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Background Animal data suggest that the antidepressant and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor modulator tianeptine is able to prevent opioid-induced respiratory depression. The hypothesis was that oral or intravenous tianeptine can effectively prevent or counteract opioid-induced respiratory depression in humans. Methods Healthy male and female volunteers participated in two studies that had a randomized, double blind, placebo-controlled, crossover design. First, oral tianeptine (37.5-, 50-, and 100-mg doses with 8 subjects) pretreatment followed by induction of alfentanil-induced respiratory depression (alfentanil target concentration, 100 ng/ml) was tested. Primary endpoint was ventilation at an extrapolated end-tidal carbon dioxide concentration of 55 mmHg (V̇E55). Next, the ability of four subsequent and increasing infusions of intravenous tianeptine (target tianeptine plasma concentrations 400, 1,000, 1,500, and 2,000 ng/ml, each given over 15 min) to counteract remifentanil-induced respiratory depression was determined in 15 volunteers. Ventilation was measured at isohypercpania (baseline ventilation 20 ± 2 l/min). The primary endpoint was minute ventilation during the 60 min of tianeptine versus placebo infusion. Results Alfentanil reduced V̇E55 to 13.7 (95% CI, 8.6 to 18.8) l/min after placebo pretreatment and to 17.9 (10.2 to 25.7) l/min after 50-mg tianeptine pretreatment (mean difference between treatments 4.2 (–11.5 to 3.0) l/min, P = 0.070). Intravenous tianeptine in the measured concentration range of 500 to 2,000 ng/ml did not stimulate ventilation but instead worsened remifentanil-induced respiratory depression: tianeptine, 9.6 ± 0.8 l/min versus placebo 15.0 ± 0.9 l/min; mean difference, 5.3 l/min; 95% CI, 2.5 to 8.2 l/min; P = 0.001, after 1 h of treatment. Conclusions Neither oral nor intravenous tianeptine were respiratory stimulants. Intravenous tianeptine over the concentration range of 500 to 2000 ng/ml worsened respiratory depression induced by remifentanil. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

Background Ketamine produces potent analgesia combined with psychedelic effects. It has been suggested that these two effects are associated and possibly that analgesia is generated by ketamine-induced dissociation. The authors performed a post hoc analysis of previously published data to quantify the pharmacodynamic properties of ketamine-induced antinociception and psychedelic symptoms. The hypothesis was that ketamine pharmacodynamics (i.e., concentration–effect relationship as well as effect onset and offset times) are not different for these two endpoints. Methods Seventeen healthy male volunteers received escalating doses of S- and racemic ketamine on separate occasions. Before, during, and after ketamine infusion, changes in external perception were measured together with pain pressure threshold. A population pharmacokinetic–pharmacodynamic analysis was performed that took S- and R-ketamine and S- and R-norketamine plasma concentrations into account. Results The pharmacodynamics of S-ketamine did not differ for antinociception and external perception with potency parameter (median [95% CI]) C50, 0.51 (0.38 to 0.66) nmol/ml; blood-effect site equilibration half-life, 8.3 [5.1 to 13.0] min), irrespective of administration form (racemic ketamine or S-ketamine). R-ketamine did not contribute to either endpoint. For both endpoints, S-norketamine had a small antagonistic effect. Conclusions The authors conclude that their data support an association or connectivity between ketamine analgesia and dissociation. Given the intricacies of the study related to the pain model, measurement of dissociation, and complex modeling of the combination of ketamine and norketamine, it is the opinion of the authors that further studies are needed to detect functional connectivity between brain areas that produce the different ketamine effects. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

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.

Background: Opioid-induced respiratory depression is antagonized effectively by the competitive opioid receptor antagonist naloxone. However, to fully understand the complex opioid agonist -antagonist interaction, the effects of various naloxone doses on morphine and morphine-6-glucuronide (M6G)-induced respiratory depression were studied in healthy volunteers. Methods: Twenty-four subjects received 0.15 mg/kg morphine intravenously at t = 0 followed by placebo, 200 or 400 = g naloxone at t = 30 min. Thirty-two subjects received 0.3 mg/kg M6G intravenously at t = 0 followed by placebo, 25, 100, or 400 = g naloxone at t = 55 min. There were a total of 8 subjects per treatment group. Respiration was measured on a breath-to-breath basis at constant end-tidal PCO2. A mechanismbased pharmacokinetic-pharmacodynamic model consisting of a part describing biophase equilibration and a part describing receptor association-dissociation kinetics was used to analyze the data. Results: Naloxone reversal of M6G-induced respiratory depression developed more slowly than reversal of the respiratory effect of morphine. A simulation study revealed that this was related to the slower receptor association-dissociation kinetics of M6G (k(off) M6G = 0.0327 +/- 0.00455 min(-1) versus morphine 0.138 +/- 0.0148 min(-1); values are typical +/- SE). Duration of naloxone reversal was longer for M6G. This was related to the three- to fourfold greater potency of naloxone as an antagonist against M6G compared with morphine. Increasing the naloxone dose had no effect on the speed of reversal, but it did extend reversal duration. Conclusions: Naloxone reversal of the opioid effect is dependent on the receptor association-dissociation kinetics of the opioid that needs reversal with respect to the rate of reversal. The pharmacodynamics of naloxone determines reversal magnitude and duration.

Introduction: Exposure to a hypoxic environment has a deleterious effect on physiological and mental functions. We studied the effect of added inspired CO2 during artificially induced hypoxic normobaric hypoxia (oxygen saturation ∼80%) on complex task performance. Methods: In random order, 22 healthy volunteers were exposed to 3 gas mixtures for 50 min each: sham hypoxia (SH, PetO2 103 mmHg without inspired CO2); isocapnic hypoxia (IH, PetO2 ∼40 mmHg, PetCO2 clamped to 0.4 mmHg above resting values); and poikilocapnic hypoxia (PH, PetO2 ∼40 mmHg; no inspired CO2). Brain oxygenation was measured using near infrared spectroscopy. During minutes 25-45 of hypoxia, subjects performed vigilance and task performance tests used in aviation research: the Vigilance and Tracking test and the Multi-Attribute Task battery (MAT-bat). The tests varied in difficulty with the tracking tests considered most difficult. Results: PetCO2 levels differed significantly among groups: IH 42.8 ± 0.7, SH 39.0 ± 0.7, and PH 36.8 ± 0.7 mmHg. Brain oxygenation levels were significantly higher during IH than PH (62.2 ± 1.0 vs. 59.1 ± 1.3%). The results of the performance tests indicated a negative effect of PH vs. SH on most function tests. For the Tracking test of the MAT-bat, performance was worst during PH, but returned to baseline during IH. Discussion: We demonstrate the ability of added inspired CO2 to improve performance during hypoxia by preventing PH-associated hypocapnia-induced vasoconstriction of brain blood vessels. Our results are relevant to aerospace medicine and other circumstances in which complex tasks are performed in a hypoxic environment such as mountain climbing and working in confined spaces. Copyright © by Aerospace Medical Association.

The general aim of this thesis is to investigate small fiber neuropathy in sarcoidosis and to asses whether ARA290 is a possible new agent to treat the neuropathic complaints in sarcoidosis population. The results of the various ARA290 trials in painful sarcoidosis are discussed. Painful neuropathy is common, difficult to treat complication.The limited efficacy of current treatment options dictates a rationalized design of novel compounds. ARA290 treatment was consistently associated with a significant improvement of neuropathic pain symptoms in sarcoidosis patients, evidenced by a decrease in pain scores on validated questionnaires. Moreover,ARA290 treatment resulted in significant increases in corneal nerve fibers, improved sensory pain thresholds,improved quality of life and physical functioning. Given the excellent safety profile while reducing neuropathy symptoms,the prospects of ARA290 treatment in sarcoidosis related neuropathy seem promising.The long lasting beneficial effects of ARA290 on both pain related and non pain related symptoms in sarcoidosis patients prompt additional studies on potential disease modifying properties of ARA290. The data collected so far suggest that ARA290 will be equally effective in SFN associated with other syndromes, including diabetes mellitus.