The Comparative Effectiveness of Fentanyl and its Newer Analogs During Extracorporeal Shock Wave Lithotripsy Under Monitored Anesthesia Care

Abstract

Many different anesthetic techniques have been used for extracorporeal shock wave lithotripsy (ESWL). Although both general and epidural anesthetic techniques have been described (1,2), these techniques were associated with prolonged recovery times and higher than expected hospital admission rates (3). More recently, IV sedative-analgesic techniques have been described that provide for shorter recovery times (4,5). Although propofol has become the drug of choice for the maintenance of sedation (6), the comparative effects of the commonly used opioid analgesics have not been studied when administered in combination with propofol as part of a monitored anesthesia care (MAC) technique. Whereas fentanyl, sufentanil, alfentanil, and remifentanil have all been used during ESWL procedures (4–8), no direct comparison of fentanyl with its newer analogs has been performed during MAC. This prospective, randomized, double-blinded study was designed to compare the clinical effectiveness of intermittent bolus injections of fentanyl with remifentanil, alfentaniln and sufentanil when administered during propofol sedation for ESWL procedures. In addition to assessing their analgesic efficacy and respiratory stability, we determined the effects of the analgesic medications on the early recovery profile. Methods We studied 54 adult outpatients, ASA physical status I–III, aged 21–80 yr, scheduled for ESWL procedures by using an unmodified Dornier HM-3 lithotriptor. After written, informed consent was obtained, patients were assigned to one of four opioid treatment groups according to an institutional review board-approved, randomized, double-blinded protocol. Exclusion criteria included age <18 yr, a history of drug or alcohol abuse, chronic use of drugs known to alter the anesthetic or analgesic requirements, or allergy to any of the study medications. All patient assessments and administration of the study drugs were performed by individuals who were blinded to the opioid used during the lithotripsy procedure. After a routine preoperative evaluation and placement of the IV catheter, baseline measurements of mean blood pressure, heart rate, respiratory rate (RR), and SpO2 were obtained. The patient’s level of sedation was assessed by using the Observer’s Assessment of Alertness/Sedation (OAA/S) scale: 5 = awake/alert to 1 = asleep/unarousable. Midazolam, 2 mg IV, was administered for premedication, and patients were then asked to position themselves in the lithotriptor chair. Supplemental oxygen (2 L/min) was administered by using nasal prongs containing a capnograph sampling port. On placement of the patient in the warm-water bath, a propofol infusion was initiated at 50 μg · kg−1 · min−1. The propofol infusion rate was varied in increments of 25% to 50% to maintain a stable level of sedation whereby the patient was resting comfortably with eyes closed, but was easily arousable with verbal and light tactile stimulation (i.e., an OAA/S score of 3) (6). An initial IV bolus injection (2 mL) of analgesic study medication (containing either fentanyl 50 μg, alfentanil 500 μg, sufentanil 10 μg, or remifentanil 25 μg) was administered 3 min before initiating the ESWL procedure. If the patient verbally complained of pain, moved, or grimaced in response to the shock waves, a supplemental IV bolus injection (1 mL) of the study medication (containing fentanyl 25 μg, alfentanil 250 μg, sufentanil 5 μg, or remifentanil 12.5 μg) was administered. The patients were asked to evaluate their level of pain on a four-point descriptive scale (0 = none, 1 = mild, 2 = moderate, or 4 = severe) at 5-min intervals. If adequate analgesia (pain score ≤ 1) could not be achieved with the supplemental opioid injections, patients were administered nitrous oxide (N2O) through a face mask. The OAA/S scores, as well as hemodynamic (mean arterial pressure and heart rate) and respiratory (RR and SpO2) variables, were recorded at 5-min intervals after the administration of midazolam until the end of the ESWL procedure. During the ESWL procedure, the frequency and duration of bradypnea (RR < 8 bpm), oxygen desaturation (SpO2 values < 90%), increased end-expiratory carbon dioxide (levels > 50 mm Hg), and oversedation (an OAA/S score of < 3) were recorded along with the patient’s level of sedation, discomfort, and pain. Apnea was defined as the absence of a respiratory effort in a 30-s interval. In response to oxygen desaturation (< 90%) associated with bradypnea, a face mask was applied to increase the inspired oxygen concentration. All other common side effects (e.g., pruritus, nausea, vomiting) were also noted. The sedation time was defined as the time from initiation of the propofol infusion until the end of the surgical procedure. The time to achieve a modified Aldrete score (9) of 10 was assessed at 1-min intervals after discontinuing the propofol infusion. Patients achieving a modified Aldrete score ≥ 9 while in the ESWL suite were transferred directly to the same-day unit, i.e., bypassing the postanesthesia care unit. During the recovery period, the patient’s level of pain and sedation was assessed at 15-min intervals until discharge. Oral acetaminophen with codeine was administered as a rescue analgesic. Patients were considered to be ready for discharge (“home ready”) when they were alert, oriented, able to ambulate unassisted, and had no active side effects (8). Finally, patients were asked to assess their satisfaction with the control of pain during the ESWL procedure on a seven-point verbal rating scale (1 = extremely satisfied to 7 = extremely dissatisfied) at the time of discharge. In a telephone interview on the first postoperative day, all patients were asked about the occurrence of adverse events after discharge and the amount of pain medication used at home. An a priori power analysis was performed to determine the minimum group sizes (n = 13) necessary to demonstrate a clinically significant difference in the time to discharge home. Data from the four analgesic groups were compared by using one-way analysis of variance followed by Duncan’s multiple comparison test where appropriate, with P values < 0.05 considered statistically significant. Data were presented as mean values (± SD), numbers, and percentages. Results The four study groups were comparable with respect to demographic data (Table 1). The remifentanil group required a smaller total dosage of propofol to maintain an OAA/s score of 3. In the sufentanil group, fewer supplemental bolus doses of the analgesic study medication were required to maintain an adequate level of analgesia. In the alfentanil group, more patients required supplemental use of N2O and airway support (Table 2). While the incidence of bradypnea was highest in the remifentanil group, there were no differences in the incidences of apnea or desaturation among the four groups during the procedure. The remifentanil-treated patients also experienced more pain in the early postoperative period. Although a higher percentage of the remifentanil-treated patients required oral analgesics after the procedure, no parenteral (opioid) analgesic medications were administered. The times to home readiness and actual discharge were shortest in the remifentanil group; however, the only statistically significant difference was a prolonged time to actual discharge in the alfentanil group (Table 3).Table 1: Demographic Data for the Four Opioid Treatment GroupsTable 2: Drug Dosage Requirements and Side Effects During and After the ESWL ProcedureTable 3: Recovery Times After Discontinuation of the Propofol Infusion in the Four Opioid Treatment GroupsDiscussion The use of propofol sedation supplemented with one of the fentanyl analogs can provide adequate patient comfort for ESWL procedures when using the Dornier HM-3 immersion lithotriptor. These data suggest that intermittent bolus injections of remifentanil compared favorably with alfentanil with respect to patient comfort during the procedure and time to discharge home. Although the use of sufentanil and fentanyl provided better intraoperative respiratory stability and required fewer supplemental bolus doses, there were no significant differences in the recovery profiles compared with remifentanil. The high incidence of bradypnea and need for more airway support in the remifentanil and alfentanil groups, respectively, may have been reduced by the use of a continuous basal infusion combined with smaller bolus doses of these potent, rapid-acting opioid analgesics (8). As expected, the acquisition (direct) cost of a new drug such as remifentanil is higher than that of fentanyl. However, the cost of remifentanil compared favorably with both alfentanil and sufentanil. For example, a 1-mg ampule of remifentanil costs US $11.70 compared with US $18.86, US $3.78, and US $42.31 for alfentanil (2.5 mg), fentanyl (500 μg), and sufentanil (50 μg), respectfully. Given the average dosage requirements during the ESWL procedure, the use of remifentanil could be associated with significantly greater drug wastage compared with the other commonly used opioid analgesics (e.g., 70% for remifentanil versus 40% for fentanyl and sufentanil). Therefore, if remifentanil is used for these short procedures, the 1-mg ampule should be prepared in divided doses (e.g., 100–200 μg per syringe) by the operating room pharmacist to enhance its cost effectiveness for ESWL procedures. In fact, remifentanil compared favorably with generic fentanyl when the wastage was minimized. The primary deficiency of the study design related to the assumed potency ratios for fentanyl:sufentanil:alfentanil:remifentanil of 1:5:0.1:2. Based on the actual amount of opioid administered, the actual ratios were closer to 1:10:0.1:1.5, suggesting that sufentanil was more potent and remifentanil somewhat less potent than expected at the outset of the study. However, the opioid dosage may also have been influenced by the amount of propofol administered to maintain a constant level of sedation. Becasue the remifentanil group received significantly less propofol to maintain an adequate level of sedation during the maintenance period (versus fentanyl), this may explain its lower than expected potency ratio. A second criticism of the study relates to the use of intermittent bolus doses of the short-acting opioid compounds rather than continuous variable-rate infusions (8,10). However, our recent study (8) would suggest that intermittent dosing of a short-acting opioid can be used effectively during ESWL procedures under MAC. In conclusion, intermittent boluses of remifentanil can be used as an alternative to fentanyl, alfentanil, and sufentanil to provide analgesia during immersion ESWL with propofol sedation. As expected, the use of remifentanil was associated with an increased requirement for oral analgesic medication after the procedure. Of the fentanyl analogs studied, alfentanil had the least favorable recovery profile. However, if remifentanil is to be a cost-effective alternative to fentanyl for brief ambulatory procedures, the ampule will have to be subdivided to allow for its use in multiple patients.