adult rats ip). However, severe life-threatening apnea was induced by the combination of the agents in vitro and in vivo via activation of GABA(A) receptors, which was exacerbated by hypoxic (8% O(2)) conditions. Administration of the ampakine CX717 alleviated a significant component of the respiratory depression in vitro (50-150 μM) and in vivo (30 mg/kg ip). Bicuculline also alleviated ethanol-/pentobarbital-induced respiratory depression but caused seizure activity, whereas CX717 did not. These data demonstrated that ethanol and pentobarbital together caused severe respiratory depression, including lethal apnea, via synergistic actions that blunt chemoreceptive responses to hypoxia and hypercapnia and suppress central respiratory rhythmogenesis. The ampakine CX717 markedly reduced the severity of respiratory depression.

Serotonin targets inhibitory synapses to induce modulation of network functions

The cellular effects of serotonin (5-HT), a neuromodulator with widespread influences in the central nervous system, have been investigated. Despite detailed knowledge about the molecular biology of cellular signalling, it is not possible to anticipate the responses of neuronal networks to a global action of 5-HT. Heterogeneous expression of various subtypes of serotonin receptors (5-HTR) in a variety of neurons differently equipped with cell-specific transmitter receptors and ion channel assemblies can provoke diverse cellular reactions resulting in various forms of network adjustment and, hence, motor behaviour. Using the respiratory network as a model for reciprocal synaptic inhibition, we demonstrate that 5-HT(1A)R modulation primarily affects inhibition through glycinergic synapses. Potentiation of glycinergic inhibition of both excitatory and inhibitory neurons induces a functional reorganization of the network leading to a characteristic change of motor output. The changes in network operation are robust and help to overcome opiate-induced respiratory depression. Hence, 5-HT(1A)R activation stabilizes the rhythmicity of breathing during opiate medication of pain.

Paediatric regional anaesthesia:new developments and improving accuracy

Regional anaesthesia can provide absolute pain relief without the risks of opiate-induced respiratory depression. The purpose of this paper is to (i) provide insight into some new techniques that may improve the success and accuracy of peripheral nerve blocks, with particular reference to the role of nerve mapping, nerve stimulators and portable ultrasound; (ii) introduce methods to reduce the risk of intraneural injection; (iii) suggest methods to prolong the analgesia provided by peripheral nerve blocks, i.e. continuous peripheral nerve catheters appropriate for use in children; and (iv) propose methods to manage local anaesthetic toxicity, with particular reference to the use of intralipid solutions.

Safe Reduction in Administration of Naloxone to Newborn Infants: An Observational Study

Naloxone, an opiate antagonist, acts on opioid receptors in the brain where it competitively binds in place of opiate-based drugs. It is widely used during neonatal resuscitation in order to reverse opiate-induced respiratory depression. However, naloxone is capable of inducing a severe withdrawal reaction including seizures in infants whose mothers have misused opiates. Other problems are that absorption of a drug given by intramuscular injection is unreliable, and that the effect of naloxone may decline before opiate is eliminated from the brain. The investigators obtained perinatal data on naloxone administration and respiratory morbidity, both retrospectively before, and prospectively after introducing the “Good Practice” guidelines for properly using naloxone (listed below). Good Practice Guidelines for Properly Using Naloxone Naloxone will only be given if: The mother received an opiate drug less than 4 hour before birth or received two doses less than 3 hour apart during labor. and after: The infant's head has been positioned to open the airway and the airway cleared by suction. Effective bag-and-mask ventilation has been established. The infant is centrally pink and has had a normal heart rate for over 60 s (greater than 120 bpm). Apnea persists for 1 minute after stopping bag-and-mask ventilation. If it is necessary to give naloxone, it will be given: Intravenously (100 mg/kg). If naloxone is administered, the infant will be admitted to the neonatal unit for 6-hour observation. There were 500 and 1000 deliveries, respectively, in the review and prospective parts of the study. Similar proportions of women in the retrospective and prospective groups received opiates during labor. However, the use of naloxone decreased markedly after the guidelines were adopted, from 5% of all newborn infants (11% of those whose mothers received opiates) to 0.1% (0.2% of those whose mothers received opiates). Low Apgar scores did not differ between the two groups after excluding preterm infants and those with specific respiratory disorders. Comparable numbers of infants in the retrospective and prospective groups had evidence of respiratory disorders before being discharged. Most of these disorders could not be related to opiate administration. All but one of eight infants with cyanotic episodes that could have resulted from opiates were seen during the time when naloxone was used less often, but there were indications that, with two exceptions, these episodes did not result from the restricted use of naloxone. None of the affected infants required more than simple stimulation or suction. These findings are the best available evidence that naloxone rarely is needed by newborn infants even when opiates are frequently given during labor. Limiting the use of naloxone does not increase respiratory morbidity.

Safe reduction in administration of naloxone to newborn infants: An observational study

Naloxone, a specific opiate antagonist, is widely used during neonatal resuscitation to reverse possible opiate-induced respiratory depression. To determine the frequency with which naloxone is administered when resuscitation guidelines are conscientiously followed and to document any effect on respiratory morbidity. Perinatal data including naloxone administration and respiratory morbidity were collected retrospectively, and compared with prospectively collected data following the introduction of "Good Practice" guidelines. There were 500 deliveries in the retrospective arm of the study and 1000 deliveries in the prospective arm. Although a similar proportion of women received opiates in labour in the two periods of study, there was a marked reduction in the use of naloxone when the guidelines were introduced (11% of opiate-exposed deliveries compared to 0.2%). There was no significant effect on respiratory morbidity with the change in practice. Naloxone is rarely needed to reverse the effects of opiates in newborn infants, and its use can be curtailed by following current resuscitation guidelines without increasing respiratory morbidity.

Randomised trial of intranasal versus intramuscular naloxone in prehospital treatment for suspected opioid overdose

To determine the effectiveness of intranasal (IN) naloxone compared with intramuscular (IM) naloxone for treatment of respiratory depression due to suspected opiate overdose in the prehospital setting. Prospective, randomised, unblinded trial of either 2 mg naloxone injected intramuscularly or 2 mg naloxone delivered intranasally with a mucosal atomiser. 155 patients (71 IM and 84 IN) requiring treatment for suspected opiate overdose and attended by paramedics of the Metropolitan Ambulance Service (MAS) and Rural Ambulance Victoria (RAV) in Victoria. Response time to regain a respiratory rate greater than 10 per minute. Secondary outcome measures were proportion of patients with respiratory rate greater than 10 per minute at 8 minutes and/or a GCS score over 11 at 8 minutes; proportion requiring rescue naloxone; rate of adverse events; proportion of the IN group for whom IN naloxone alone was sufficient treatment. The IM group had more rapid response than the IN group, and were more likely to have more than 10 spontaneous respirations per minute within 8 minutes (82% v 63%; P = 0.0173). There was no statistically significant difference between the IM and IN groups for needing rescue naloxone (13% [IM group] v 26% [IN group]; P = 0.0558). There were no major adverse events. For patients treated with IN naloxone, this was sufficient to reverse opiate toxicity in 74%. IN naloxone is effective in treating opiate-induced respiratory depression, but is not as effective as IM naloxone. IN delivery of naxolone could reduce the risk of needlestick injury to ambulance officers and, being relatively safe to make more widely available, could increase access to life-saving treatment in the community.

Physostigmine: short history and its impact on anaesthesiology of present days

In the 1860s, the extract of the Calabar bean or Esère nut was studied as a poison but was also introduced into ophthalmology as an antagonist for atropine. Kleinwächter of Prague described it in 1864 as a successful and specific antidote for atropine poisoning. Several decades passed before physostigmine was isolated, but this substance has remained famous because it enabled discovery and establishment of neurotransmission which started with the discovery of mucarinic action of acetylcholine. The anti-curare properties of physostigmine were demonstrated in 1900 by Pal. However, when curare was at long last introduced into clinical anaesthesia in 1942, the antagonist used became the synthetic neostigmine. In the 1960s and 1970s, physostigmine played a crucial role in reversal of anticholinergic effects of drugs in psychiatry, toxicology and, later on, during recovery from anaesthesia. The complex behavioural central anticholinergic syndrome (CAS) was described by Longo. Nowadays, physostigmine remains a safe and quite unique agent wherever increase of acetylcholine in the brain is necessary, examples being intoxications with anticholinergic drugs, recovery from anaesthesia and in psychiatry. Physostigmine is being investigated not only for its role in alleviating symptoms of Alzheimer's disease, but also for its capacity to counteract opiate-induced respiratory depression without abolishing analgesia. Eseroline, the first metabolite of physostigmine, is being investigated for its opioid-like and cholinesterase-inhibiting properties. Effects of physostigmine applied into spinal liquor will probably be studied soon.

Opiate-Induced Respiratory Depression in Young Pediatric Burn Patients

Three children younger than 5 with minor burns (< 5% total body surface area) experienced opiate-induced respiratory depression early in hospitalization. This prompted a decrease in the recommended opiate analgesic-dose ranges on our pediatric worksheet. In reviewing 57 admissions, 31 pre- and 26 post-dose change, the amount of opioid equivalents/kg received on admission day did not differ significantly. However, the incidence of respiratory depressive events decreased. Lower opiate-dose guidelines might improve the safe administration of these medications to young children. Other factors- such as concomitant sedative medications, previously administered opiate analgesics, and underlying medical conditions-also must be considered when giving initial doses of opiate analgesics in the burn center.

Central effects of morphine and morphine-6-glucuronide on tissue protein synthesis.

The central and peripheral effects of morphine sulfate (Mor) and morphine-6-glucuronide (M6G) on the fractional rates of tissue protein synthesis (kappa s) were determined. We determined ks in conscious rats 2 h after intracerebroventricular injection of Mor (80 micrograms/rat), M6G (1 microgram/rat), or H2O (5 microliters). Intracerebroventricular Mor and M6G administration decreased ks in the liver by 19 and 18% spleen by 19 and 17%, and gastrocnemius by 18 and 17%, respectively. Intravenous injection of Mor (8 mg/kg) or M6G (0.4 mg/kg) did not affect ks in any of the tissues studied. Intracerebroventricular Mor and M6G resulted in an equivalent 10- to 15-fold increase in plasma epinephrine, 2- to 3-fold increase in norepinephrine, and 80-90% increase in corticosterone, with no change in insulin levels. Intracerebroventricular Mor produced a significant 30% decrease in arterial partial O2 pressure (PaO2) and no significant changes in arterial pH and arterial partial CO2 pressure (PacO2). Intracerebroventricular M6G decreased PaO2 (40%) and pH (from 7.44 +/- 0.01 to 7.34 +/- 0.02) and increased Paco2 (36%). The potential contribution of hypoxia to the opiate-induced decrease in ks was assessed in an additional set of rats exposed to 5% O2-95% N2. One or 2 h of hypoxia decreased protein synthesis in the brain by 47 and 56%, liver by 69 and 69%, and skeletal muscle by 51 and 52%, respectively. Our results indicate that Mor and M6G suppress tissue protein synthesis through central mechanisms, most likely mediated by opiate-induced respiratory depression in association with neural and hormonal alterations.

Alterations in diaphragm EMG activity during opiate-induced respiratory depression

While opiate-induced increases in thoracic muscle tone may contribute to impaired ventilation during opiate anesthesia, the effects of high-dose opiates on diaphragm muscle activity have not been elucidated. The effects of the opiate agonist alfentanil (ALF, 500 μg/kg subcutaneously) on diaphragm (DIA) and intercostal (IC) electromyographic (EMG) activity in spontaneously ventilating adult rats were studied. EMG segments corresponding to inspiration and expiration were selected using an impedance plethysmographic respiratory waveform. Total EMG activity over a respiratory cycle was significantly greater in the DIA than in the IC. ALF produced a decrease in inspiratory and an increase in expiratory DIA EMG activity. These changes in diaphragm function following ALF were accompanied by significant respiratory depression. The effects of the alpha-2 agonist dexmedetomidine on ALF-induced changes in diaphragm and intercostal EMG activity were also examined. While dexmedetomidine alone had minimal effects on DIA activity, it significantly attenuated the ALF-induced increase in expiratory DIA EMG. The potential etiology and implications of these opiate-induced changes in diaphragm muscle function are discussed.

Effects of naloxene on the subjective and psychomotor effects of nitrous oxide in humans

The effects of naloxone on the mood-altering and psychomotor-impairing effects of nitrous oxide were examined in two studies. Each of the double-blind, randomized trials tested effects of three doses of naloxone or saline placebo during inhalation of 30% nitrous oxide in oxygen or 100% oxygen placebo. Experiment 1 tested a range of naloxone doses used clinically to reverse opiate-induced respiratory depression (0, 0.01, 0.1, 1.0 mg/70 kg) and Experiment 2 included a dose approximately 25 times higher than that needed to reverse opiate-induced respiratory depression (0, 1.0, 3.0, 10 mg/70 kg). Nitrous oxide increased subject-rated reports of “feel drug effect”, “carefree,” “drunk,” “sedated,rd and “high,” and decreased psychomotor performance in both experiments. Naloxone had no effects by itself in either experiment, and, for the most part, did not significantly interact with nitrous oxide-induced changes in mood or psychomotor performance. Naloxone, in doses of 10 mg or less, does not appear to affect the subjective and psychomotor effects of nitrous oxide.

Differential Roles of Opioid Receptors in Respiration, Respiratory Disease, and Opiate-induced Respiratory Depression

In summary, these findings indicate the importance of designing future experiments that delineate between opioid and nonopioid forms of respiratory disease and dysfunction, and the need to identify means of diagnosing them in order to achieve successful recovery. Apparently there is great diversity between animal species in terms of contributions of endogenous opioids to tonic control of ventilation, and future work should strive to identify which species is most appropriate as a model of human ventilatory control and disease. Certain opioid receptor types appear to be linked to independent respiratory functions. For instance, mu receptors in the brain stem produce strong inhibitory actions on respiratory parameters, including RR, VT, VE, and CO2 sensitivity. These effects have been observed in vivo and by electrophysiologic recordings in vitro. Delta receptors may also exert some inhibitory effect on respiration, especially in the NTS. In the CNS, the ventral surfaces of the medulla and pons, especially the NTS and NA, seem to be important sites for opioid-induced inhibition of respiration, whereas the spinal cord probably is not involved in opioid-mediated ventilatory depression. Kappa receptors appear to be devoid of respiratory depressant activity, whereas sigma receptors may stimulate some ventilatory parameters. Morphine and similar pure mu agonists, such as fentanyl and oxymorphine, probably produce their analgesic and respiratory depressant effects through stimulation of mu receptors. Mixed agonists/antagonists that have mu antagonist (or partial agonist) activity plus kappa agonist and/or sigma agonist activity show a ceiling effect for respiratory depression. Future tests need to determine which opioid receptor may be responsible for the ceiling effect. In addition, the effects of mu, delta, kappa, and sigma selective agonists on hypoxic drive should also be determined, as a drug that stimulates hypoxic sensitivity in the face of hypercapnic depression may produce less overall respiratory depression due to counteractive effects. In the future, clinically optimal opiates should have more specificity of action than those available now. This may be achieved by creating drugs selective for single receptors or by creating drugs with desirable combinations of receptor selectivities. The combinations of mixed agonists/antagonists with pure mu agonists currently in use today are promising, as they provide analgesia with reduced respiratory depression. In the early days of opiate research and development, combination drug regimens were thoroughly tested to determine the "ideal ratios" that would retain analgesic properties but not the other undesirable effects such as respiratory depression (196).(ABSTRACT TRUNCATED AT 400 WORDS)

Methohexital vs midazolam/flumazenil anaesthesia during laryngoscopy under jet ventilation

In a randomised clinical study, two total intravenous anaesthesia techniques for microlaryngoscopic laser surgery were compared. After an induction dose of 100 mg methohexital, Group I received a maintenance infusion of 10 mg.min-1. In Group II anaesthesia was obtained by 15 mg midazolam followed by 0.1 mg.min-1 continuously and terminated by the injection of flumazenil. For analgesia 5 mg alfentanil were administered. Opiate-induced respiratory depression was antagonised by 0.08 to 0.12 mg naloxone. Prior to, during, and after surgery, adrenergic response was assessed by HPLC-analysis of blood taken from a peripheral vein. Haemodynamic responses to the operation and during the post-operative period were almost identical in both groups. In Group I, the mean recovery period of 14 min was significantly longer than in Group II (9 min), where patients received a mean dose of 0.53 mg (+/- 0.15) flumazenil. Resedation could be observed in all patients receiving flumazenil within 60 min after antagonisation, which was associated with a mean decrease in O2-saturation from 95% to 88%. There was no difference in epinephrine and norepinephrine blood levels between the two groups prior to and during anaesthesia. In all patients, arousal was associated with a significant increase in the epinephrine plasma concentration. While blood levels in Group I decreased during the post-operative period to levels prior to surgery, the concentrations in Group II remained elevated. In one patient who received no naloxone, the reversal of midazolam action induced a 16-fold increase in catecholamine levels (from 50 to 800 ng.l-1) associated with a tachycardia of 170 b.min-1 and hypertension of 160 mmHg.(ABSTRACT TRUNCATED AT 250 WORDS)