Study Design The following study drugs were administered on 4 separate study days, at least 1 week apart in a double-blind, randomized order: 0.5 mg low-dose oliceridine (Trevena Inc., USA), 2.0 mg high-dose oliceridine, 2.0 mg low-dose morphine hydrochloride (Centrafarm BV, Etten-Leur, The Netherlands), or 8.0 mg highdose morphine hydrochloride. The study drugs were administered intravenously for over 60 s. The study drugs were prepared by the pharmacy and dispensed to the study team in identical, unmarked, numbered (subject and visit numbers) syringes on the morning of the experiment. Randomization was performed using a computer-generated randomization list; the list was available to the pharmacy and the data safety monitoring committee. Unblinding was only justified in case of drug-related serious adverse events. The choice of the opioid doses was based on earlier clinical studies. Available oliceridine and morphine comparative data from the literature suggest that oliceridine is 6.7 times more potent than morphine in the cold pressor test and 3.3 times more potent in pupil constriction as derived from a phase 1 study obtained in younger adults (less than 50 yr),14 and 4 times more potent in decreasing pain intensity as derived from a phase 2 study in 144 postoperative patients (age range 18 to 75 yr).15 Based on these observations, we consider that the doses used in our study (2.0 mg and 8.0 mg morphine and 0.5 and 2.0 mg oliceridine) are equianalgesic. Before each visit, participants were asked to fast for at least 8 h. Upon arrival in the research unit, the subjects were screened for the use of illicit substances by using a urine dipstick (Alere Toxicology Plc., Oxfordshire, United Kingdom), and screened for alcohol use with a breath analysis test (AlcoHawk CA-120, USA). Thereafter, the participants received an intravenous catheter in the median cubital vein of the left or right arm and an arterial line in the left or right radial artery. The arterial line was connected to a FloTrac Sensor and HemoSphere (Edwards Lifesciences, USA) for hemodynamic monitoring. Finally, a 3-lead electrocardiogram (Datex Cardiocap, Helsinki, Finland) and a finger probe for pulse oximetry (Masimo Corporation, USA) were placed. Respiratory Measurements After a short period of relaxation, the ventilatory response to hypercapnia was measured by using a modified rebreathing method.16,17,18 During respiratory testing, the subjects were semirecumbent and breathed through a face mask positioned over the mouth and nose. The face mask was connected to a pneumotachograph and pressure transducer system (Hans Rudolph Inc., USA) to measure ventilation on a breath-to-breath basis. Inspired and expired carbon dioxide concentrations were measured at the mouth using a Datex Capnomac (Datex, Finland). After a 4-min period of relaxed breathing of room air, 68
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