REGIONAL ANESTHESIA AND PAIN MEDICINE
Opiates are widely known to have an antinociceptive effect at the central and/or spinal cord level (1). However, evidence has begun to accumulate that opioid antinociception can be initiated by activation of peripheral opioid receptors (2). The presence of peripheral opioid receptors is shown in immune cells and primary afferent neurons in animals (3,4). If peripheral opioid administration improves regional anesthesia without centrally mediated side effects, it would be useful in clinical practice. However, the effects of opioids on regional blockade are controversial. The addition of opioids in brachial plexus block is reported to improve success rate and postoperative analgesia by some authors (5–7), whereas others have found no effect (8,9). It is still unclear whether these effects, if they exist, result from a truly peripheral rather than from a central site of action, because peripheral uptake of opioids into the circulation and transport to the central nervous system can not be excluded.
The purposes of the current study were to determine whether the addition of fentanyl to a brachial plexus block improves success rate and postoperative analgesia and whether fentanyl has central nervous system-mediated effects during brachial plexus block.
We studied 66 ASA physical status I or II patients who were scheduled for elective hand and forearm surgery under axillary brachial plexus block. Written, informed consent was obtained from each patient before surgery, and the protocol was approved by the institutional ethics committee. Patients with any conditions precluding axillary block (i.e., local infection or abnormal coagulation) and those receiving preoperative narcotics were excluded from the study. The patients were premedicated with an IM injection of 0.5 mg atropine and 2.5 mg midazolam 30 min before admission into the operating room. After insertion of an IV catheter, axillary brachial plexus block was performed by following Winnie’s method (10). The patient was placed supine with the arm abducted 90° so as to identify the pulse of the axillary artery proximal to the axilla. After disinfection, the skin was punctured with a 23-gauge, short-bevel needle inserted parallel and close to the artery and directed toward the apex of the axilla. Indications of a correct cannula position were either a fascial click or paresthesia of the forearm or hand. All blocks were performed by an experienced anesthesiologist. A nerve stimulator was not used.
On the morning of surgery, patients were randomized into three groups by means of 66 randomly allocated cards. The patients and the anesthesiologist were unaware of group assignment. In a double-blinded manner, Group 1 patients (n = 22) received 40 mL of 1.5% lidocaine with 1:200,000 epinephrine containing 2 mL of normal saline for axillary brachial plexus block plus 2 mL of normal saline IV. Patients in Group 2 (n = 22) received 40 mL of 1.5% lidocaine with 1:200,000 epinephrine containing 100 μg fentanyl for axillary brachial plexus block plus 2 mL of normal saline IV. Group 3 patients (n = 22) received 40 mL of 1.5% lidocaine with 1:200,000 epinephrine containing 2 mL of normal saline for axillary brachial plexus block plus 100 μg fentanyl IV. These solutions were prepared by a colleague who took no further part in the study. The pH of the mixed solutions in each group was measured by using a pH meter.
The onset time of the sensory blockade, defined as the time between injection and the total abolition of the pinprick response, was evaluated in four nerve areas (median, ulnar, radial, and musculocutaneous) at every minute until 40 min after the injection. The block was judged to have failed if anesthesia was not present in two or more peripheral nerve distributions. In case of blockade failure, the patient was excluded from the study and replaced in the randomization list by resetting the card. In the case of the requirement for further supplemental analgesia during surgery, an infiltration of 1% lidocaine was applied to surgical area. The durations of sensory blockade (the time between the injection and the complete recovery from sensory disturbance) and analgesia (the time between the injection and the onset of pain) were also recorded. Motor blockade was determined by measuring the gripping force with a dynamometer 10 min after the injection, as described by Kanaya et al. (11).
The results were expressed as mean ± sd. Statistical analysis for continuous variable were evaluated by using one-way analysis of variance followed by Fisher’s protected least significant difference by using StatView 228 (SAS Institute Inc., Cary, NC). Statistical analysis for the onset of the block was performed by using survival analysis (Kaplan-Meier curves) and one-way analysis of variance. To compare the success rate of block, the overall significance of the 2 × 3 contingency table was tested followed by a Fisher’s exact test. Differences were considered to be statistically significant when P values were <0.05.
Of the 69 patients recruited, 3 were withdrawn because of failure of the block. The mean ages, weights, and heights of patients and the duration of surgery were similar in all three groups (Table 1). The success rate of sensory blockade (the complete abolition of the pinprick response) for each nerve trunk is shown in Table 2. The addition of fentanyl to axillary brachial plexus block caused a higher success rate in radial and musculocutaneous nerve trunks (P = 0.02). IV fentanyl did not improve the success rate in any of the nerve trunks. One patient in each group had paresthesias during needle placement. No patient complained of nerve deficit after surgery.
The time to onset of sensory blockade is shown in Figure 1. The addition of fentanyl to axillary brachial plexus block prolonged the onset of analgesia in every nerve trunk (P < 0.01). However, the systemic administration of fentanyl had no effect on the onset of analgesia.
The durations of sensory blockade and analgesia in the axillary fentanyl group were significantly longer (323 ± 96 and 295 ± 85 min for the duration of sensory blockade and analgesia, respectively) than those in the other groups (250 ± 79 and 215 ± 78 min in Group 1 and 230 ± 65 and 210 ± 62 min in Group 3 for the duration of sensory blockade and analgesia, respectively). The gripping forces significantly decreased (P < 0.01) 10 min after the injections, and there were no significant differences among the three groups (Table 3).
In a different set of experiments, the pH of lidocaine solutions were measured. At room temperature, the pH was 6.2 ± 0.1 (n = 4) in 1.5% lidocaine solution containing 1:200,000 epinephrine. It was decreased to 5.2 ± 0.1 (n = 4) by adding 100 μg fentanyl
This study demonstrated that the addition of fentanyl to 1.5% lidocaine with 1:200,000 epinephrine for axillary brachial plexus block increased the success rate of sensory blockade for radial and musculocutaneous nerves and prolonged the duration of blockade. However, the onset time of analgesia was prolonged in every nerve trunk by adding fentanyl to axillary brachial plexus block. Systemic fentanyl had no effect on the success rate, onset, or duration of blockade in any of the four nerves.
In animals, the presence of peripheral opioid receptors has been reported (2–4); however, it is still unclear whether functional opioid receptors exist in human peripheral tissue. Several studies have attempted to determine whether the addition of opioids to local anesthetics would improve the efficacy of peripheral nerve blocks. Morphine and buprenorphine are reported to cause profound analgesia for brachial plexus block with or without local anesthetic (6,7). Similar findings were observed with the perineural injection of morphine (12). Mays et al. (12) reported that perineural morphine provided longer lasting pain relief than did either IM morphine or perineural bupivacaine in patients with chronic pain. Conversely, morphine and fentanyl were reported to have had no additional effect when they were added to axillary brachial plexus block (8,9). Racz et al. (9) observed that the addition of morphine to a local anesthetic solution (a mixture of plain lidocaine and plain bupivacaine) for axillary block changed neither the onset time nor the quality of postoperative pain relief. Fletcher et al. (8) suggested that the addition of fentanyl to lidocaine with 1:200,000 epinephrine for axillary brachial plexus block produced no clinical benefit except for faster onset in the musculocutaneous nerve trunk. These conflicting results are probably caused by differences in opioids, anesthetics, or techniques for nerve blockade. Most importantly, the lack of comparison between systemic and peripheral opioid administration would cause confusion as to the site of effect of the opioid.
In our study, the addition of fentanyl to lidocaine for axillary brachial plexus block improved the success rate of sensory blockade. In contrast, Fletcher et al. (8) reported that no changes were observed in the success rate, onset time, or duration of analgesia by axillary fentanyl administration. Because neither of these reports included an axillary fentanyl alone group, it is rather difficult to evaluate the pure peripheral opioid receptor-mediated effect. However, local anesthetic is required to obtain surgical anesthesia. Fletcher et al. (8) used a nerve stimulator to localize the nerve plexus. Although a nerve stimulator is useful to accurately place the needle near the plexus, we did not use one, to minimize irritation or discomfort. In addition, Fletcher et al. (8) did not mention the pH changes in their anesthetic solution. Because it is widely known that pH plays a role in the onset of local anesthetics (10,11), the changes in pH of an anesthetic solution can alter the quality of brachial plexus block. These discrepancies may offer an explanation for the different results between their study and ours.
We postulate three possible mechanisms of action for the improved analgesia produced by the peripheral application of fentanyl. First, fentanyl could act directly on the peripheral nervous system. Primary afferent tissues (dorsal roots) have been found to contain opioid binding sites (4). Because the presence of bidirectional axonal transport of opioid binding protein has been shown (13), fentanyl may penetrate the nerve membrane and act at the dorsal horn. This could also account for the prolonged analgesia. However, fentanyl is reported to have a local anesthetic action (14). Gormley et al. (5) suggested that alfentanil also prolonged postoperative analgesia by local anesthetic action. However, it is unlikely that the small-dose of fentanyl (100 μg) used in our present study could have a local anesthetic action because a higher concentration (50 μg/mL) is required in vitro (14). Second, fentanyl may diffuse from the brachial plexus sheath to epidural and subarachnoid spaces and then bind with the opioid receptor of the dorsal horn, but it is unclear from this study whether a sufficient dose of fentanyl diffused to the epidural or subarachnoid spaces to cause adequate analgesia. To clarify this issue, the spinal fluid fentanyl concentrations should be measured. Third, fentanyl may potentiate local anesthetic action via central opioid receptor-mediated analgesia by peripheral uptake of fentanyl to systemic circulation. However, this mechanism is unlikely because the systemic application of fentanyl had no effect on axillary brachial plexus block in the present study.
In our study, the addition of fentanyl to lidocaine with 1:200,000 epinephrine caused a delayed onset of analgesia. We hypothesized that the changes in pH of anesthetic solution could be responsible for this effect. The onset time of local anesthetics is greatly influenced by the relative amounts of ionized and nonionized forms present. Only the nonionized form of lidocaine can diffuse through interstitial tissues and nerve membranes. The fraction of the nonionized lidocaine is increased by elevating the pH. Kanaya et al. (11) reported that alkalinized lidocaine solution for axillary brachial plexus block caused a faster onset of analgesia. In the present study, the pH of lidocaine solution was decreased from 6.2 to 5.2 by the addition of fentanyl. This may have reduced the rate of nerve membrane penetration of lidocaine, resulting in the slower onset of analgesia. To confirm this hypothesis, further studies are required comparing the effect of fentanyl on brachial plexus block by using different pH solutions.
In conclusion, the addition of small-dose fentanyl to lidocaine solution in axillary brachial plexus block can increase the success rate and prolong the duration of analgesia, but it delays the onset time of sensory blockade as compared with the same dose of commercial lidocaine.
1. Yaksh KL. Multiple opioid receptor systems in brain and spinal cord. Eur J Anaesthesiol 1984; 1:171–3.
2. Stein C. Peripheral mechanisms of opioid analgesia. Anesth Analg 1993; 76:182–91.
3. Sibinga NES, Goldstein A. Opioid peptides and opioid receptors in cells of the immune system. Annu Rev Immunol 1988; 6:219–49.
4. Fields HL, Emson PC, Leigh BK, et al. Multiple opiate receptor sites on primary afferent fibres. Nature (Lond) 1980; 284:351–3.
5. Gormley WP, Murray JM, Fee JPH, Bower S. Effect of the addition of alfentanil to lignocaine during axillary brachial plexus anaesthesia. Br J Anaesth 1996; 76:802–5.
6. Sanchez R, Nielsen H, Heslet L, Iverse AD. Neuronal blockade with morphine: a hypothesis. Anaesthesia 1984; 39:788–9.
7. Viel EJ, Eledjam JJ, de la Coussaye JE, D’athis F. Brachial plexus block with opioids for postoperative pain relief: comparison between buprenorphine and morphine. Reg Anesth 1989; 14:274–8.
8. Fletcher D, Kuhlman G, Samii K. Addition of fentanyl to 1.5% lidocaine does not increase the success of axillary plexus block. Reg Anesth 1994; 19:183–8.
9. Racz H, Gunning K, Santa DD, Forster A. Evaluation of the effect of perineuronal morphine on the quality of postoperative analgesia after axillary plexus block: a randomized double-blind study. Anesth Analg 1991; 72:769–72.
10. Winnie AP. Axillary perivascular technique of brachial plexus block: plexus anesthesia. vol 1. Edinburgh: Churchill Livingstone, 1983: 121–31.
11. Kanaya N, Imaizumi H, Matsumoto M, et al. Evaluation of alkalinized lidocaine solution in brachial plexus blockade. J Anesth 1991; 5:128–31.
12. Mays KS, Lipman JJ, Schnapp M. Local analgesia without anesthesia using peripheral perineural morphine injections. Anesth Analg 1987; 66:417–20.
13. Laduron PM. Axonal transport of opiate receptors in capsaicin-sensitive neurones. Brain Res 1984; 294:157–60.
© 2000 International Anesthesia Research Society
14. Gissen AJ, Gugino LD, Datta S, et al. Effects of fentanyl and sufentanil on peripheral mammalian nerves. Anesth Analg 1987; 66:1272–6.