Anesth Analg 2003;96:1079-1082
© 2003 International Anesthesia Research Society
PAIN MEDICINE
A Small Preoperative Test Dose of Intravenous Fentanyl Can Predict Subsequent Analgesic Efficacy and Incidence of Side Effects in Patients Due to Receive Epidural Fentanyl
Kazuyoshi Ueta, MD*,
,
Kiyoshi Takeda, MD PhD*,
,
Hisatoshi Ohsumi, MD PhD*,
Junichi Haruna, MD*,
Hiromi Shibuya, MD*, and
Takashi Mashimo, MD PhD
*Department of Anesthesia, Osaka National Hospital, Osaka, Japan;
Department of Anesthesiology, Osaka University Medical School, Osaka, Japan; and
Department of Anesthesiology, Fujita Health University, Aich, Japan
Address correspondence and reprint requests to Kazuyoshi Ueta, MD, Department of Anesthesiology, Osaka University Medical School, 2-2 Yamadaoka, Suita, Osaka, Japan 565-0871. Address e-mail to kueta{at}anes.med.osaka-u.ac.jp
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Abstract
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Because individual variation is a likely factor affecting both the incidence and severity of side effects and the analgesic efficacy of epidural opioids, assessment of individual variation could be useful in deciding optimal dosage. By evaluating the response to a small test dose of IV fentanyl, we designed this study to predict the degree of pain relief and the incidence of side effects in patients who would be receiving postoperative epidural fentanyl. Before the induction of anesthesia, 50 µg of fentanyl was administered IV, and 2 min after fentanyl, the patient response was evaluated. Twenty-three patients, who reported nausea, sleepiness, dizziness, sensation of warmth, and other symptoms, were categorized as responders (Group R); the remaining 20 patients were categorized as nonresponders (Group NR). At the completion of surgery, infusion of epidural fentanyl was administered (0.3 mg/d in 0.25% bupivacaine) for 96 h. At postoperative Hours 6 and 24, Group R had significantly lower visual analog scale scores for postoperative pain intensity and required fewer analgesics than Group NR. The incidence of side effects, however, was 74% for Group R and 10% for Group NR (P < 0.05), and side effects were more serious in Group R. This study demonstrates that preoperative administration of a small dose of fentanyl during the induction of anesthesia enables prediction of the analgesic efficacy of postoperative epidural fentanyl and the incidence and severity of side effects.
IMPLICATIONS: Preoperative administration of a small dose of fentanyl during the induction of anesthesia enables prediction of the analgesic efficacy of postoperative epidural fentanyl and the incidence and severity of side effects.
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Introduction
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Although the use of epidural opioids is an effective method of postoperative pain therapy, side effects, which may result in delayed ambulation, often occur. Individual variation is a likely factor associated both with the incidence and severity of side effects and the analgesic efficacy of IV opioids (1). Fentanyl has been administered epidurally for postoperative pain relief, and small doses have also been used to reduce the hemodynamic response to laryngoscopy and tracheal intubation during anesthetic induction (2,3) . Even a small dose, however, may cause unwanted side effects in some patients (4). To test whether the presence or absence of side effects might be influenced by individual sensitivity to opioids, we designed this study to see whether it was possible to predict, by preoperatively evaluating their response to a small dose of IV fentanyl, the degree of pain relief and the incidence of side effects in patients due to receive postoperative epidural fentanyl.
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Methods
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After receiving approval from the institutional ethics committee and informed consent from the patients, we recruited into this study 43 ASA status I–II patients who were scheduled for elective abdominal surgery. No other premedication was given. In the operating room, an epidural catheter was inserted at an appropriate level, depending on the site of surgery, between the 7th and 11th thoracic interspace. A test dose of 3 mL of 1.5% lidocaine with epinephrine (1:200,000) was injected into the catheter to exclude subarachnoidal placement and migration into the epidural vein. Before the induction of anesthesia, 50 µg of fentanyl was administered IV, and 2 min later, subjective patient response was elicited. Although the peak response to fentanyl usually occurs at approximately 5 min, we tested the response earlier because peak efficacy was required for intubation. Twenty-three patients reported nausea, sleepiness, dizziness, a sensation of warmth, and other reactions. These patients were categorized as responders (Group R), and the 20 remaining patients, who reported no symptoms, were categorized as nonresponders (Group NR).
After this, general anesthesia was induced with thiopentone (3–4 mg/kg) and fentanyl (50 µg), and tracheal intubation was facilitated with vecuronium (0.1 mg/kg). Anesthesia was maintained with nitrous oxide in oxygen with sevoflurane, combined with a continuous epidural injection of 1.5% lidocaine. At the completion of surgery, epidural fentanyl (50 µg) was administered and continued via an infusion (0.3 mg/d in 0.25% bupivacaine) for 96 h.
Analgesic efficacy was assessed in two ways: at 6 and 24 h after surgery, subjective evaluation of postoperative pain intensity in a state of rest was evaluated by using a visual analog scale (VAS). We also analyzed the frequency of other postoperative analgesic requirements. The incidence of nausea/vomiting, pruritus, sleepiness, and dizziness and the frequency of postoperative antiemetic requirements and respiratory depression, which was defined as a respiratory rate less than 10 breaths/min, were noted during the first 24 h after surgery and were considered as evidence of side effects. The severity of these side effects was rated as follows: 0, no side effect; 1, moderate, no delay in postoperative mobilization; and 2, severe, delayed mobilization. The anesthesiologist who was responsible for the assessment of postoperative pain and side effects was blinded to the response to preoperative fentanyl. Patient characteristics were analyzed with Student’s t-tests, and the frequency of side effects was analyzed with 
2 analysis. VAS scores, the severity of side effects, the frequency of the administration of postoperative analgesics and antiemetic drugs, and time to ambulation were analyzed with the Mann-Whitney U-test. Data are presented as mean ± SD, and P < 0.05 was considered significant.
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Results
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Demographically, except for age, the two groups were comparable (Table 1). Although the difference was not significant, the proportion of women in Group R was larger. In Group R, VAS scores at postoperative Hour 6 were 2.0 ± 2.1 and at postoperative Hour 24 were 1.5 ± 1.2, significantly less than the values for Group NR (3.7 ± 2.3 at 6 h and 3.1 ± 2.0 at 24 h; P < 0.05). Compared with Group NR, patients in Group R required fewer analgesics (0.7 ± 0.9 versus 1.5 ± 1.0; P < 0.05). In Group R, the overall incidence of side effects was 74% (17 of 23), and in Group NR it was 10% (2 of 20) (P < 0.05; Table 2). Moreover, the side effect symptoms were more serious in Group R (Table 3). Although the difference was not significant, Group R patients also required more antiemetics (0.7 ± 1.2) than Group NR (0.2 ± 0.4). Nausea was a common side effect, occurring in 35% (8 of 23) of Group R and 5% (1 of 20) of Group NR patients. Severe nausea with vomiting was restricted to Group R (26%; 6 of 23). Pruritus occurred in 30% (7 of 23) of Group R and 10% (2 of 20) of Group NR patients. No respiratory depression (respiratory rate <10 breaths/min) was observed in the two patients in Group R who became sedated. For six patients in Group R, postoperative ambulation was delayed because of either fentanyl-induced nausea/vomiting or sedation (Table 3). By contrast, all patients in Group NR were ambulatory on postoperative Day 1.
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Discussion
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Small doses of fentanyl have often been used to reduce the hemodynamic response to laryngoscopy and tracheal intubation during the induction of general anesthesia (2,3) . In even smaller doses, however, fentanyl can produce coughing, nausea, dizziness, and other detrimental side effects (4). The incidence and severity of these side effects, as well as the analgesic efficacy of epidural opioids, is quite likely due, mainly, to individual susceptibility. By evaluating the individual response to a small preoperative dose of IV fentanyl, in this study we investigated whether it is possible to predict the degree of pain relief and the incidence of side effects in patients who would be receiving postoperative epidural fentanyl. A dose of 2 µg/kg given five minutes before tracheal intubation, which is consistent with the peak analgesic effect, has been reported as the most effective fentanyl dosage for reducing hemodynamic response to tracheal intubation (3). Rather than hemodynamic effect, in this study we focused on fentanyl sensitivity, and we assumed that a dose of 50 µg (approximately 1 µg/kg) given two minutes before starting normal tracheal intubation procedures would be sufficient to evoke evidence of individual susceptibility to fentanyl.
Postoperative VAS scores and the frequency of analgesic requirements in Group R were less than in Group NR. Compared with Group NR, patients in Group R, although they more frequently and severely suffered from side effects, experienced better pain relief. A previous study from our institution, reporting that patients with side effects have less pain, presented results similar to the present study (5). Various pharmacological therapies have been used to reduce the side effects of epidural opioids. For example, although there is a risk that analgesia may not be preserved, naloxone reduces respiratory depression and many of the other side effects of epidural opioids (6). Droperidol-supplemented anesthesia decreases postoperative nausea and vomiting but impairs postoperative mood and feelings of well-being (7). Antiemetic drugs are not sufficiently effective for postoperative nausea and vomiting (8). A previous study has demonstrated that, along with the severity of postoperative pain, the reduction of epidural fentanyl dosage had some effect in reducing the incidence of side effects (5). For morphine, whereas the analgesic effect has been shown to reach a plateau, the incidence of side effects continues to increase along with larger doses (9). Similarly, if epidural fentanyl lessens pain but produces side effects, it could be due to overdosage. The practical strategy then becomes the administration of an appropriate analgesic dose. If the appropriate fentanyl dosage varies from person to person because of individual susceptibility to the effects of opioids, personal sensitivity may be predicted by evaluating the response to a small test dose of IV fentanyl.
The goal of postoperative epidural opioids is to provide sufficient pain relief and, without side effects, to achieve early ambulation (10). For approximately a quarter of the patients in Group R, postoperative ambulation was delayed because of side effects. By contrast, all the patients in Group NR were mobile on postoperative Day 1.
Our findings suggest that individual susceptibility is the major cause of different responses. The NR group was significantly older, but for older people, smaller doses of opioids are usually effective. This suggests that the older age of Group R was not in itself a major predictive factor. Neither was sex predictive. The larger proportion of women in Group R was too small to be considered significant. Other studies (11,12) have found women to be more susceptible to postoperative nausea and vomiting; the findings of our study cannot be construed as corroborating evidence. Even though epidural opioids provided sufficient pain relief, the severity of subsequent side effects may have contributed to delayed ambulation. If this is the case, to reduce side effects, it would be sensible to tailor the fentanyl dosage to the individual.
Uhl et al. (13) altered the gene for the µ-opiate receptor in several mouse strains to reflect the genetic variations seen in people. Mice expressing fewer receptors were more sensitive to baseline and needed more morphine to quell pain. In fact, mice with half the usual number of receptors had half the response, indicating a direct dose response. The report suggested that receptor measurement before surgery could be used to predict patient response to opioid analgesia and to improve the management of chronic pain (14).
Such types of assessment may one day become practical. The method reported here, however, is easy to use in clinical situations. Further studies of the correlation between the response to a small dose of fentanyl and the incidence and severity of side effects will contribute to practical evaluation of the likely individual response to the therapeutic administration of fentanyl.
In summary, in this study we have demonstrated that a small test dose of fentanyl given during the induction of anesthesia enables prediction of the analgesic efficacy of postoperative epidural fentanyl and of the incidence and severity of side effects. If physicians take individual variation into account, we can use epidural analgesia to provide efficient pain relief, reduce side effects, and improve patient outcome.
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References
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Accepted for publication December 17, 2002.
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Abstract
Introduction
