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REGIONAL ANESTHESIA AND PAIN MEDICINE

A Comparison of Intrathecal Analgesia with Fentanyl or Sufentanil After Total Hip Replacement

Department of Anesthesiology, University Hospital of Geneva, Geneva, Switzerland

Address correspondence and reprint requests to Roxane Fournier, MD, Département d’Anesthésiologie, Hôpital Cantonal Universitaire, CH-11 Geneve 14, Switzerland. Address e-mail to Roxane.Fournier{at}hcuge.ch

	Abstract

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We designed this study to compare the postoperative analgesic effects of intrathecal fentanyl and sufentanil, the end points being onset, quality, and duration of action. A total of 42 geriatric patients, scheduled for elective total hip replacement under continuous spinal anesthesia, were randomized in two double-blinded groups as soon as they experienced a pain score higher than 3 of 10 on the visual analog scale in the recovery room. Either 7.5 µg sufentanil or 40 µg fentanyl in 2 mL normal saline were intrathecally administered. Pain scores, rescue analgesia (ketorolac and morphine), and adverse effects (respiratory depression, postoperative nausea and vomiting, and itching) were recorded for 24 h after surgery. In both groups, comparing sufentanil to fentanyl, the time to a pain score <3 (9 ± 9 vs 11 ± 8 min), the time to the lowest pain score (18 ± 6 vs 20 ± 15 min), and the time to the first systemic analgesic intervention for a pain score >3 (241 ± 102 vs 214 ± 120 min) were comparable as were the analgesic requirements during the first 24 h. We conclude that, after total hip replacement, both lipid soluble opioids produce excellent analgesia with comparable onset, duration of action, and low incidence of minor adverse effects.

Implications: We compared the postoperative analgesic properties of 40 µg intrathecal fentanyl and 7.5 µg sufentanil after total hip replacement. Both opioids provided satisfactory analgesia, with comparable onset (11 ± 8 vs 9 ± 9 min) and duration of action (214 ± 120 vs 241 ± 102 min), as well as low incidence of minor side effects.

	Introduction

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Intrathecal (IT) opioid analgesia is a popular method for treatment of postoperative and labor pain (1–6). For pain relief during labor, mostly lipophilic drugs, such as sufentanil or fentanyl, are administered and their onset and duration of action are well documented (4–6). In contrast, IT morphine is more frequently used for postoperative analgesia. Morphine provides excellent and long-lasting analgesia after different types of surgical procedures (2,3,7). However, because of its hydrophilic properties, the administration of IT morphine can be associated with delayed respiratory depression, requiring prolonged monitoring, which is not always available.

Continuous spinal anesthesia is widely used in our institution, mainly for lower limb orthopedic procedures in elderly patients (8). After surgery, the ITcatheter is often used for postoperative pain relief (9). When the overnight supervision of these elderly patients in the recovery room unit is not possible, lipophilic opioids, such as sufentanil or fentanyl are considered. For these drugs, the risk of respiratory depression is predominantly limited to the first 2 h after IT injection, which is an important advantage for monitoring and patient safety over IT morphine (10). After lower extremity revascularization surgery, 40 µg of IT fentanyl is an optimal dose, providing satisfactory analgesia of rapid onset and a duration of approximately 5 h (1).

Although IT sufentanil is the opioid most often used for labor analgesia, its postoperative analgesic properties are poorly documented. The purpose of this study is to compare as main end points, the analgesic characteristics (onset, quality, and duration of analgesia) of 40 µg of IT fentanyl versus 7.5 µg of IT sufentanil for postoperative pain relief after total hip replacement surgery in elderly patients. Ancillary end points are the postoperative 24 h analgesic requirements, the hemodynamic changes, and the adverse effects.

	Methods

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After institutional approval and informed consent, we investigated 42 patients older than 70 yr, ASA physical status II–IV, scheduled for elective total hip replacement in the lateral decubitus position under continuous spinal anesthesia. Patients in whom there was a history of psychiatric illness, allergy to opiates, or severe chronic obstructive respiratory decease (peak expiratory flow <600 mL), were not included in the study. We observed a 30% to 50% standard deviation in the delay and duration of action of IT sufentanil (5,6,11), and IT fentanyl (4,11). Considering the largest liposolubility of sufentanil (10), we hypothesized that its delay, as well as its duration, would be shorter than fentanyl, and arbitrarily choose a 35% difference between the two drugs. The prospective power analysis indicated that 21 patients per group were required for a ß = 0.2 and an = 0.05.

All patients were premedicated with 0.1 mg/kg of subcutaneous morphine 60 min before surgery. This was given to avoid opioid supplementation during prolonged surgery in the lateral decubitus position, which is sometimes poorly tolerated (shoulder pain). Before anesthesia, an IV infusion of lactated Ringer’s solution was started through a 17-gauge peripheral catheter. In all patients, electrocardiogram, noninvasive arterial blood pressure, and peripheral oxygen saturation were monitored, and an indwelling urinary catheter was inserted. With the patient in the lateral position with the operated side up, dural puncture was performed at the L2-3 or L3-4 intervertebral space by using a 18-gauge Tuohy needle (epidural minipack; Portex, Hythe, UK). A 20-gauge IT catheter was inserted 3–4 cm into the subarachnoid space. Anesthesia was obtained with repeated injections of 2.5 or 5 mg plain bupivacaine 0.5% (Carbostésine^®; Astra, Dietikon, Switzerland) as required. Surgery was performed according to a standardized protocol.

After surgery, the indwelling IT catheter was flushed with 2 mL of normal saline, to avoid residual bupivacaine effects during injection of IT opioids, and left in place. All patients were transferred to the recovery room and received 4 L oxygen by face mask. In the recovery room, as soon as the pain score on the operated side was higher than 3 of 10 on the visual analog scale (VAS, 0 = no pain at all and 10 = unbearable pain), either 7.5 µg of sufentanil or 40 µg of fentanyl in 2 mL normal saline were administered over 30 s in a double-blinded, randomized manner through the IT catheter. The anesthetist in charge prepared the IT opioid mixture. One of the authors blindedly injected the IT opioid and tested the patients during the first hour. Afterwards, the patients were blindedly tested by nurses in charge, and after leaving the recovery room, by ward nurses, who collected the data and administered the analgesics according to the study protocol. One of the authors collected the data again 24 h after the IT opioid injection.

Pain score, respiratory rate, oxygen saturation, sedation score (1 = awake and alert, 2 = awake however, drowsy, responding to verbal stimulus, 3 = drowsy however, rousable, responding to physical stimulus, 4 = unrousable, not responding to physical stimulus), and hemodynamic changes were assessed at injection and then, every 2.5 min during the first 15 min, every 5 min for the following 45 min, and every hour for the following 5 h. Nurses in the recovery room recorded the times to a VAS <3, to the lowest VAS, and to the first systemic analgesic intervention (reappearance of hip pain, VAS >3). Ketorolac and morphine requirements (rescue analgesia given by the systemic route) during the first 24 h after IT injection and side effects, such as nausea and vomiting, pruritus (grade 1 = mild, not disturbing; grade 2 = moderate, disturbing not requiring treatment; grade 3 = severe, requiring treatment), and respiratory depression (respiratory rate <8 breaths/min) were noted.

Systemic rescue analgesia was given whether the pain score was still higher than 3 of 10 at 30 min after IT injection or the IT analgesia faded. Ketorolac 30 mg IV was administered first followed by morphine 0.1 mg/kg subcutaneous when the VAS was still higher than 3 of 10 at 30 min later. Afterwards, these analgesics were administered on demand (pain score >3) with a maximum of 3 doses over 24h for ketorolac and 8 doses over 24h for morphine.

Nausea and vomiting were treated by 10 mg of IV metoclopramide and a decrease by 30% of systolic blood pressure from baseline values by a rapid infusion of 250 mL of normal saline, and when necessary 5 mg of IV ephedrine. Naloxone 40 µg IV was administered for severe pruritus and respiratory depression (respiratory rate < 8 breaths/min). The patients left the recovery room for the ward only after the first rescue analgesia had been administered.

Data were presented as mean ± SD or median (ranges) and groups were compared with the unpaired Student’s t-test or Mann-Whitney U-test as required; a P < 0.05 was considered significant.

	Results

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Demographic data, such as age (80 ± 5 vs 79 ± 6 yr), height (163 ± 10 vs 163 ± 9 cm), weight (69 ± 18 vs 71 ± 17 kg), women/men ratio (14/7, 11/10), and ASA physical status were comparable between the sufentanil and fentanyl group, respectively. No supplementary IV opiates nor sedatives were administered throughout surgery.

Pain scores and onset and duration of action of IT sufentanil versus fentanyl are presented in Table 1. Results were comparable in both groups. After IT injection in all patients receiving sufentanil, VAS decreased to 0, whereas in two patients receiving fentanyl, the lowest VAS achieved remained at 1 of 10. For both opioids, median and mean values, the 25th to 75th percentiles, and the 10th to 90th percentiles are illustrated for onset of action (VAS <3) in Figure 1, and the duration of action (first analgesic intervention for a VAS >3) in Figure 2. Although a slightly shorter onset and longer duration of action is observed for sufentanil, the differences are not statistically significant.

View larger version (18K): [in this window] [in a new window]   Figure 1. Box plots representing the onset of action (time between initial intrathecal injection and a decrease to a pain score <3) for 7.5 µg IT sufentanil vs 40 µg IT fentanyl. Open boxes represent the 25th to 75th percentiles and contain the median (horizontal bar) and mean () values; vertical bars represent 10th to 90th percentiles.

View larger version (21K): [in this window] [in a new window]   Figure 2. Box plots representing the duration of action (time from initial intrathecal injection to reappearance of VAS >3 requiring the first systemic analgesic intervention) for 7.5 µg IT sufentanil vs 40 µg IT fentanyl. Open boxes represent the 25th to 75th percentiles and contain the median (horizontal bar) and mean () values; vertical bars represent 10th to 90th percentiles.

Respiratory depression as defined was not observed. However, in the first hour, five patients in the sufentanil group and six patients in the fentanyl group had an oxygen saturation under 95% of short duration after IT injection, requiring adjustment of oxygen administration. Before rescue analgesia, seven patients in the sufentanil group and three in the fentanyl group complained of grade 1 (mild) pruritus and two patients in each group had nausea and vomiting requiring antiemetic therapy. Sedation score never exceeded 2 in any patient of either groups.

	Discussion

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We examined the efficacy in terms of onset, quality and duration of analgesia of two spinal opioids after total hip replacement. Once local anesthetic effects waned, IT fentanyl and sufentanil showed similar analgesic characteristics and adverse effects.

One can question the equipotency of 40 µg of IT fentanyl and 7.5 µg of IT sufentanil. Although we did not find any study reporting the equipotent ratio of these two opioids administered by the IT route, there are arguments in favor of equipotency of the dosages we investigated. Some authors concluded that sufentanil administered IV (12) or epidurally (13) was 5 to 7 times more potent as an analgesic than fentanyl injected by the same route. Moreover, two dose-response studies performed during labor showed a median effective dose (ED₅₀) of 2.6 µg for IT sufentanil (6) and of 14 µg for IT fentanyl (4), indicating that IT sufentanil was approximately 5 times more potent than IT fentanyl. Finally, Reuben et al. (1) reported that 40 µg of IT fentanyl is an optimal dose for pain relief after lower extremity revascularization procedures in elderly patients. There are no published data about IT sufentanil administration after general surgery, however, 8.9 µg of IT sufentanil was reported to be the 95% effective dose (ED₉₅) for obstetric analgesia (6). Taking into account these considerations, we choose to compare 40 µg of IT fentanyl with 7.5 µg of IT sufentanil.

Our study design did not include a control (IT placebo) group. This group may be considered only when IT local anesthetics are mixed with IT opiates; taking into account our discussion with the Ethics Committee, it was felt that the administration of IT normal saline for an established pain was not ethical. Previously, in a dose-response study for fentanyl (1), IT placebo was shown to be ineffective. We think that in our study, the control group would have been useful when the main end points were global analgesic consumption over 24 hours and not the onset, the quality, and the duration of analgesia.

Only a limited number of reports documented the use of a single bolus injection of IT fentanyl given alone for postoperative analgesia (1,14,15). In elderly patients, with a study design similar to ours, Reuben et al. (1) compared different doses of IT fentanyl (5 to 50 µg) for postoperative relief after lower extremity revascularization surgery. An optimal dose of 40 µg provided an excellent quality of analgesia within 10 minutes that lasted approximately 5 hours. In our study, with the same dose of IT fentanyl, we obtained a similar onset (11 ± 9 minutes) and a similar quality of analgesia (complete pain relief in 19 of 21 patients). However, the duration of analgesia was shorter (3.5 hours). We think that this difference in duration can be mainly attributed to the different type of surgical procedure (peripheral vascular versus hip replacement), inducing different patterns of postoperative surgical pain. A single dose of 25 µg of IT fentanyl was also given in one patient for early postoperative phantom limb pain (14) and in eight patients for established postamputation stump pain (15). When compared with our findings, for the case report patient, the onset and the duration of analgesia were similar, whereas for the other eight patients, the onset was similar; however, the duration was much longer (8 h). The small number of patients, the absence of a double-blinded assessment, and the presence of an established pain for at least 4 months, with a median VAS pain score of 3.5 of 10 at injection should lead to a cautious interpretation of these results. Niemi et al. (16) reported that after hip arthroplasty a continuous infusion at a rate of 5 µg/h of IT fentanyl over 24 hours (equivalent to 20–25 µg/4–5 hours) which started immediately after IT bupivacaine and before beginning of surgery, did not provide a satisfactory postoperative analgesia. It should be noted that for labor analgesia, the doses of 35 and 45 µg IT fentanyl produced excellent analgesia starting within 10 minutes; however, it lasted only 90 minutes (4), emphasizing marked differences in obstetrical and postoperative pain patterns.

To our knowledge, the only description of the IT administration of sufentanil as the sole postoperative analgesic is a case report (9). For postoperative pain relief 5 µg of IT sufentanil were given after bilateral total knee replacement. This dose provided an excellent and long-lasting analgesia; however, it was associated with respiratory depression requiring respiratory assistance and IV opioid antagonism. In our study, 7.5 µg of IT sufentanil resulted in a rapid onset of pain relief (VAS <3 after 9 ± 9 min) and complete abolition of pain in all patients, lasting approximately 4 hours. The duration of analgesia of 4 hours is in agreement with findings of Dahlgren et al. (11), who compared the postcesarean section analgesia of an IT mixture of 12.5 mg hyperbaric bupivacaine with 5 µg sufentanil versus placebo, which showed complete pain relief lasting 214 and 90 minutes, respectively. Nevertheless, IT sufentanil given as the sole analgesic is largely investigated only in obstetric analgesia. During labor, 5 to 10 µg IT sufentanil also provided rapid pain relief within 5 to 10 minutes, however, lasting only 60 to 95 minutes (5,6). Again, this difference in duration can be mainly attributed to the different type of pain, with an increasing and changing pattern during labor (somatic to visceral), contrary to postoperative pain which tends to fade with time.

Sufentanil, being 2 times more lipophilic than fentanyl would, in theory, have a shorter onset of action when given by the IT route (10). Although, in our study, there is a tendency to a quicker onset of analgesia with IT sufentanil (Table 1 and Figure 1), the differences are not significant. One possible explanation for this finding is that fentanyl, being also a largely lipophilic compound (liposolubility ratio of fentanyl versus morphine is 800:1) (10), acts too rapidly to allow the detection of this theoretical advantage in onset of action.

Itching is the most common side effect of IT opioids (17). In our study, the incidence for IT sufentanil was 33% (7 of 21 patients), which is lower than the 47% to 100% reported for laboring patients (5,17–19). It is possible that the incidence of pruritus is lower in elderly patients, as suggested by the data for IT fentanyl. Indeed, after IT fentanyl, 92% of parturients (4), however, only 10% of elderly patients, complained of itching (1). The later data are in agreement with our findings of a 14% incidence of pruritus (3 of 21 patients receiving fentanyl). In all our patients, pruritus was of mild intensity, not requiring treatment.

Concerning other relevant adverse effects of IT opioids, nausea and vomiting leading to a treatment was observed in <10% of our patients in both groups, and is comparable to the incidence observed for parturients (18) and elderly patients (1). In our study, no respiratory depression (defined as a respiratory rate under 8 breaths/min) was observed. However, a comparable number of patients in each group needed adjustment of oxygen therapy to maintain peripheral oxygen saturation above 95%. In contrast to IT sufentanil (9), clinically irrelevant respiratory depression has been reported after 25 to 45 µg of IT fentanyl (20).

Hemodynamic alterations are not recognized as side effects of IT opioids (10). However, some authors did observe significant decreases in arterial pressure after IT fentanyl (4) and sufentanil (21), whereas others did not (1,22). In our study, a moderate, and clinically not relevant, decrease in mean arterial pressure of 14% to 17% was observed; however, it did not require any treatment. This event is generally attributed to the establishment of good analgesia (4,21). However, the existence of opioid receptors on preganglionic sympathetic nerves, the block of which can reduce preganglionic sympathetic activity, has been reported (23,24).

In conclusion, after total hip replacement, both 40 µg IT fentanyl or 7.5 µg IT sufentanil produced excellent analgesia with a comparable onset (11 ± 8 vs 9 ± 9 minutes), and duration of action (214 ± 120 vs 241 ± 102 minutes), as well as a low incidence of minor adverse effects.

	Footnotes

 
Presented, in part, at the Annual Meeting of the European Society of Anesthesiology, Amsterdam, The Netherlands, May 1999.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (15) Citing Articles via Google Scholar Google Scholar Articles by Fournier, R. Articles by Gamulin, Z. Search for Related Content PubMed PubMed Citation Articles by Fournier, R. Articles by Gamulin, Z.