The purpose of this article is to systematically review the current evidence for the analgesic benefit of adding opioids, tramadol, clonidine, and neostigmine to brachial plexus block. Epinephrine and bicarbonate have also been used as adjuncts to brachial plexus block, epinephrine to prolong duration, and bicarbonate to hasten onset. The use of these two drugs has been adequately discussed in the literature (1), and thus, they were not considered further. The addition of analgesic adjuncts to spinal and epidural anesthesia enhances postoperative analgesia and, when combined with smaller concentrations of local anesthetic drugs in the postoperative period, may reduce adverse effects, such as motor, sensory, and autonomic block (2).
The observation that these drugs have analgesic effects at the spinal level has stimulated research to examine whether they also have analgesic effects in the periphery. A variety of receptors mediate nociception on peripheral sensory axons, and the peripheral administration of appropriate drugs may have analgesic benefit and reduce systemic adverse effects (3). Studies examining the benefit of adding analgesic adjuncts to brachial plexus block have produced mixed results. The mechanism of action of these analgesics remains unclear. It may be by a direct local action on the nerve itself, facilitation of local anesthetic action, or systemic absorption. Previous studies have shown large variations in design that have made interpretation difficult. Most studies addressed the question of whether analgesic adjuncts prolong regional analgesia when added to local anesthetics for brachial plexus block. By adding a systemic analgesic control group, more recent studies have extended the question of whether the analgesic effect is a local or systemic effect. The administration of adjuncts to local anesthetics in brachial plexus block must demonstrate prolonged analgesic efficacy over systemic administration, if they are to be useful in clinical practice. This review will examine these two questions.
Studies were identified in a search of MEDLINE (between July 1966 and December 1999) and EMBASE (from 1980) by using the following MeSH terms: brachial plexus block or nerve block, clonidine, opioids, morphine, fentanyl, sufentanil, alfentanil, tramadol, and neostigmine. The reference section of eligible articles were then examined for relevant publications that may have been omitted by computer search. All abstracts, letters, and nonpeer-reviewed publications were excluded from consideration. Individual authors were not contacted to obtain further information.
Relevant studies included all studies that analyzed the effect of novel analgesic adjuncts with local anesthetic in brachial plexus block. Of the 24 studies identified, only those that were prospective, randomized, controlled, and double-blinded were selected for further analysis: Selected studies also included a measure of postoperative pain (visual analog scale [VAS], verbal response scale, time to first analgesic, or total analgesic consumption). In addition, for each study, the regional anesthetic technique, concentration and volume of local anesthetic, type and dose of adjunct, and type of surgery were recorded. We independently reviewed each study by using these criteria, and results are summarized in Tables 1 and 2. In addition, each study was assessed for appropriate statistical analysis. Studies were classified as “supportive” if the use of the adjunct demonstrated significant analgesic benefit versus control and “negative” if they did not (Table 3).
Studies using analysis of postoperative motor and sensory block without analysis of pain were excluded from the main analysis; however, they are described in Table 4. Each study was assessed for appropriate recording, analysis, and interpretation of adverse effects. When adverse effects were statistically analyzed, the result was recorded. Adverse effects not statistically analyzed were not included. In addition, all studies using a systemic control group to differentiate systemic from peripheral effect of the analgesic adjunct were commented on separately.
A total of 24 studies, all of adults, were considered for inclusion. Only three studies were not blinded (4–6) and were excluded. An additional four studies did not assess postoperative pain (7–10) and were excluded from the main analysis, although their results have been included in Table 4 to allow further examination.
In the remaining 17 studies, five included a systemic analgesic control group. Studies using a systemic control group included four with opioids and one with clonidine. The total number of patients was 796. The efficacy of adjuncts was assessed in a variety of surgical settings, and the brachial plexus block was performed by axillary (11), supraclavicular (5), and interscalene (1) approaches. Opioids used included morphine (5), fentanyl (1), alfentanil (1), buprenorphine (2), butorphanol (2), and sufentanil (2). Other drugs included clonidine (6) and neostigmine (1). Of the 12 supportive studies only three had a systemic control group. There were five negative studies overall, two of which had systemic control.
Randomized, Controlled Trials Using Opioid with Systemic Control
Of five studies examining the effect of morphine in brachial plexus block, two studies had systemic control. Bourke and Furman (11) evaluated the addition of morphine 0.1 mg/kg or saline to lidocaine 1.5% plus epinephrine 5 μg/mL for axillary block. There were no differences in VAS scores in the first 24 h; however, patients who had morphine added to the axillary block consumed significantly fewer oral analgesics than control.
Racz et al. (12) randomized 40 patients to have an axillary brachial plexus block with lidocaine and bupivacaine (20 mL of 1% lidocaine + 20 mL of bupivacaine 0.5%) and morphine 5 mg in the brachial plexus block or as an IM injection. The addition of morphine to the axillary block did not provide improved analgesia when compared with the systemic control group.
Fentanyl added to supraclavicular block showed a significant decrease in VAS for the fentanyl group at 1 h after surgery (13). This decrease was not sustained in the 10 patients per group, and there was no overall clinical benefit when compared with the IV fentanyl group.
Butorphanol without local anesthetic was administered at a rate of 83.3 μg/h as a postoperative axillary infusion. We noted decreased pain in patients receiving axillary butorphanol infusion as opposed to systemic administration (14). VAS scores were significantly lower in the axillary butorphanol group between 6 and 24 h in the measured 72 h; however, there were no differences in supplemental analgesic intake between groups.
Randomized, Controlled Trials Using Nonopioid Adjuncts with Systemic Control
Of seven studies examining the effect of clonidine added to brachial plexus block, only one had a systemic control group. Singelyn et al. (15) evaluated 30 patients receiving an axillary brachial plexus block with 40 mL of 1% mepivacaine plus epinephrine 5 μg/mL. Patients were randomized to three groups and received either: 1) local anesthetic alone, 2) local anesthetic plus clonidine 150 μg administered subcutaneously, or 3) clonidine 150 μg in the brachial plexus block with local anesthetic. Clonidine added to the axillary brachial plexus block delayed the onset of pain by twofold, without adverse effects when compared with systemic control. However, the study conclusions are limited by the low number of patients and by the fact that they did not receive identical protocols, for example, only one in three groups received a subcutaneous injection. In addition, there were no differences in maximal postoperative pain scores or supplemental analgesic intake between groups.
Randomized, Controlled Trials Using Opioid Analgesics Without Systemic Control
Bazin et al. (16) reported sustained analgesic effect from opioids used in supraclavicular brachial plexus block which outlasted the local anesthetic action of bupivacaine. Patients (n = 20 per group) reported prolonged satisfactory analgesia with buprenorphine (median 20 h, range 14–34), morphine (21 h, range 9–27) and sufentanil (24.5 h, range 11–38) compared with saline (11.5 h, range 8–15). An earlier study by this group demonstrated prolonged postoperative analgesia after the addition of sufentanil 0.2 μg/kg to supraclavicular block (17) (median 24 h, range 8–48). Butorphanol added to mepivacaine in axillary block produced greater duration of analgesia compared with either mepivacaine or butorphanol alone (18); however, no differences in supplemental analgesic consumption were found between groups. In another study, the addition of buprenorphine 3 μg/kg to bupivacaine with supraclavicular block was reported to prolong significantly the analgesic duration when compared with morphine 50 μg/kg (P < 0.001) (19). This study compared buprenorphine with morphine without using a placebo or systemic control. Other studies reported no improvement in quality of analgesia or patient satisfaction after 5 mg of morphine added to 0.5% bupivacaine 40 mL for supraclavicular block (20) or from the addition of alfentanil to axillary block (21). The addition of alfentanil may have prolonged motor and sensory block when compared with control; however, no clinical analgesic benefit was reported.
Randomized, Controlled Trials Using Nonopioid Adjuncts Without Systemic Control
Small doses of clonidine 30–90 μg in combination with lidocaine administered with axillary block reduced sensory block onset time and significantly prolonged analgesia (P < 0.01) (22). In this study larger doses of clonidine (300 μg) were associated with significant adverse effects. In a similar study, 0.5 μg/kg of clonidine provided an analgesic effect (time to first postoperative pain) that lasted as long as 1.5 μg/kg of clonidine and twice as long as placebo (492 vs 260 min) (23). There were no significant adverse effects, even at a dose of 1.5 μg/kg. The clinical significance of this study is reduced by the fact that there were no intergroup differences in postoperative pain score or analgesic requirement. Buttner et al. (24) noted that both 120 μg and 240 μg clonidine provided prolonged analgesia at the expense of sedation and cardiovascular adverse effects in both groups, whereas others have reported that a total 150 μg clonidine produces prolonged analgesia with minimal adverse effects (P < 0.001) (25). Two studies compared clonidine with epinephrine. One study reported prolonged analgesia with clonidine compared with epinephrine (25). The second found that analgesia was similar in both groups over 18 h except for superior analgesia in the epinephrine group at 6 h (26).
Neostigmine 500 μg added to mepivacaine 500 mg resulted in no overall difference with regard to onset of analgesia or motor function when compared with control. However, the number of patients not requesting pain medication in the first 24 h was significantly lower in the neostigmine group (P < 0.05) and postoperative pain was significantly lower at 24 h (27).
It is not clear whether opioids added to brachial plexus block provide significant analgesic benefit. Overall, of 10 studies examined in this area, six were supportive and four were negative. Of four studies using a systemic control, two were supportive and two were negative. Of the six studies not using systemic control, four were supportive. Studies using an opioid systemic control group were less likely to demonstrate analgesic benefit compared with those that did not. There is minimal evidence for any analgesic benefit of using opioid analgesics in brachial plexus block over systemic administration. In addition, there appeared to be no advantage for reduced adverse effects by the peripheral administration of opioid analgesics.
Only two studies used more than 20 patients per group. Lack of power in studies caused by inadequate sample size may contribute to the continuing controversy about whether opioids have any analgesic benefit in plexus analgesia or whether they have a peripheral analgesic effect. It is also important to measure pain as an outcome when attempting to analyze benefit from the addition of these drugs to brachial plexus block.
There were no serious adverse effects mentioned in any of the studies. Nausea, vomiting, and pruritus occurred both with peripheral and systemic administration of opioids.
Clonidine, in contrast, appears to have an analgesic benefit when administered as an adjunct to brachial plexus block. Of the six studies using clonidine as an adjunct, five were supportive and one was negative. Only one study showed a peripheral analgesic effect using clonidine, which may be outweighed by significant adverse effects including sedation, hypotension, and bradycardia at doses greater than 150 μg.
One study using neostigmine has shown analgesic benefit. However, further studies are required and should use a systemic control group.
The analgesic mechanism of opioids administered into the brachial plexus is unknown. They may activate peripheral receptors or have a peripheral effect at other sites, however, not in a manner consistent with that produced by opioids administered systemically. Few studies addressed a peripheral mechanism in their methodology and this may perpetuate the controversy of the value of opioid administration to the brachial plexus. This needs to be resolved with a randomized, controlled trial using a systemic control group with sufficient power to validate a negative result.
Clonidine has shown greater analgesic potential, and would appear to have analgesic benefit with minimal adverse effects at a dose of up to 150 μg. However, a well designed study using clonidine as an adjunct to local anesthetic with a systemic control group is still required. The evaluation of neostigmine, adenosine, and tramadol will continue in both human and animal studies and may present some exciting possibilities. It is important to include an assessment of postoperative analgesia as an outcome measurement in the design of future studies. Recent data suggest that, with the complexity of neurotransmitters responsible for nociception both at the peripheral and central level, it may be necessary to use combinations of adjuncts to achieve maximal benefit with minimal adverse effects (2).
In summary, evidence for the benefit of using opioids as analgesic adjuncts in brachial plexus block is weak. Clonidine seems to provide analgesic benefit without major side effects at doses of up to 150 μg.
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