EDITORIAL VIEWS Primum Non Nocere or How to Resolve -induced Respiratory Depression

Drug-induced to overcome -induced Respiratory Depressidon impairment of airway patency.2,3 and One important feature of MANY of the used cur- the attenuation by CX717 of rently by anesthesiologists pro- OIRD is that this effect was not duce serious side effects, of accompanied by a significant 4 which respiratory depression reduction in analgesia. Ampak- Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/118/6/1261/260457/20130600_0-00012.pdf by guest on 27 September 2021 is one that is potentially fatal. ines act at AMPA (amino-3-hy- Although we know that anes- droxy-5-methyl-d-aspartate) thetics and are relatively receptors. Glutataminergic trans- safe in the hands of anesthesiolo- mission through AMPA receptors gists and other well-trained anes- within the brainstem respira- thesia specialists (although there tory centers, most importantly are always potential problems), the pre-Bötzinger complex, the risks from the use of these is essential for rhythmogen- drugs are potentially increas- esis and induction of increased ing with the growing trend of “... before we start come- respiratory frequency. Various their use by nonanesthesia care- ampakines that interact with the givers. Consequently, with the dicating our patients with AMPA receptor have been stud- increased use and prescription ampakines or any of the of potent drugs that depress the ied in respiratory systems; the 10.1097/ALN.0b013e31829107d5 ventilatory control system and/ other respiratory stimu- most studied agent is CX717. or increase the probability of an A major advantage of CX717 is lants, we will need further that it is available for human use Asha upper airway patency problem, one may expect to see an increase evidence that these posi- and has been tested for safety in morbidity and mortality, and efficacy in the treatment of Editorial Views especially when monitoring is tive effects are maintained human attention deficit hyper- insufficient and/or the caregiver under a variety of circum- activity disorders and Alzheimer Editorial Views is insufficiently able to diagnose disease. Indeed, a proof of or treat respiratory depression. stances ... and that patient concept study with CX717 In the current issue of Anesthesi- in human volunteers demon- 1 June ology, Ren et al. report a study safety is guaranteed.” strated that a single oral dose on the effect of an on of CX717 (1500 mg) reduced 2013 propofol-induced respiratory low-dose (plasma concentration 100 ng/ml) alfentanil– depression and fatal apneas in rodents. They demonstrate induced respiratory depression without significant effects elegantly that coadministration of the ampakine CX717 on analgesia.4 These data suggest that, in patients, the 2013 attenuates respiratory depression induced by propofol. coadministration of an ampakine during exposure to This group previously demonstrated in rats that the potent opioids and anesthetics such as propofol will be Anesthesiology same ampakine also alleviates opioid-induced respira- tory depression (OIRD) and suppression of hypoglossal a major step forward in the prevention of drug-induced motoneuron activity that suggest the ability of this drug respiratory depression without negating their analge- 118 sic (and possibly hypnotic) effects. Evidently, further clinical studies are required showing that CX717 works in patients as well and is not associated with serious 6 Photo: J. P. Rathmell. side effects. Accepted for publication January 30, 2013. The Anesthesia and Pain Research Unit is or has been involved in research on 1261 opioid-induced respiratory depression sponsored by Grünenthal GmbH (Aachen, Germany), Mundipharma Research Ltd. (Cam- ◆ This Editorial View accompanies the following article: Ren J, bridge, United Kingdom), and Galleon Pharmaceuticals (Horsham, Lenal F, Yang M, Ding X, Greer JJ: Coadministration of the 3 Pennsylvania). AMPAKINE CX717 with propofol reduces respiratory depres- Copyright © 2013, the American Society of Anesthesiologists, Inc. Lippincott sion and fatal apneas. Anesthesiology 2013; 118:1437–45. Williams & Wilkins. Anesthesiology 2013; 118:1261-3

Anesthesiology, V 118 • No 6 1261 June 2013 Editorial Views

Ampakines versus Other Respiratory affinity for the μ-opioid receptor than naloxone (buprenor- phine is such an opioid).5,6 Otherwise, our familiarity with Apart from ampakines, there are various other nonopioid naloxone and its safety make it the primary agent for rever- respiratory stimulants clinically available or under sal of acute opioid toxicity and life-threatening respiratory 8 investigation to combat the risks of respiratory depression depression. One further note of caution may be illustrated 1 including potassium channel modulators (such as ), by CX717 in the recent study by Ren et al. is that this agent serotonin receptor agonists, and phosphodiesterase failed to reverse established propofol-induced respiratory inhibitors.5,6 Although most of these agents are effective in depression, although it had been previously shown to reverse animal models, there is little evidence that, in contrast to the established OIRD. Hence, it is likely that an agent required ampakine CX717, the coadministration of these respiratory for the reversal of an established drug-induced respiratory Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/118/6/1261/260457/20130600_0-00012.pdf by guest on 27 September 2021 stimulants provides sufficient reduction of drug-induced depression may have different pharmacological (including respiratory depression in a clinical setting. Hence, we should specific pharmacokinetic and pharmacodynamic) properties be cautious to dismiss other approaches to reverse OIRD than those required for the prevention of respiratory depres- (including naloxone-reversal). An exception might be GAL- sion by prior or coadministration. 021 an agent that selectively inhibits a sub-type of potassium channel in the carotid bodies and that is currently under Monitoring Remains Key investigation and seems able to effectively reverse OIRD The list of respiratory stimulants aforementioned is large and in humans.* possibly a novel agent, such as CX717, will soon be clinically available for the prevention of respiratory depression in our Who Do We Treat with the Coadministration patients. However, before we start comedicating our patients of Respiratory Stimulants? with ampakines or any of the other respiratory stimulants, An important question is which patients or patient groups we will need further evidence that these positive effects are are best served by coadministration of a respiratory stimu- maintained under a variety of circumstances (at high drug lant? As indicated earlier, we believe that foremost among dose, in polypharmacia, in patients with obstructive sleep patients who will benefit from these agents are those being apnea, in the elderly, and so on) and that patient safety is treated with potent anesthetics or opioids by nonanesthe- guaranteed. If so, we can begin to envision our ideals for sia personnel. Certainly, there is also a group of patients these respiratory stimulants to increase the safety of potent in the postanesthesia care unit or in the ward after surgery anesthetics and opioids. However, as an ideal world does that may benefit from these stimulants and possibly even not exist, coadministration of respiratory stimulants will patients being treated in the intensive care unit. Whether never relieve us from the obligation to apply optimal patient these agents are suitable for symptomatic treatment of monitoring during and after the administration of potent patients with sleep-related obstructive breathing disor- modulators of the ventilatory control system and educate ders requires study. Another question is whether these nonanesthesia care givers involved in the prescription and respiratory stimulants are of any use in patients treated administration of opioids, sedatives, and anesthetics. Only at home with potent opioids for chronic (cancer and then we can state that our intents were to primum non nocere noncancer) pain? Possibly, but as these patients are often (above all, do no harm). prone to polypharmacy, illicit drug use, and/or Albert Dahan, M.D., Ph.D., Margot Roozekrans, M.D., (ab)use, this is an uncertain group. However, taken Rutger van der Schrier, M.D., Terry Smith, Ph.D., Leon the high incidence of fatalities in this population from Aarts, M.D., Ph.D., Department of Anesthesiology, Anes- their drug use,7 further studies on coadministration thesia and Pain Research Unit, Leiden University Medical of a respiratory such as CX717 are strongly Center, Leiden, The Netherlands. [email protected] indicated. References 1. Ren J, Lenal F, Yang M, Ding X, Greer JJ: Coadministration Prevention versus Reversal of Drug-induced of the AMPAKINE CX717 with propofol reduces respira- Respiratory Depression tory depression and fatal apneas. Anesthesiology 2013; 118: 1437–45 A final question is whether these agents will eventually replace 2. Ren J, Ding X, Funk GD, Greer JJ: Ampakine CX717 protects the potent opioid-antagonist naloxone in case of established against fentanyl-induced respiratory depression and lethal apnea in rats. Anesthesiology 2009; 110:1364–70 severe OIRD? This is not easily answered, but in some spe- 3. Lorier AR, Funk GD, Greer JJ: Opiate-induced suppression cific circumstances a nonopioid antagonist may be preferable of rat hypoglossal motoneuron activity and its reversal by over naloxone, such as in case of opioids with a much greater ampakine therapy. PLoS One 2010; 5:e8766 4. oertel BG, Felden L, Tran PV, Bradshaw MH, Angst MS, Schmidt H, Johnson S, Greer JJ, Geisslinger G, Varney * Available at: http://www.trialregister.nl/trialreg/admin/rctview. MA, Lötsch J: Selective antagonism of opioid-induced ven- asp?TC=3718. Accessed January 28, 2013. tilatory depression by an ampakine molecule in humans

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without loss of opioid analgesia. Clin Pharmacol Ther respiratory depression. Curr Pharm Des 2012; 18:5994– 2010; 87:204–11 6004 5. Dahan A, Aarts L, Smith TW: Incidence, reversal, and preven- 7. okie S: A flood of opioids, a rising tide of deaths. N Engl J tion of opioid-induced respiratory depression. Anesthesiology Med 2010; 363:1981–5 2010; 112:226–38 8. van Dorp E, Yassen A, Dahan A: Naloxone treatment in opi- 6. Boom M, Niesters M, Sarton E, Aarts L, Smith TW, oid addiction: The risks and benefits. Expert Opin Drug Saf Dahan A: Non-analgesic effects of opioids: Opioid-induced 2007; 6:125–32

ANESTHESIOLOGY REFLECTIONS FROM THE WOOD LIBRARY-MUSEUM Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/118/6/1261/260457/20130600_0-00012.pdf by guest on 27 September 2021 From Fish Poison to Merck Picrotoxin

For countless centuries, many fishermen in South and Southeast Asia used a stupefy- ing fish poison derived from the seeds of the fishberry shrub (Anamirta cocculus). Picro-

toxin, the active ingredient of fishberry seeds, acts as a noncompetitive GABAA . A neurostimulant and occasional convulsant, picrotoxin can block chloride

conductance enhanced by GABAA receptor agonists such as propofol and . Thus, picrotoxin has been employed to investigate anesthetic mechanisms of action at

the GABAA receptor, as well as used as an antidote for toxicity. Manufactured by Merck in Germany, the bottle of picrotoxin (above) is now part of the collection of the Wood Library-Museum. (Copyright © the American Society of Anesthesiologists, Inc.) George S. Bause, M.D., M.P.H., Honorary Curator, ASA’s Wood Library-Museum of Anesthesiology, Park Ridge, Illinois, and Clinical Associate Professor, Case Western Reserve University, Cleveland, Ohio. [email protected].

Anesthesiology 2013; 118:1261-3 1263 Dahan et al.