Anesth Analg 2000;91:379-383
© 2000 International Anesthesia Research Society
REGIONAL ANESTHESIA AND PAIN MEDICINE
Brachial Plexus Anesthesia with Verapamil and/or Morphine
Scott S. Reuben, MD, and
John P. Reuben, PhD
Department of Anesthesiology, Baystate Medical Center and the Tufts University School of Medicine, Springfield, Massachusetts
Address correspondence and reprint requests to Scott S. Reuben, MD, Department of Anesthesiology, Baystate Medical Center, 759 Chestnut St., Springfield, MA 01199. Address e-mail to scott .reuben{at}bhs.org
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Abstract
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Calcium channel blockers potentiate the analgesic properties of both local anesthetics and opioids. We examined the analgesic effects of administering morphine, verapamil, or its combination into the brachial plexus sheath with lidocaine in 75 patients undergoing upper extremity orthopedic surgery. All patients received brachial plexus anesthesia with 40 mL of 1.5% lidocaine and epinephrine 5 µg/mL. In addition, patients were randomized to 1 of 5 groups: Group 1 received IV saline; Group 2 received IV verapamil 2.5 mg and morphine 5 mg; Group 3 received IV verapamil 2.5 mg and morphine 5 mg was added to the lidocaine solution; Group 4 received IV morphine 5 mg and verapamil 2.5 mg was added to the lidocaine solution; and Group 5 received verapamil 2.5 mg and morphine 5 mg were added to the lidocaine solution. Postoperatively, patients rated their pain (0–10) at 1, 6, 12, and 24 h. Patients were instructed to take 1 acetaminophen 325 mg/oxycodone 5 mg tablet every 3 h whenever the pain score exceeded 3. Analgesic duration was significantly increased in those patients receiving brachial plexus blocks with morphine (Groups 3 and 5) (P < 0.005). The total 24 h acetaminophen/oxycodone use was also less in Groups 3 and 5 (P < 0.03). Duration of anesthesia (time of abolition of pinprick response) was significantly increased in those patients receiving brachial plexus blocks with verapamil (Groups 4 and 5) (P = 0.002). We conclude that the addition of verapamil to brachial plexus block with lidocaine can prolong the duration of sensory anesthesia, but it had no effect on analgesic duration of 24 h analgesic use.
Implications: The addition of verapamil to brachial plexus block with lidocaine and morphine prolongs the duration of sensory anesthesia, but has no effect on analgesic duration or 24 h analgesic use.
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Introduction
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In an attempt to improve perioperative analgesia, a variety of opioids have been administered concomitantly with local anesthetics into the brachial plexus sheath (1–7). The results of these studies have been inconclusive, with some investigators reporting prolonged analgesia (1–4), and others observing no benefit from the use of brachial plexus opioids (5–7). However, the only two studies (5,6) that failed to reveal an analgesic benefit from morphine, used 0.5% bupivacaine as the local anesthetic solution. This may have potentially masked the analgesic effect of morphine. The present study, therefore, was performed to evaluate the analgesic effect of morphine when administered with lidocaine, a shorter-acting local anesthetic.
In addition, we designed this study to further evaluate whether an additional analgesic effect could be derived from the administration of verapamil, a calcium channel blocker, into the brachial plexus sheath. Calcium ions play an important role in opioid-receptor–mediated analgesia. After binding to the µ-opiate receptor, morphine increases potassium permeability and decreases calcium influx in the cell bodies of sensory neurons, which can lead to the inhibition of neuronal transmission (8). One study suggested a pharmacologic role of calcium channel blockers in the modulation of antinociception under acute conditions (9). Several studies suggest that the analgesic effects of opioids might be increased by the concomitant administration of calcium channel blockers (9–15) and that these drugs by themselves may possess analgesic properties (15).
Calcium ions also have an important role in the analgesia mediated by local anesthetics. Calcium permeability is reduced by local anesthetics, and clinical investigations have shown that verapamil can potentiate the analgesic effect of local anesthetics (16).
For these reasons, it is hypothesized that verapamil may potentiate both the local anesthetic properties of lidocaine and the analgesic effect of morphine when administered via the brachial plexus route. This study was designed to determine the analgesic effects of administering morphine and/or verapamil into the brachial plexus sheath with lidocaine for upper extremity orthopedic surgery.
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Methods
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Eighty-two patients scheduled for elective upper extremity orthopedic surgery gave formal, written consent to participate in this double-blind randomized study that was approved by our local committee on human research. We informed the research committee and the patients that verapamil did not have a product license for use in the brachial plexus space, but that many animal studies and several clinical studies used spinal calcium channel blockers.
Patients did not receive any premedication, and perioperative sedation was achieved with IV midazolam (2–5 mg). Opioids were not a component of the intraoperative sedation. After placement of routine ASA monitors, axillary blockade was performed with the patient in the supine position and the upper arm abducted 90° and the elbow flexed at 110°. The axillary artery was palpated and a 22-gauge 5-cm Stimuplex needle (B/Braun, Bethlehem, PA) connected to a nerve stimulator was inserted in the proximal part of the axilla. The needle was considered to be placed correctly when contraction of the biceps or muscle groups in the forearm was seen in response to stimuli of  0.5 mA. All patients received an injection of 40 mL of 1.5% lidocaine with epinephrine 5 µg/mL. In addition, patients were randomized to either 1 of 5 groups: Group 1 (control) received normal saline (NS) 2 mL IV and 2 mL NS was added to the lidocaine solution; Group 2 (IV verapamil/morphine) received a 2 mL solution of verapamil 2.5 mg and morphine 5 mg IV and 2 mL NS was added to the lidocaine solution; Group 3 (brachial plexus morphine) received verapamil 2.5 mg (2 mL) IV and morphine 5 mg (2 mL) was added to the lidocaine solution; Group 4 (brachial plexus verapamil) received morphine 5 mg (2 mL) IV and verapamil 2.5 mg (2 mL) was added to the lidocaine solution; and Group 5 (brachial plexus morphine/verapamil) received 2 mL NS IV and 2 mL of verapamil 2.5 mg and morphine 5 mg were added to the lidocaine solution. All IV solutions were administered after placement of the brachial plexus block and prior to tourniquet inflation. All local anesthetic solutions and adjuvant drugs were prepared by an anesthesiologist not involved in the performance of the block or data collection. Verapamil 2.5 mg was chosen for this study because this dose has previously been shown in human studies to have no analgesic effects by itself, but when used in combination with morphine was shown to potentiate its antinociceptive properties (13).
After performance of the nerve block, patients were evaluated every 5 min until complete sensory block was achieved in the distribution of the radial, ulnar, median, and musculocutaneous nerves. Sensory block was evaluated by the pinprick test. After completion of the surgical procedure, evaluation of the nerve block was performed every 15 min until complete recovery of sensation had occurred. Duration of anesthesia was defined as the time during total abolition of the pinprick response.
Postoperatively, patients were asked to quantify their pain on a integer verbal pain score between 0 and 10, with 0 representing no pain and 10 the worst imaginable pain. Pain scores were recorded at 1, 6, 12, and 24 h after completion of the surgical procedure. On discharge, patients were instructed to take one acetaminophen 325 mg/oxycodone 5 mg tablet every 3 h whenever the verbal pain score > 3. All patients were contacted by telephone the day after surgery. The time from completion of surgery until the patient first required acetaminophen/oxycodone (analgesic duration) was noted, as well as the total number of acetaminophen/oxycodone tablets required during the first postoperative 24 h.
Demographic data were analyzed using analysis of variance. Duration of procedure, time to discharge, anesthetic and analgesic duration, pain scores, and amount of postoperative analgesics were analyzed by using Kruskal-Wallis. If a significant result was obtained, the Mann-Whitney U-test was performed to determine between which groups there was a significance; a Bonferroni adjustment was made for multiple comparisons. A P value of less than 0.05 was considered significant. All data are reported as mean ± SD.
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Results
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Seven of the 82 patients originally included in the trial were subsequently not studied because of incomplete analgesia or discomfort during surgery requiring supplementation with either local anesthesia or IV opioids: two were in Group 1, two in Group 2, and one in Groups 3 to 5. There were no significant differences among the five treatment groups with respect to demographic variables, duration of surgical procedures, discharge times, or perioperative midazolam use (Table 1), or pain scores at all time intervals (Table 2). The time to onset of sensory anesthesia (min) was similar among the five groups: Group 1 (19 ± 9), Group 2 (18 ± 6), Group 3 (22 ± 6), Group 4 (22 ± 8), or Group 5 (20 ± 9). The duration of sensory anesthesia (min) was significantly increased in those patients receiving brachial plexus blocks with verapamil: (Groups 4 [302 ± 22] and 5 [309 ± 37]), compared with Groups 1 (225 ± 35), 2 (205 ± 19), or 3 (210 ± 23) (P = 0.002) (Fig. 1). Analgesic duration (min) was significantly increased in those patients receiving brachial plexus blocks with morphine: [Groups 3 (720 ± 270) and 5 (730 ± 267)], compared with Groups 1 (295 ± 75), 2 (305 ± 56), or 4 (444 ± 127) (P < 0.005) (Fig. 2). There were no significant differences in analgesic duration among Groups 1, 2, and 4. Total 24 h acetaminophen/oxycodone use followed a similar pattern with significantly lower consumption (tablets) in Groups 3 (4.1 ± 2.6) and 5 (3.9 ± 2.0), compared with Groups 1 (8.4 ± 2.3), 2 (8.0 ± 2.9), or 4 (7.1 ± 2.6) (P < 0.03) (Fig. 3).
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Figure 1. Duration of sensory anesthesia in minutes in the five groups. Group 1 (control) received normal saline intravenously (IV); Group 2 (IV verapamil/morphine) received verapamil 2.5 mg and morphine 5 mg IV; Group 3 (brachial plexus morphine) received verapamil 2.5 mg IV and morphine 5 mg was added to the brachial plexus; Group 4 (brachial plexus verapamil) received morphine 5 mg IV and verapamil 2.5 mg was added to the brachial plexus; and Group 5 (brachial plexus morphine/verapamil) received verapamil 2.5 mg and morphine 5 mg into the brachial plexus. Box represents the 25th–75th percentiles, and the median is represented by the solid line. Extended bars represent the 10th–90th percentiles. Solid circles represent values outside this range. The duration of sensory anesthesia was significantly increased in those patients receiving brachial plexus blocks with verapamil: (Groups 4 and 5) compared with Groups 1, 2, or 3; *P = 0.002. There were no significant differences in analgesic duration among Groups 1 to 3.
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Figure 2. Analgesic duration in minutes in the five groups. Group 1 (control) received normal saline intravenously (IV); Group 2 (IV verapamil/morphine) received verapamil 2.5 mg and morphine 5 mg IV; Group 3 (brachial plexus morphine) received verapamil 2.5 mg IV and morphine 5 mg was added to the brachial plexus; Group 4 (brachial plexus verapamil) received morphine 5 mg IV and verapamil 2.5 mg was added to the brachial plexus; and Group 5 (brachial plexus morphine/verapamil) received verapamil 2.5 mg and morphine 5 mg into the brachial plexus. Box represents the 25th–75th percentiles, and the median is represented by the solid line. Extended bars represent the 10th–90th percentiles. Solid circles represent values outside this range. Analgesic duration was significantly increased in those patients receiving brachial plexus blocks with morphine: (Groups 3 and 5), compared with Groups 1, 2, or 4; *P < 0.005. There were no significant differences in analgesic duration among Groups 1, 2, and 4.
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Figure 3. Total 24 h percent (acetaminophen/oxycodone) use in the five groups. Group 1 (control) received normal saline intravenously (IV); Group 2 (IV verapamil/morphine) received verapamil 2.5 mg and morphine 5 mg IV; Group 3 (brachial plexus morphine) received verapamil 2.5 mg IV and morphine 5 mg was added to the brachial plexus; Group 4 (brachial plexus verapamil) received morphine 5 mg IV and verapamil 2.5 mg was added to the brachial plexus; and Group 5 (brachial plexus morphine/verapamil) received verapamil 2.5 mg and morphine 5 mg into the brachial plexus. Box represents the 25th–75th percentiles, and the median is represented by the solid line. Extended bars represent the 10th–90th percentiles. Solid circles represent values outside this range. Total 24 h acetaminophen/oxycodone use was significantly lower in Groups 3 and 5, compared with Groups 1, 2, or 4; *P < 0.03. There were no significant differences in 24 h analgesic use among Groups 1, 2, and 4.
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Discussion
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This study confirms the benefit of adding morphine into the brachial plexus sheath for prolonged postoperative analgesia. The use of morphine in brachial plexus blocks has previously resulted in equivocal results. Some investigators have reported improved postoperative analgesia (2,4), whereas others have reported no significant analgesic benefit (5,6) when morphine was administered into the brachial plexus sheath. These latter two studies, however, used 0.5% bupivacaine as the local anesthetic solution. The use of a long-acting local anesthetic may have produced a prolonged period of analgesia that could have masked the analgesic effect of morphine. Our results, similar to Bourke and Furman (2), revealed a prolonged postoperative analgesic-sparing effect when morphine was added to lidocaine in patients undergoing axillary block. Patients in Groups 3 and 5 who received brachial plexus morphine had a mean duration of analgesia greater than 11.5 h with significantly less opioid use, compared with those patients not receiving morphine. This analgesic effect appears to be peripherally mediated rather than secondary to a systemic analgesic effect. Patients receiving IV morphine (Group 2) failed to demonstrate any additional analgesia when compared with IV saline (control group). Some experimental research indicates that locally administered opioid agonists can produce pronounced analgesic effects by interacting with peripheral opioid receptors (17).
In addition to the beneficial effects of morphine, verapamil was shown to significantly prolong the anesthetic duration of lidocaine in our study. This was evidenced by a longer time during which patients experienced lack of sensation to pinprick when receiving verapamil and lidocaine (Groups 3 and 5), compared with lidocaine alone (control group). Verapamil inhibits various ionic processes, and its analgesic effects are complex. Verapamil blocks the slow inward transmembrane ionic current carried by calcium and/or sodium in cardiac and vascular smooth muscle (18). It also induces fast channel-blocking effects similar to local anesthetics, and alters neuromuscular transmission (19). A series of in vitro experiments on the rat sciatic nerve revealed that verapamil inhibits fast channel activity in a dose-dependent manner and was equipotent to procaine as a local anesthetic (20). Verapamil has also been shown to potentiate the effects of other local anesthetics. When administered via the intrathecal route, verapamil prolonged the anesthetic effect of both lidocaine and tetracaine in a synergistic manner (16). When administered via the epidural route, the combination of verapamil and bupivacaine resulted in less postoperative analgesic consumption than bupivacaine alone (21). However, when administered subcutaneously, verapamil failed to prolong the duration of lidocaine anesthesia (22) and produced considerable erythema and/or edema, which may have altered the drug bioavailability. Our study is the first to demonstrate a significant prolongation of a local anesthetic by verapamil when administered in the brachial plexus sheath.
However, our study failed to demonstrate any additional analgesic effect when verapamil and morphine were administered together in the brachial plexus sheath. Patients in Group 5 (brachial plexus morphine/verapamil) had a similar mean duration of analgesia as those patients receiving only brachial plexus morphine (Group 3). This result appears to be in contrast to other studies that demonstrate an increased analgesic effect when opioids are administered concomitantly with calcium channel blockers (9–15). Previous data indicate that a reduction of calcium influx is important in mediating the analgesic effect of opiates, and that calcium channel blockers can potentiate morphine-induced analgesia (9). Opioids increase potassium permeability, and therefore decrease calcium currents in the cell bodies of sensory neurons that leads to inhibition of neuronal firing and transmitter release (8).
The reason why our patients derived no additional analgesic benefit from verapamil is unclear. Verapamil has been shown to potentiate the antinociceptive effects of both systemically and spinally administered morphine (9,12,13). However, no previous study has investigated the analgesic effects of a calcium-channel blocker used in conjunction with peripherally administered morphine. Perhaps a different calcium channel blocker other than verapamil may enhance the peripheral analgesic effect of morphine. Sensory neurons possess four types of voltage-dependent calcium channels: L, N, P, and T (23). The significance of several different calcium channel types in contributing to calcium fluxes in a given cell type is not completely understood. Both of the L- and N-type calcium ion channels have been implicated in the release of neurotransmitters from peripheral neurons (24). Analgesic research has been restricted to the use of nonpolypeptide L-type calcium channel blockers with three different structures: dihydropyridine (nicardipine, nifedipine, and nimodipine), diphenylalkylamine (verapamil), and benzothiazepine (diltiazem). However, evidence indicates that blockage of N-type calcium channels is effective in potentiating morphine-induced analgesia (25). Unfortunately, the only agents presently available that block the N-type channels with high affinity are polypeptides (toxins). Because verapamil is not a highly selective blocker of calcium channels (it can block sodium and potassium channels), it would be important to test other calcium channel blockers before excluding any role in their ability to potentiate peripheral morphine antinociception.
Some researchers have suggested that the analgesic effect of verapamil is centrally and not peripherally mediated. Del Pozo et al. (14) found that subcutaneous verapamil failed to exhibit antinociceptive effects in the rat, but was clearly analgesic when administered by the intracerebroventricular route. The authors concluded that this was due to decreased central nervous system concentrations when verapamil was administered by the peripheral route. However, even the systemic administration of verapamil and morphine (Group 2) in our study failed to demonstrate an enhanced analgesic effect, compared with the control group. Perhaps the analgesic effect of verapamil and morphine was short-lived and masked by the local anesthetic effect of the lidocaine.
In conclusion, analgesic duration was significantly increased in those patients receiving brachial plexus blocks with morphine. Although the addition of verapamil to brachial plexus block with lidocaine can prolong the duration of anesthesia, it had no effect on analgesic duration or 24-hour analgesic use.
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Acknowledgments
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Support for this study was provided solely from institutional and/or departmental sources.
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Footnotes
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Presented in part at the annual meeting of the American Society of Regional Anesthesia, Philadelphia, PA, May 7, 1999.
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Accepted for publication April 27, 2000.
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NOTICE OF RETRACTION
Anesth. Analg.,
April 1, 2009;
108(4):
1350 - 1350.
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Abstract
Introduction
