Remifentanil as an Analgesic Adjunct in Local/Regional Anesthesia and in Monitored Anesthesia Care

Surgery performed under local or regional anesthesia in both inpatient and outpatient settings and under monitored anesthesia care (MAC) is becoming an increasingly common practice. The ASA (1) defines MAC in the context of anesthesia practice in which an anesthesiologist provides anesthesia services for a particular patient undergoing a planned surgical/medical procedure, for which the patient may receive only limited nerve block anesthesia with directly injected local anesthesia drugs or, in some cases, no anesthesia at all. In such cases, the anesthesiologist’s services are focused primarily on monitoring the vital signs and stability of the patient and anticipating any conditions that may require the administration of anesthetics or other medical care during the perioperative period. During MAC, opioid analgesics may be used either alone or in combination with sedatives such as benzodiazepines to provide analgesia and patient comfort and to maintain hemodynamic stability during placement of nerve blocks and surgery. The efficacy and adverse events of remifentanil as an adjunct to local and regional anesthesia have been evaluated in nine clinical trials (2–9), 1 which are summarized in this article. In all of the studies, respiratory depression was defined as a respiratory rate of <8 breaths/min or apnea for >15 s. Efficacy of Remifentanil When Used as an IV Analgesic Adjunct The initial studies with remifentanil in this clinical setting investigated efficacy in terms of sedation, which is usually assessed by the Observer’s Assessment of Alertness/Sedation (OAA/S) scale. This scale assesses alertness and sedation by assigning a composite score ranging from 1 to 5 based on the investigator’s evaluation of the patient’s responsiveness, speech quality, alertness of eyes, and facial expression (10). The OAA/S was used as an end point in these earlier studies to be consistent with the approach taken in other MAC studies with the sedatives midazolam and propofol. These studies showed that the usual clinical end point corresponding to OAA/S level of 3 (response only after name is called loudly) was not appropriate when a potent opioid such as remifentanil was used because of unacceptable respiratory depression. Sedation, defined as an alteration of vigilance and consciousness, is rather a side effect of opioids, and the end point sought should be patient’s comfort. These studies also confirmed the remifentanil doses required to provide analgesia and patient comfort and the doses above which there is a clinically unacceptable incidence of respiratory depression. In addition, bolus dosing of remifentanil (especially multiple boluses) should not be used in conjunction with a continuous infusion to achieve a sedation score of ≥3 in the MAC setting because of the unacceptable incidence of chest wall muscle rigidity. The focus for the more recent studies regarding remifentanil in MAC has been on the end points of analgesia and patient comfort during placement of the regional or local blocks and throughout the procedure. Based on the results of an early, open-label, dose-ranging study (data on file, Glaxo Wellcome), a dose of 0.1 μg · kg−1 · min−1 was chosen as the maximal dose for the studies of remifentanil during MAC (4). A randomized, double-blind, placebo-controlled trial evaluated the efficacy of three initial rates of remifentanil infusion, 0.04, 0.07, and 0.1 μg · kg−1 · min−1, or placebo in providing adequate comfort (OAA/S score 2) in patients undergoing hip or hand surgery under regional anesthesia. This comprehensive study confirmed that a remifentanil infusion provides adequate comfort within 15 min compared with placebo (P< 0.001) and that comfort was increased proportionally with the increasing rates of infusion of remifentanil (Figure 1). The effect of treatment with remifentanil was consistent within and between surgery groups. For both hip and hand surgery groups, there was a significant dose-related decrease in the requirement for supplemental midazolam with increasing doses of remifentanil (P< 0.001). The percentages of patients in whom an OAA/S score of 2 could not be achieved with study drug alone, and who therefore required the administration of midazolam, ranged from 95% of patients given placebo to 18% of those receiving remifentanil 0.1 μg · kg−1 · min−1 in the two surgery groups combined. Clinical investigators blinded to the patient’s group expressed greater satisfaction with the outcome when using a remifentanil infusion compared with placebo (i.e., midazolam alone). This study provided data for the calculation of an infusion rate coefficient describing the dose required to achieve a sedation level of 2 in 50% of the patients (ED50): 0.043 μg · kg−1 · min−1 (confidence interval 0.001, 0.059). Figure 1: Proportion of patients undergoing hip or hand surgery under regional anesthesia who achieved adequate sedation within 15 min of initiating a continuous infusion of remifentanil, and proportion of patients in the same study who required supplementary midazolam (4). *P< 0.001 compared with placebo.The sedative and analgesic effects of remifentanil used as an adjunct to local anesthesia in ophthalmic surgery were compared with those of alfentanil in a double-blind, randomized study. 1 Thirty-eight patients received a continuous infusion of remifentanil 0.05 μg · kg−1 · min−1 or alfentanil 0.5 μg · kg−1 · min−1 supplemented with intermittent bolus injections (remifentanil 0.5 μg/kg or alfentanil 5 μg/kg) after 6 min. The bolus doses were separated by an interval of at least 1 min and were given slowly until a sedation level ≥3 was achieved. One of the primary aims of this study was to determine whether remifentanil influenced intraocular pressure. There were no significant differences in intraocular pressure between remifentanil- and alfentanil-treated patients at any time. The mean total doses of remifentanil or alfentanil required to achieve adequate sedation were 2.7 ± 0.3 and 31.8 μg/kg, respectively. Sedation for Nerve Block Placement: Bolus Versus Continuous Infusion Effective blunting of the pain associated with local or regional nerve block placement can be established by either single-dose or continuous infusion delivery of remifentanil. In a randomized, double-blind study (2), remifentanil was administered either as a single dose (1 μg/kg over 30 s) 90 s before placement of an ophthalmic block (n= 28) or as the same single dose followed by an infusion of remifentanil 0.2 μg · kg−1 · min−1 (n= 29), and alfentanil was administered as a 7-μg/kg bolus dose in a third group of patients. Patients receiving remifentanil by either dosing schedule experienced significantly fewer incidences of pain than patients receiving a single dose of alfentanil (P< 0.05). Pain was also less severe in the remifentanil group. In total, 77% of patients receiving a single dose of remifentanil and 85% of those receiving a single dose plus infusion did not report any pain during placement of the ophthalmologic nerve block, compared with 44% of patients receiving alfentanil (P< 0.01). The addition of a remifentanil infusion to the single dose administration of remifentanil did not statistically enhance the analgesia reported by patients under these conditions. An assessment of respiratory rates from this study showed that rates of <8 breaths/min occurred in 5 of 26 (19%) patients treated with remifentanil single dose plus infusion and in 4 of 26 (15%) of the patients given a single dose of remifentanil (data on file, Glaxo Wellcome). Most of these respiratory depression episodes occurred after the remifentanil bolus administration, and their incidence was not enhanced by the adjunction of an infusion. This experience suggests that respiratory depression associated with the clinical use of remifentanil is directly associated with bolus administration. Respiratory depression is linked to the blood concentration of remifentanil (11). Peak concentrations of drugs can be avoided by slow administration. The danger of bolus administrations of remifentanil has also been outlined in studies in which remifentanil was used to provide postoperative analgesia in spontaneously breathing patients (12). Therefore, bolus doses of remifentanil must be administered slowly over 30–60 s to minimize the risk of respiratory depression. The respiratory status of patients receiving opioid and sedative drugs must remain an important clinical and safety consideration in MAC/adjunct to regional anesthesia; however, when they did occur, these events resolved within a median of 3 min after remifentanil dosing was reduced or stopped. Two other studies (3,5) have confirmed the efficacy of remifentanil administration for providing analgesia in preparation for local or regional anesthesia. These studies show that a remifentanil infusion rate of 0.1 μg · kg−1 · min−1 is adequate because it provides satisfactory analgesia and comfort in >90% of patients while preserving respiratory rate, and that all patients remained responsive and were therefore able to follow commands during placement of a nerve block. In the study by Desmonts et al. (5), the difference between patients receiving remifentanil and patients receiving propofol was not statistically significant as far as experiencing a pain or discomfort on infusion was concerned (remifentanil group 0 of 62, propofol group 3 of 63). A subsequent study (8) examined the use of an initial remifentanil infusion of 0.2 μg · kg−1 · min−1 administered 5 min before the expected placement of nerve block, the rate being decreased to 0.1 μg · kg−1 · min−1 after the block placement. In this study, 83% of the patients receiving remifentanil, compared with 31% of the patients receiving propofol, did not experience any pain during block placement. However, the time to complete the block for many patients was longer than the anticipated 5-min initiation of analgesia period, and the 0.2-μg · kg−1 · min−1 remifentanil infusion was therefore prolonged for >5 min. This prolonged administration of the initial infusion of remifentanil probably resulted in higher remifentanil blood concentrations and was associated with a high incidence (21%) of respiratory depression without providing improved analgesia. The incidence of patients showing responses to pain (6%) in this study was consistent with that seen in another study (3) that used an initial remifentanil infusion rate of 0.1 μg · kg−1 · min−1 and found 11% of patients to be responsive to painful stimuli. The suitability of remifentanil 0.1 μg · kg−1 · min−1 as the maximal appropriate infusion rate for the induction of analgesia is thus confirmed. Maintaining Analgesia and Patient Comfort After Nerve Block Placement The efficacy of remifentanil in providing analgesia and maintaining patient comfort after nerve block placement has been evaluated in a variety of surgical procedures, including orthopedic surgery, lower abdominal surgery, and breast biopsy (2,3,5,6,8). In these studies, the starting maintenance infusion rate was 0.1 μg · kg−1 · min−1, which was then titrated according to the clinical end points of comfort, relief of anxiety and pain, and attenuation of hemodynamic responses to surgical stimuli without excess sedation, respiratory depression, or apnea. The final infusion rate of remifentanil required was usually less than the initial rate of 0.1 μg · kg−1 · min−1 used for the induction of analgesia (range 0.05–0.08 μg · kg−1 · min−1), although, in one study (6), the final infusion rate was slightly higher (0.123 μg · kg−1 · min−1). Among the six studies, the mean final maintenance infusion rate was 0.084 μg · kg-1 · min−1. Of those patients with reduced infusion rates of remifentanil, most (60%) had the rate decreased to alleviate respiratory depression. The study drug infusion rate was increased for intraoperative discomfort in fewer patients who received remifentanil than those who received propofol (3% vs 12%) (8). Similarly, the number of treated discomfort responses was lower when remifentanil, rather than when propofol, was used (3% vs 16%, respectively;P< 0.05) (5). The Effects of Midazolam in Combination with Remifentanil in Monitored Anesthesia Care Two studies have focused on the interaction between benzodiazepine (midazolam) and remifentanil administration during MAC. In a double-blind, randomized study (6), 159 patients undergoing superficial surgical procedures, such as breast or lymph node biopsy, were given either remifentanil alone (1-μg/kg bolus followed by a 0.1-μg · kg-1 · min−1 continuous infusion, titrated upward in 0.05-μg · kg−1 · min−1 increments as clinically indicated) or midazolam (2 mg) associated with 50% of the remifentanil doses. The final mean remifentanil infusion rates were 0.123 μg · kg−1 · min−1 when administered alone compared with 0.065 μg · kg−1 · min−1 when used in combination with midazolam. The clinical efficacy of both schedules was similar, a result consistent with the synergistic interactions of other opioid-benzodiazepine combinations (13). However, during maintenance of analgesia/sedation, a significantly higher proportion of patients in the remifentanil plus placebo group (36%) than in the remifentanil plus midazolam group (20%, P< 0.05) displayed some level of anxiety. Another double-blind, placebo-controlled, randomized study (3) investigated the efficacy of remifentanil alone and in conjunction with fixed doses of midazolam (2, 4, or 8 mg) in providing analgesia and patient comfort in 81 women undergoing breast biopsy procedures. The initial infusion rate of remifentanil 0.1 μg · kg−1 · min−1 in all the groups was titrated upward according to pain/discomfort responses or downward in response to decreased respiratory rate in incremental changes of 0.025 or 0.05 μg · kg−1 · min−1 to achieve a balance between adequate patient comfort and respiration. As the midazolam dose increased, there was a corresponding decrease in the required infusion rate of remifentanil, which resulted in mean final infusion rates of 0.11 μg · kg−1 · min−1 (placebo) to 0.05 μg · kg−1 · min−1 (midazolam 8 mg) (P< 0.05). The proportion of patients requiring a decrease in the remifentanil infusion rate because of respiratory depression, apnea, or excessive sedation increased with increasing midazolam doses. Simultaneously, the incidence of amnesia of local blockade also increased with increasing midazolam doses: 0%, 27%, 76% (P< 0.05), and 95% (P< 0.05) for placebo, midazolam 2 mg, midazolam 4 mg, and midazolam 8 mg. Pain on local anesthetic injection was not different in the four groups of patients. These data suggest that combining midazolam and remifentanil during MAC can serve effectively and safely to alleviate anxiety and provide desirable perioperative amnesia. A relatively small dose of midazolam (2 mg) provides an adequate benzodiazepine effect without conveying an increased incidence of adverse events. As with any combination of benzodiazepines and opioids, the remifentanil infusion rate should be reduced in the presence of midazolam to accommodate the well recognized pharmacodynamic interactions of these two drug categories (13). Adverse Effects of Remifentanil as an Analgesic Adjunct The adverse effects associated with remifentanil as an adjunct during local or regional anesthesia (see Table 1) are predictable and typical of all μ-opioid receptor agonists. Remifentanil produced a reduction in respiratory rate (5,7) (Figure 2), which sometimes led to respiratory depression (respiratory rate <8 breaths/min and/or SpO2 ≤90%) (3,4,6,7,9). Nevertheless, this respiratory depression was easily managed and resolved in approximately 3 min by discontinuing or reducing the remifentanil infusion rate. The incidence of respiratory depression was significantly increased compared with placebo (4) or propofol (7,9). It was increased by increasing doses of associated midazolam (3). Nausea was observed during remifentanil administration or in the early postoperative period in approximately 30% of the patients: 17.5%(4), 26%(5), 32%(3), 37%(6), 41%(7). Remifentanil treatment was associated with vomiting in approximately 10% of the patients (3,5,6). This incidence is higher than that observed with placebo (4) or propofol (5,7). The association of small doses of midazolam (2 mg) reduces the incidence of nausea and vomiting, whereas larger doses of midazolam do not have this effect (3). In the ambulatory setting, the occurrence of nausea and vomiting might explain a delayed time for phase II discharge (street-fitness) when remifentanil was administered alone compared with midazolam 2 mg, which was associated with 50% of the remifentanil doses (6) (78 vs 63 min;P< 0.01). Nevertheless, postoperative nausea and vomiting associated with remifentanil was observed in the early postoperative period (3), 1 contrasting with what was observed with alfentanil, in which postoperative nausea and vomiting was observed in the 24-h follow-up. 1 Pruritus was also observed in some patients (3,4), and anxiety was more frequent in patients who received remifentanil alone compared with those who received propofol (7) or midazolam with remifentanil (6). Pain at the IV injection site was reported more frequently by the propofol-treated patients than by those receiving remifentanil. Table 1: Adverse Events Associated with Remifentanil in Monitored Anesthesia CareFigure 2: Time course of SpO2, respiratory rate, and PETCO2 during monitored anesthesia care (MAC) for breast biopsy in patients receiving remifentanil 0.1 μg · kg−1 · min−1 or propofol 75 μg · kg−1 · min−1 (9). Reprinted with permission from Smith I, Avramov M, White I, et al. A comparison of propofol and remifentanil during monitored anesthesia care. J Clin Anesth 1997;9:148–54.In summary, the clinical trials with remifentanil in monitored anesthesia care demonstrated the following key findings: • Remifentanil provides effective analgesia during nerve block placement when given as either a single dose of 0.5–1.0 μg/kg administered over 30–60 s and given 90 s before the placement of the block, or as a continuous infusion at an initial rate of 0.1 μg · kg−1 · min−1 beginning 5 min before placement of the block and thereafter decreased to 0.05 μg · kg−1 · min−1 for maintenance of comfort and analgesia, with adjustments of 0.025 μg · kg−1 · min−1 according to clinical response. • More remifentanil-treated patients were pain-free than those receiving recommended doses of alfentanil or propofol for local or regional nerve block placement. • Respiratory depression is an expected adverse effect of remifentanil administration. It is more frequently observed with infusion rates >0.2 μg · kg−1 · min−1. Decreases in respiratory rate resolved within approximately 3 min after decreasing the remifentanil infusion rate. • During MAC, bolus doses should not be administered concurrently with a continuous infusion of remifentanil. • When administered as a continuous infusion during MAC, remifentanil is more appropriately titrated to provide analgesia and comfort rather than sedation. • The concomitant administration of midazolam (2 mg) decreases the dose requirements of remifentanil by up to 50%. Conclusion Remifentanil is an effective adjunct to regional/local anesthesia. It provides satisfactory analgesia during nerve block placement and during the surgical procedure while maintaining hemodynamic stability. Like traditional opioids, remifentanil may be associated with respiratory depression, which requires appropriate monitoring. However, the rapid onset and offset of action of remifentanil (14) mean that the blood concentration can be rapidly titrated by decreasing the infusion rate to reduce respiratory depression without compromising analgesia and patient comfort.