The demonstration of opioid receptors outside the central nervous system (1,2) has led to the study of the efficacy of combining opioids and local anesthetics for peripheral nerve blocks. Numerous studies assessing the analgesic efficacy of opioids in the brachial plexus have been published. Opioids evaluated include morphine, fentanyl, alfentanil, sufentanil, buprenorphine, and butorphanol. The results of these trials are inconclusive, some showing a benefit (3–10) and others showing no effect (11–17). No study has evaluated the use of opioids in the brachial plexus in a dose-dependent manner. The aim of this prospective, randomized, double-blinded study was to evaluate the effect of the addition of 5, 10, and 20 μg sufentanil to mepivacaine 1.5% on the onset and duration of sensory and motor anesthesia in axillary plexus block.
After institutional ethics approval and written, informed consent, 92 patients (ASA grades I and II) undergoing carpal tunnel release under axillary plexus block were enrolled in the study. Patients with conditions precluding brachial plexus block (local infection, coagulopathy) were excluded.
All brachial plexus blocks were performed with 40 mL 1.5% mepivacaine. In addition, patients were randomly allocated to receive either saline (Group 1, n = 20), 5 μg sufentanil (Group 2, n = 20), 10 μg sufentanil (Group 3, n = 20), or 20 μg sufentanil (Group 4, n = 20) in the axillary plexus block. Sufentanil was diluted so that the injected volume was the same in all groups.
All patients were not premedicated and received no sedation before the axillary plexus block, all of which were performed in the following manner. The axillary crease was identified and a 22-gauge insulated needle connected to a peripheral nerve stimulator (Stimuplex® Dig; Braun, Melsugen, Germany) was used to identify the median nerve. The evoked motor activity elicited included wrist, second and third finger flexion, and pronation. A stimulus intensity of ≤0.5 mA was required before the injection of the local anesthetic solution. All patients received a single injection of 40 mL 1.5% mepivacaine. In addition, in all groups, the intercostobrachial and median (brachial and antebrachial) nerves were blocked by 5 mL 2% lidocaine injected subcutaneously on both sides of the axillary artery. All blocks were performed by one of the authors, who was blind to the solution used. Likewise, a blind observer performed assessment of the block.
Demographic data recorded included sex, age, weight, height, and ASA physical status. After performance of the block (T0), both motor and sensory components of the block were assessed every 5 min for 30 min and thereafter on arrival in the postoperative care unit and on discharge from the hospital. Not only were sensory and motor assessments made on each nerve, but also the time point at which all four nerves were blocked was recorded. Sensory assessment included the response to light touch in each of the four nerve distributions in both the arm and the forearm. The response was scored according to the following scale (0 = no perception, 1 = reduced sensation, and 2 = normal sensation). Likewise, each of the motor components of the four nerves was assessed (ulnar nerve, opposition of the thumb; median nerve, wrist flexion; musculocutaneous nerve, elbow flexion; radial nerve; and elbow and wrist extension). The motor block was scored on a similar scale (0 = absence of movement against gravity, 1 = partial movement against gravity, or 3 = absence of motor block). Onset of sensory and motor block for the four nerves was recorded. Duration of motor block was defined as the time of complete motor block to the restoration of full mobility of the hand and wrist as assessed by the patient. Sensory duration was defined as the time from complete block to restoration of sensation at the site of the operation. Heart rate, SpO2, and blood pressure were measured before the axillary plexus block and every 5 min for 15 min and thereafter every 30 min for 2 h. In addition, respiratory rate was recorded every 30 min for a period of 150 min after T0. The presence and severity of systemic side effects of opioid use (pruritus, somnolence, nausea, and vomiting) were documented.
Previous studies by our group using an equivalent dose of mepivacaine demonstrated an onset time for complete motor blockade of 20 ± 10 min (mean ± SD) with a duration of sensory block of 247 ± 30 min and motor block of 218 ± 25 (mean ± SD) (18). We sought a clinically relevant difference of 7 and 30 min for onset and duration of motor and sensory block, respectively, in the sufentanil groups, using a power of 90% and with an α risk of 0.05. The homogeneity of the demographic data of the four groups was tested by using the Student’s t-test with Bonferroni’s correction for continuous data and by using χ2 analysis for categorical data. Heart rate, mean arterial pressure, respiratory frequency, and SpO2 were compared among groups using analysis of variance for repeated measures. P < 0.05 was considered significant throughout.
Ninety-two patients were included in the study. Twelve patients were excluded because of the need for supplemental analgesia. This consisted of an additional block required for the surgical procedure. The groups were similar with respect to age, weight, height, sex, and ASA physical status (Table 1). Groups 2 (5 μg sufentanil) and 4 (20 μg sufentanil) had a significant prolongation of onset time for sensory block in the ulnar nerve distribution as compared with the control group. Furthermore, in Group 4, the duration of motor block was significantly decreased in comparison to the control group. Mean onset times for a four-nerve block were similar in all groups.
There was an inverse relationship between the amount of sufentanil added to the axillary plexus block and the duration of sensory and motor anesthesia. Duration of sensory block was longest in the control group, 241 (188–284) min as compared with 233 (150–315) min in Group 2, 220 (143–312) min in Group 3, and 216 (115–315) min in Group 4; however, this difference was not statistically significant (P = 0.43). Likewise, duration of motor block was longest in the control group, 234 (128–305) min versus 211 (101–345) min and 200 (100–260) min in Groups 2 and 3, respectively (Table 2). However, duration of motor block was significantly reduced only in Group 4 compared with Group 1 at 172 (115–260) min (P < 0.01). Cardiovascular and respiratory variables were similar in all groups. No respiratory depression was noted in any patient. Reported side effects were more frequent in the patients who received sufentanil. All side effects were considered mild and of short duration. Only one patient in one of the sufentanil groups had an episode of vomiting (Table 3).
The most important finding of this study is that the addition of sufentanil to the axillary plexus block in a dose-dependent manner did not increase the efficacy of the block, either in terms of speed of onset or increasing the duration of the sensory or motor block. The onset of sensory anesthesia was prolonged in Groups 2 and 4. Indeed, paradoxically, the duration of both sensory and motor anesthesia was longest in the control group (Group 1). There was a significant reduction in the duration of motor block in patients who received 20 μg sufentanil (Table 2).
Although the presence of peripheral opioid receptors in human primary afferent neurons and peripheral sensory nerve fibers is well documented (19,20), their mechanism of action remains unclear. The proposed antinociceptive actions of peripherally administered opioids include a nonspecific, local, anesthetic-like effect. This includes a decrease in K + conduction and an increase in Ca2+conduction in the cell body of the sensory neuron (21–23). This reduces excitability of the nociceptive neuron and attenuates the propagation of the action potential. Opioids also inhibit the release of the excitatory neurotransmitter substance P from the peripheral sensory nerve endings (24). Finally, perineurally administered opioids may have a central action caused by the centripetal movement of opioids by opioid binding proteins from the periphery to the dorsal horn (25,26).
In 1997, Picard et al. (17) undertook a review of all published randomized controlled trials assessing the analgesic efficacy of peripheral opioids (excluding meperidine and intraarticular opioid use). They identified 10 randomized trials assessing the use of opioids in the brachial plexus. Of these trials, only five demonstrated a benefit. Several of these positive trials were judged to be either methodologically deficient or of questionable clinical relevance. Gobeaux et al. (7) demonstrated a reduction in the onset of a brachial plexus block by five minutes in patients who received 10 μg fentanyl in the axillary plexus block. This finding, although statistically significant, is of doubtful clinical relevance. The effect of the addition of 5 mg morphine (IV or in the brachial plexus) was studied by Bourke et al. (4). Patients in both groups in this study had similar postoperative pain scores, with minimal differences in postoperative analgesic consumption. Gormley et al. (8) studied the effect of the addition of 10 μg/kg alfentanil to the brachial plexus. Although they reported a prolonged sensory and motor block in the opioid group, this did not result in an improvement in the quality of postoperative analgesia. A further study compared the addition of buprenorphine and morphine to the brachial plexus (3). The authors found the duration of analgesia was longer in the buprenorphine group. The results of this study are difficult to interpret because there was no control group. The methodological quality of the trials were scored by Picard et al. (17) on a scale of one to five. Their review revealed that negative trials had a higher quality score (2 or greater), whereas those trials that reported a positive result had a lower score (2 or less). Higher quality trials were more likely to be associated with a negative result.
To date, there are two randomized controlled trials published assessing the analgesic efficacy of sufentanil in the brachial plexus. The first of these trials by Bazin et al. (6) showed a two-fold prolonged duration of postoperative analgesia after the addition of 0.2 μg/kg sufentanil to a lidocaine and bupivacaine mixture. Unfortunately, because the control group received no opioids, the effect of systemic absorption of opioids on the prolonged duration of analgesia cannot be eliminated. Furthermore, it was not reported whether this difference in duration of analgesia resulted in a decrease in postoperative analgesic consumption in the opioid group. It is interesting to note in this study that, in the sufentanil group (n = 20), eight patients had a duration of analgesia that did not exceed that of the control group. The same authors performed a similar study comparing the effects of adding 75 μg/kg morphine, 3 μg/kg buprenorphine, or 0.2 μg/kg sufentanil to a similar axillary plexus block (6). The addition of opioids to the brachial plexus was associated with a prolongation of analgesia, which was most pronounced in the sufentanil group (24.5 vs 11.5 hours control). Again, the control group did not receive any form of opioids, and thus, the possible systemic effect of the opioid in prolonging the duration of analgesia cannot be excluded.
Our study was homogenous, in that all patients had the same surgical procedure and blocks were performed by one of the authors. We added more sufentanil to the axillary plexus block than Bazin et al. (6); however, we were unable to demonstrate any benefit. These contradictory results are difficult to compare, because not only was the site of brachial block different (axillary versus supraclavicular), the local anesthetics used were different (mepivacaine versus lidocaine/bupivacaine). Furthermore, we demonstrated that, paradoxically, the addition of opioids decreased the duration of sensory and motor block (Table 2). The duration of anesthesia was longest in the control group. We hypothesized that the addition of sufentanil may have resulted in a change in the pH of the mepivacaine solution and, thus, an alteration in the duration of block. However, using a pH meter, we found that at both 37°C and 21°C the addition of saline and 5, 10, and 20 μg sufentanil did not alter measured pH of the mepivacaine solution. The reasons for this inverse-relationship finding remain to be elucidated. Because our patients were all day-case surgical patients and discharge occurred within hours of surgery, we did not measure visual analog scores because of organizational reasons; however, we chose to measure the efficacy of the block for duration of sensory and motor blockade.
To date, the results of clinical trials assessing the use of opioids in the brachial plexus are inconclusive. These differences may be explained by the heterogenicity of the studies, small study samples, the differences in opioid used, the site of brachial-brachial block (interscalene, supraclavicular versus axillary), the difference in the surgery performed, the presence of an acute inflammatory process, and the methodological differences in study design. Furthermore, at the level of the plexus, the axon is covered in a myelin sheath, and thus, unlike inflamed tissue, or the peripheral sensory neuron, the drugs do not easily reach opioid receptors. Opioid receptors themselves may have varying functional activity, and thus axonal receptors may be less effective than receptors at nerve endings (1,2). Individual variability is often reported, and this may explain the conflicting results seen in previous trials.
The physiochemical properties of the opioids may be important. Both liposolubility and pKa will determine the amount of nonionized opioid that will cross the myelin sheath. However, this alone does not explain why sufentanil, which is an extremely lipid soluble, was ineffective in our study, whereas morphine, which is a poorly lipid soluble, has been reported to be effective (3). The choice of local anesthetic may play a role. Negative results have been reported for lidocaine (11) and bupivacaine (12). No study using an opioid mepivacaine mixture has demonstrated a prolonged duration of analgesia (9,16). The reason for this is unclear and should form the basis of further studies.
In keeping with previous studies, the addition of an opioid to the axillary plexus block in our study was associated with an increase in opioid-related side effects (5,22) reported in 11, 12, and 11 patients in Groups 2, 3, and 4, respectively. In contrast, side effects were reported in only two patients in the control group. The most frequent side effect reported was somnolence. Although this was more common in the sufentanil groups, there was no association between the incidence of somnolence and the dose of sufentanil. There was a clear dose-related trend in the increase in nausea in patients who receives sufentanil. Nausea occurred in four patients each in Groups 3 and 4 as opposed to one patient each in Groups 1 and 2. One patient in Group 4 vomited. These side effects were mild and self limiting (Table 3).
Our results would suggest that the addition of sufentanil to the axillary plexus block did not improve the efficacy of the block. The addition of 5, 10, and 20 μg sufentanil to 1.5% mepivacaine in the brachial plexus was associated with neither a faster onset nor a prolongation of either sensory or motor block. Patients who received sufentanil had an increased incidence of opioid-related side effects.
We would like to thank Dr. Jean Xavier Mazoit for statistical assistance.
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© 2000 International Anesthesia Research Society
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