Objectives The objective was to assess the effect on stress biomarkers of supplemental opioid to a standard propofol dosing protocol for emergency department (ED) procedural sedation (PS). The hypothesis was that there is no difference in the change in serum catecholamines between PS using propofol with or without supplemental alfentanil. Methods This was a randomized, nonblinded pilot study of adult patients undergoing PS in the ED for the reduction of fractures and dislocations. Patients with pain before the procedure were treated with intravenous (IV) morphine sulfate until their pain was adequately treated for at least 20 minutes before starting the procedure. Patients were randomized to receive either 10 μg/kg alfentanil followed by 1 mg/kg propofol, followed by 0.5 mg/kg every 3 minutes as needed, or propofol only, dosed in similar fashion without supplemental alfentanil. Doses, vital signs, nasal end-tidal CO2 (ETCO2), pulse oximetry, and bispectral electroencephalogram (EEG) analysis scores were recorded. Subclinical respiratory depression was defined as a change in ETCO2 > 10 mm Hg, an oxygen saturation of < 92% at any time, or an absent ETCO2 waveform at any time. Clinical events related to respiratory depression were noted during the procedure, including the addition of or increase in the flow rate of supplemental oxygen, the use of a bag-valve-mask apparatus, airway repositioning, or stimulation to induce breathing. Blood was drawn 1 minute prior to the administration of the medications for PS and again 1 minute after completion of the procedure for which the patient was sedated. Serum was tested for total catecholamines, epinephrine, norepinephrine, and dopamine. Postprocedure, patients were asked to report any pain perceived during the procedure. Data were analyzed using descriptive statistics, Wilcoxon rank sum tests, and chi-square tests, as appropriate. Results Twenty patients were enrolled; 10 received propofol and 10 received propofol with alfentanil. No clinically significant complications were noted. Subclinical respiratory depression was seen in four of 10 (40%) patients in the propofol group and five of 10 (50%) patients in the propofol/alfentanil group (effect size = -10%, 95% confidence interval [CI] = -53% to 33%). There was no difference in the rate of clinical signs of respiratory depression between the two groups. Pain during the procedure was reported by two of 10 (20%) patients in the propofol group and five of 10 (50%) patients in the propofol/alfentanil group (effect size = -30%, 95% CI = -70% to 10%). Recall of some part of the procedure was reported by 0 of 10 (0%) patients in the propofol group and five of 10 (50%) of patients in the propofol/alfentanil group (effect size = -50%, 95% CI = -81% to -19%). There was no difference in the baseline or postprocedure catecholamine levels between the groups. Conclusions No difference in serum catecholamines was detected immediately after PS between patients who receive propofol with and without supplemental opioid in this small pilot study. PS using propofol only without supplemental opioid did not appear to induce markers of physiologic stress in this small pilot study.