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Buprenorphine added to the local anesthetic for axillary brachial plexus block prolongs postoperative analgesia
Buprenorphine Added to the Local Anesthetic for Axillary Brachial Plexus Block Prolongs Postoperative Analgesia Kenneth D. Candido, M.D., Alon P. Winnie, M.D., Ahmed H. Ghaleb, M.D., Maher W. Fattouh, M.D., and Carlo D. Franco, M.D. Background and Objectives: Buprenorphine added to local anesthetic solutions for supraclavicular block was found to triple postoperative analgesia duration in a previous study when compared with local anesthetic block alone. That study, however, did not control for potentially confounding factors, such as the possibility that buprenorphine was affecting analgesia through intramuscular absorption or via a spinal mechanism. To specifically delineate the role of buprenorphine in peripherally mediated opioid analgesia, the present study controlled for these 2 factors. Methods: Sixty American Society of Anesthesiologists (ASA) P.S. I and II, consenting adults for upper extremity surgery, were prospectively assigned randomly in double-blind fashion to 1 of 3 groups. Group I received local anesthetic (1% mepivacaine, 0.2% tetracaine, epinephrine 1:200,000), 40 mL, plus buprenorphine, 0.3 mg, for axillary block, and intramuscular (IM) saline. Group II received local anesthetic-only axillary block, and IM buprenorphine 0.3 mg. Group III received local anesthetic-only axillary block and IM saline. Postoperative pain onset and intensity were compared, as was analgesic medication use. Results: The mean duration of postoperative analgesia was 22.3 hours in Group I; 12.5 hours in group II, and 6.6 hours in group III. Differences between groups I and II were statistically significant (P ⫽ .0012). Differences both between groups I and III and II and III were also statistically significant (P ⬍ .001). Conclusions: Buprenorphine-local anesthetic axillary perivascular brachial plexus block provided postoperative analgesia lasting 3 times longer than local anesthetic block alone and twice as long as buprenorphine given by IM injection plus local anesthetic-only block. This supports the concept of peripherally mediated opioid analgesia by buprenorphine. Reg Anesth Pain Med 2002;27:162-167. Key Words:
Axillary block, Buprenorphine, Postoperative analgesia.
I
n the decades following the description of multiple opiate receptor sites on primary afferent fibers by Fields et al.1 in 1980, many laboratory studies in animals indicated that antinociception can be induced by opioids acting at these peripheral receptors. During the past decade, however, there has been significant controversy regarding the efficacy, as well as the mechanism of action of perineurally injected opioids administered for the management of postoperative pain. In a previous study
From the Departments of Anesthesiology and Pain Management, Cook County Hospital (A.H.G., M.W.F.), and Rush Medical College (K.D.C., A.P.W., C.D.F.), Chicago, Illinois. Accepted for publication October 18, 2001. Reprint requests: Kenneth D. Candido, M.D., Department of Anesthesiology, Northwestern Memorial Hospital, 251 East Huron St, Wesley Pavilion, Suite 101, Chicago, IL 60611. E-mail: [email protected] © 2002 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/02/2702-0005$35.00/0 doi:10.1053/rapm.2002.30671
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performed at this institution, the addition of 1 such opioid, buprenorphine, to local anesthetic solutions administered for subclavian perivascular brachial plexus block provided postoperative analgesia lasting 3 times as long as local anesthetic block alone.2 It was tempting to attribute the prolongation of postoperative analgesia when buprenorphine was added to local anesthetic solutions and injected perineurally in that previous study to an interaction with peripheral nervous system opiate receptors.1,3 However, to ensure that the prolongation of analgesia is primarily mediated by a peripheral opioid receptor interaction, one needs to exclude antinociception produced by 2 other potential mechanisms: (1) systemic absorption of buprenorphine and (2) spread of buprenorphine to the central neuraxis. This prospective, randomized double-blind study was undertaken to specifically examine if the prolongation of postoperative analgesia produced by buprenorphine injected near the brachial plexus is
Regional Anesthesia and Pain Medicine, Vol 27, No 2 (March–April), 2002: pp 162–167
Buprenorphine Prolongs Plexus Block Analgesia
peripherally mediated. The analgesic profile of buprenorphine added to local anesthetic was examined in a group of patients who were undergoing upper extremity surgical procedures utilizing axillary perivascular blocks of the brachial plexus. A second group of patients received local anestheticonly axillary blocks with buprenorphine injected intramuscularly to examine the possible contribution of systemic opioid absorption. A third, control group, received local anesthetic blocks devoid of opioid and intramuscular (IM) saline. It was presumed that the axillary perivascular space is situated sufficiently distal to the central neuraxis to reduce the likelihood of opioid spread to the central nervous system (CNS) with resultant neuraxially mediated analgesia, especially when compared with the subclavian perivascular space or to the interscalene perivascular space.
Methods Following approval of the protocol by the Institutional Review Board of Cook County Hospital, 60 American Society of Anesthesiologists (ASA) Physical Status I and II adults free of substance abuse problems and who were scheduled to undergo upper extremity surgery under regional anesthesia were enrolled in the study. Informed and written consent was obtained from each patient. Patients were randomly assigned to 1 of 3 groups by The Department of Pharmacy using a computer generated random chart. All brachial blocks, as well as IM medications, were prepared by 1 anesthesiologist, who did not perform any of the subsequent blocks or IM injections or any of the patient follow-ups. After the application of a noninvasive blood pressure cuff, electrocardiogram (ECG), and a pulse oximeter, and after the placement of a nasal cannula and administration of oxygen at 2 L/min, midazolam 2 mg/70 kg (maximum of 3 mg) was administered intravenously for sedation. With patients in the supine position, axillary perivascular blocks of the brachial plexus were performed following a single-injection technique previously described by one of the authors4 using a 2-inch, 22gauge, insulated needle (Stimuplex; B. Braun, Bethlehem, PA) and a nerve stimulator (StimuplexDig, B. Braun; product code # stim-200 333542). Following the production of a motor response identifying the median, radial, or ulnar nerve obtained at ⱕ 0.5 mA, the local anesthetic solution was incrementally injected. The onset of sensory and motor block was monitored and documented using preprinted score sheets to ensure that anesthesia was adequate for surgery without the need for local anesthetic supplementation or adjuvant analgesics.
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Patients in group I received an axillary perivascular brachial plexus block using 40 mL of the local anesthetic mixture consisting of 1% mepivacaine, 0.2% tetracaine and epinephrine, 1:200,000 (5 g/ mL), to which was added 1 mL of buprenorphine, 0.3 mg (total volume, 41 mL). Additionally, these patients received an IM injection into the substance of the ipsilateral deltoid muscle of 1 mL of Normal Saline Solution (NSS). Group II patients received 40 mL of the same local anesthetic mixture to which was added 1 mL of NSS (41 mL total) for the block, followed by an IM injection of 1 mL of buprenorphine, 0.3 mg. Group III patients received 40 mL of the same local anesthetic mixture to which was added 1 mL of NSS (41 mL total) followed by an IM injection of 1 mL of NSS. Following the completion of surgery, patients were monitored to assess the quality and duration of postoperative analgesia. Visual analog pain score assessment was utilized at each hour for the first 6 hours and at 12, 24, 36, and 48 hours. The timing of each patient’s first reported pain and the actual pain score at that time were documented. Patients who reported pain scores ⱖ 5 were given parenteral opioid analgesics (morphine), and patients who reported pain scores of ⬍ 5 and who requested pain medication were given oral analgesics. Once a given patient had requested and received postoperative analgesics, they were considered to have completed the analgesic phase of the study. All patients, regardless of analgesic medication use postoperatively, were assessed for the presence of complications at the subsequent timing intervals until 48 hours had elapsed from the time of injection of local anesthetic. Thus, at each time interval, patients were observed and/or questioned about any subjective and/or objective side effects (sedation, pruritis, nausea, vomiting, or respiratory depression). Data were analyzed using the unpaired t test (analysis of variance [ANOVA]) to compare demographics; the Kruskal-Wallis test for postoperative data with the Mann-Whitney test for nonparametric data being implemented when significance was noted. In addition, Fisher’s Exact Test was used for frequency analysis. A P value of less than .05 was considered to be statistically significant. The data are presented as mean ⫾ SEM.
Results The study included only those patients who had successful surgical anesthesia from the axillary block alone. Patients who required general or local anesthetic supplementation or intravenous sedatives/hypnotics/analgesics were excluded. There were 6 such patients, represented across all 3 study
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Regional Anesthesia and Pain Medicine Vol. 27 No. 2 March–April 2002 Table 1. Patient Characteristics and Duration of Surgery Parameter Gender n (%) Male Female Age (yr) Mean Range Weight (kg) Mean Range Duration of surgery (min) Mean Range
Group I
Group II
Group III
12 (60) 8 (40)
15 (75) 5 (25)
11 (55) 9 (45)
38.9 ⫾ 2.99 19-70
34.95 ⫾ 2.86 20-61
35.9 ⫾ 3.15 19-68
77.02 ⫾ 2.66 61.4-109
81.41 ⫾ 4.03 45-118.2
84.11 ⫾ 5.73 50-150
67.10 ⫾ 7.73 20-145
82.30 ⫾ 11.8 30-225
77.86 ⫾ 11.1 10-230
NOTE. Values expressed as mean ⫾ SEM.
groups (Group I-2, Group II-1, Group III-3). These 6 patients were eliminated and replaced to maintain 20 patients in each group. There were no significant differences between the 3 groups with respect to age, sex, weight, physical status, or duration of the surgical procedure (see Table 1). Table 2 shows the 3 groups were well matched for the type and number of surgical procedures, suggesting postoperative pain of similar intensity. The mean duration of postoperative analgesia (time from completion of the block to first pain score ⱖ 1) in the 3 study groups is represented in Table 3. The differences in results between groups I and III is statistically significant (P ⬍ .001). There was a more than 3-fold increase in the average duration of postoperative analgesia in group I as compared with group III. Additionally, 25% of the patients in group I had no pain at the longest assessment time of 48 hours (Table 3). Comparing groups I and II, there was an almost doubling of the average duration of postoperative analgesia when buprenorphine was added directly to the local anesthetic solution compared to its use intramuscularly. Once again, these results are both statistically (as well as clinically) significant (P ⫽ .0012). Comparing groups II and III, there was a virtual doubling of postoperative analgesia when buprenor-
phine was given intramuscularly as when both the blocks and IM injections were devoid of opioid. These results, too, are statistically significant (P ⬍ .001). The average first reported pain scores among the 3 groups are listed in Table 3. Patients in group I had lower average visual analog pain scores at their first reported pain than patients in group II or group III. Table 4 depicts parenteral opioid requirements, oral analgesic requirements, and side effects in each of the 3 groups. Thirty percent of patients in group I requested no analgesic medications in the first 48 hours postoperatively compared with 15% in group II and 0% in group III. The need for parenteral opioids was significantly higher in group III as compared with groups I and II, since more patients in this group had first pain scores of ⱖ 5. The incidence of nausea, vomiting, and headache was comparable in the 3 groups and is represented in Table 5.
Discussion Animal studies provided the first evidence that primary afferent nerve terminals have significant numbers of opiate receptor sites on their central processes.1 The neurophysiological evidence sup-
Table 2. Types of Surgical Procedures Type of Surgery
Group I
Group II
Group III
ORIF fracture Finger pinning Tendon repair Carpal tunnel release Excision mass Hardware removal Liposuction of hand Finger amputation Incision & drainage Wrist arthroscopy Wrist fusion DeQuervain’s release
9 1 4 1 3 1 1 0 0 0 0 0
6 3 5 1 2 1 0 1 1 0 0 0
5 1 2 5 2 2 0 0 0 1 1 1
Buprenorphine Prolongs Plexus Block Analgesia
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Table 3. Average Duration of Postoperative Analgesia and First Reported Pain Scores Parameter
Group I
Group II
Group III
Postoperative analgesia (hr) (range) Percentage of patients with “0” pain score up to 48 hr First reported pain score (0-10)‡ (range)
22.3 ⫾ 3.1*† (11-48 hr) 25 2.5 ⫾ 0.54§ (0-7)
12.5 ⫾ 1.5† (4-33 hr) 15 4.4 ⫾ 0.64㛳 (2-10)
6.6 ⫾ 1.02 (5-8.5 hr) 0 6.2 ⫾ 0.58 (2-9)
*P ⫽ .0012 between groups I and II. †P ⬍ .01 between groups I and III and II and III. ‡Visual analog score 0 ⫽ 10; 0 ⫽ “no pain,” 10 ⫽ “worst possible pain.” §P ⬍ .05 between groups I and II and I and III. 㛳P ⬍.05 between groups II and III.
ports the tenet that exogenously administered opioids might mediate analgesia both via peripheral, as well as by central, mechanisms.5,6 In 1993, Stein3 proposed that 4 criteria should be met when evaluating peripherally-mediated opioid effects in any animal research model. The 4 criteria referenced above include: (1) exclusion of central effects; (2) demonstration of opioid receptor interaction (met by demonstrating antagonism of analgesic agonist effects by naloxone); (3) measurement of pain intensity in a standardized fashion, and finally; (4) standardization of the type of tissue insult whereby both tissue injury and inflammation are assured. The inflammatory process was considered to be important for the mediation of peripheral opioid antinociceptive actions. While animal models may address all 4 criteria stated, criteria “2” raises ethical issues in a surgical patient population, since it requires antagonizing opioid-induced analgesia by the administration of naloxone. In the present study, therefore, all the proposed criteria, except “2,” were met. Mays et al.,7 in 1987, demonstrated a prolonged analgesic effect of injecting morphine perineurally in patients with chronic pain when compared with IM morphine or perineural bupivacaine. Several studies that have specifically examined the peripheral site of action of opioids using a brachial plexus model in human subjects, however, have offered conflicting results. While some studies have supported the existence of a peripheral mechanism of opioid analgesia,2 others have failed to provide
compelling evidence of such a mechanism.8-12 The reason for such discrepancy may be that the site of opioid injection near the brachial plexus has not been uniform, with some studies examining an interscalene model, others a subclavian perivascular model, and still others an axillary perivascular one. There are differences between the 3 approaches with respect to the proximity of the central neuraxis to the site of injection. Compared with the axillary approach, opioids administered via supraclavicular techniques are administered closer to the central neuraxis, and opioid injected at this site may theoretically diffuse into the CNS with resultant centrally mediated analgesia. Most of the studies have also differed with respect to the type of opioid analgesic studied, with some investigating hydrophilic agents (i.e., morphine) and others lipophilic opioids (i.e., fentanyl, sufentanil, buprenorphine). Although the opioid used in the present study, buprenorphine, is lipophilic and has a high affinity for receptors, with a half-life for dissociation from the receptor of 166 minutes,13 it was presumed that by depositing it at a site far removed from the central neuraxis, there would be limited central neuraxial antinociceptive effects produced by the drug. In a previous study performed at this institution, a subclavian perivascular brachial plexus block model was used to evaluate peripherally mediated effects of buprenorphine.2 The local anesthetic mixture used for the block in that study was similar to that used in the present study (mepivacaine 1%
Table 4. First Medication Use Postoperatively Type of Medication No medication NSAIDS Opioid Acetaminophen
Group I
Group II
Group III
30% (6/20) 20% (4/20) 30% (6/20)* 20% (4/20)
15% (3/20) 20% (4/20) 40% (8/20)† 25% (5/20)
0% (0/20) 25% (5/20) 70% (14/20) 5% (1/20)
Abbreviation: NSAIDS, nonsteroidal anti-inflammatory drugs. *P ⫽ .026 between groups I and III. †P ⫽ .111 between groups II and III.
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Regional Anesthesia and Pain Medicine Vol. 27 No. 2 March–April 2002 Table 5. Side Effects—First 48 Hours Postoperatively Side Effect Reported
Group I
Group II
Group III
Nausea Vomiting Headache Twitching of hand (lasting 30 min)
5% (1/20) 5% (1/20) 5% (1/20) 0
5% (1/20) 25% (5/20) 5% (1/20) 0
5% (1/20) 10% (2/20) 5% (1/20) 5% (1/20)
and tetracaine 0.2% with epinephrine 1:200,000). The dose of buprenorphine added to the local in the opioid-local group was also similar (0.3 mg). Patients who received blocks with buprenorphine added to the local anesthetic mixture had a tripling of the mean duration of postoperative analgesia when compared with the patients who received blocks performed with local anesthetic mixtures alone. That previous study, however, did not include an IM opioid group nor did it address the fact that the subclavian perivascular brachial plexus block is performed at the level of the 3 trunks of the plexus, which lie in close proximity to the central neuraxis. The present study addressed these 2 potential shortcomings of the previous work by evaluating an IM opioid group and by moving the perivascular brachial plexus block site distally. The data from the present study, similar to the previous one, demonstrate that the addition of buprenorphine 0.3 mg to the local anesthetic mixture for a perivascular brachial plexus block results in a 3-fold increase in the duration of postoperative analgesia when compared with a control block using local anesthetic alone. Also demonstrated was a doubling of postoperative analgesia in comparison to patients who received local anesthetic axillary perivascular blocks and IM buprenorphine. The fact that the group receiving IM buprenorphine (group II) had a longer duration of postoperative analgesia than the control group (group III) supports the concept of systemic pain relief due to the parenteral opioid which, however, is about half the duration observed by adding buprenorphine directly to the local anesthetic solution. In fact, this finding may be the strongest evidence from the present study to support a peripheral mechanism of analgesia when buprenorphine is added to the local anesthetic for plexus block, since it shows that systemic analgesic effects of 0.3 mg given intramuscularly following upper extremity surgery typically last about 12 hours. This is far shorter than the analgesic effect demonstrated by adding the same buprenorphine dose to the local anesthetic for plexus block. Similarly, in previous studies, 0.3 mg of epidurally administered buprenorphine was shown to produce postsurgical analgesia lasting between 3 and 12 hours, with a mean value of 6.5 hours.14,15 This, again, would
tend to negate a centrally mediated antinociceptive effect of buprenorphine in the present study, since buprenorphine-local anesthetic plexus blocks provided postoperative analgesia lasting 2 to 3 times as long as that demonstrated in the epidural buprenorphine studies. We believe a mechanism other than systemic absorption or central antinociception must be responsible for the prolonged duration of postoperative analgesia noted in the group I patients. Finally, in comparison to group II patients or group III patients, group I patients had lower mean first pain scores, and several required no rescue analgesics for the first 48 hours following surgery. The observations made in the present study suggest an opioid-peripheral receptor site of action mediating analgesia. Although the actual neurophysiochemical mode of action involved is speculative at present, the clinical benefits of adding buprenorphine to local anesthetic solutions of mepivacaine, tetracaine, and epinephrine for upper extremity plexus blocks is convincing to us from the results of the present study.
Acknowledgment The authors gratefully wish to acknowledge the indispensable contributions made by Dr. Shameem Sultana and our research volunteers, Venu Madhipatla and Aslam Syed, whose tireless efforts at collecting and organizing data greatly assisted our project.
References 1. Fields HL, Emson PC, Leigh BK, Gilbert RFT, Iverson LL. Multiple opiate receptor sites on primary afferent fibers. Nature 1980;284:351-353. 2. Candido KD, Franco CF, Khan MA, Winnie AP, Raja DS. Buprenorphine added to the local anesthetic for brachial plexus block to provide postoperative analgesia in outpatients. Reg Anesth Pain Med 2001;26: 352-356. 3. Stein C. Peripheral mechanisms of opioid analgesia. Anesth Analg 1993;76:182-191. 4. Winnie AP. Perivascular techniques of brachial plexus block. In Ha˚kansson L (ed): Plexus Anesthesia, vol 1. Copenhagen, Denmark: Schultz Medical Information; 1983:121-144. 5. Bentley GA, Newton SH, Starr J. Evidence for an action of morphine and enkephalins on sensory
Buprenorphine Prolongs Plexus Block Analgesia
6. 7.
8.
9.
10.
nerve endings in the mouse peritoneum. Br J Pharmacol 1981;73:325-332. Laduron PM. Axonal transport of opiate receptors in capsaicin-sensitive neurons. Brain Res 1984;294:157-160. Mays KM, Lipman JJ, Schnapp M. Local analgesia without anesthesia using peripheral perineural morphine injections. Anesth Analg 1987;66:417-420. Racz H, Gunning K, Della Santa D, Forster A. Evaluation of the effect of perineural morphine on the quality of postoperative analgesia after axillary plexus block: A randomized double-blind study. Anesth Analg 1991;72:769-772. Morros VC, Perez CMD, Castillo MJ, Cedo VF. Addition of fentanyl to mepivacaine in axillary brachial plexus block. Effects on the anesthetic and postoperative analgesic quality. Rev Esp Anestesiol Reanim 1991; 38:87-89. Singelyn F, Contreras V, Lefebvre B, Gouverneur JM. Adding sufentanil to mepivacaine results in faster but
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not prolonged anesthesia and analgesia after brachial plexus blockade. Anesthesiology 1993;79:A832. 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;19:183-188. Gormley WP, Murray JM, Fee JPH, Bower S. Effect of the addition of alfentanil to lignocaine during axillary brachial plexus anesthesia. Br J Anaesth 1996;76:802-805. Gutstein HB, Akil H. Opioid analgesics. In: Hardman J, Limbird L (eds): Goodman & Gilman’s The Pharmacologic Basis of Therapeutics, ed 10. New York, NY: McGraw-Hill; 2001:569-619. Ackerman WE, Juneja MM, Colclough GW. A comparison of epidural fentanyl, buprenorphine and butorphanol for the management of post cesarean section pain. Anesthesiology 1988;69:A401. Lanz E, Simko G, Theiss D, Glocke MH. Epidural buprenorphine — A double-blind study of postoperative analgesia and side effects. Anesth Analg 1984;63:593-598.
Axillary block, Buprenorphine, Postoperative analgesia.
I
n the decades following the description of multiple opiate receptor sites on primary afferent fibers by Fields et al.1 in 1980, many laboratory studies in animals indicated that antinociception can be induced by opioids acting at these peripheral receptors. During the past decade, however, there has been significant controversy regarding the efficacy, as well as the mechanism of action of perineurally injected opioids administered for the management of postoperative pain. In a previous study
From the Departments of Anesthesiology and Pain Management, Cook County Hospital (A.H.G., M.W.F.), and Rush Medical College (K.D.C., A.P.W., C.D.F.), Chicago, Illinois. Accepted for publication October 18, 2001. Reprint requests: Kenneth D. Candido, M.D., Department of Anesthesiology, Northwestern Memorial Hospital, 251 East Huron St, Wesley Pavilion, Suite 101, Chicago, IL 60611. E-mail: [email protected] © 2002 by the American Society of Regional Anesthesia and Pain Medicine. 1098-7339/02/2702-0005$35.00/0 doi:10.1053/rapm.2002.30671
162
performed at this institution, the addition of 1 such opioid, buprenorphine, to local anesthetic solutions administered for subclavian perivascular brachial plexus block provided postoperative analgesia lasting 3 times as long as local anesthetic block alone.2 It was tempting to attribute the prolongation of postoperative analgesia when buprenorphine was added to local anesthetic solutions and injected perineurally in that previous study to an interaction with peripheral nervous system opiate receptors.1,3 However, to ensure that the prolongation of analgesia is primarily mediated by a peripheral opioid receptor interaction, one needs to exclude antinociception produced by 2 other potential mechanisms: (1) systemic absorption of buprenorphine and (2) spread of buprenorphine to the central neuraxis. This prospective, randomized double-blind study was undertaken to specifically examine if the prolongation of postoperative analgesia produced by buprenorphine injected near the brachial plexus is
Regional Anesthesia and Pain Medicine, Vol 27, No 2 (March–April), 2002: pp 162–167
Buprenorphine Prolongs Plexus Block Analgesia
peripherally mediated. The analgesic profile of buprenorphine added to local anesthetic was examined in a group of patients who were undergoing upper extremity surgical procedures utilizing axillary perivascular blocks of the brachial plexus. A second group of patients received local anestheticonly axillary blocks with buprenorphine injected intramuscularly to examine the possible contribution of systemic opioid absorption. A third, control group, received local anesthetic blocks devoid of opioid and intramuscular (IM) saline. It was presumed that the axillary perivascular space is situated sufficiently distal to the central neuraxis to reduce the likelihood of opioid spread to the central nervous system (CNS) with resultant neuraxially mediated analgesia, especially when compared with the subclavian perivascular space or to the interscalene perivascular space.
Methods Following approval of the protocol by the Institutional Review Board of Cook County Hospital, 60 American Society of Anesthesiologists (ASA) Physical Status I and II adults free of substance abuse problems and who were scheduled to undergo upper extremity surgery under regional anesthesia were enrolled in the study. Informed and written consent was obtained from each patient. Patients were randomly assigned to 1 of 3 groups by The Department of Pharmacy using a computer generated random chart. All brachial blocks, as well as IM medications, were prepared by 1 anesthesiologist, who did not perform any of the subsequent blocks or IM injections or any of the patient follow-ups. After the application of a noninvasive blood pressure cuff, electrocardiogram (ECG), and a pulse oximeter, and after the placement of a nasal cannula and administration of oxygen at 2 L/min, midazolam 2 mg/70 kg (maximum of 3 mg) was administered intravenously for sedation. With patients in the supine position, axillary perivascular blocks of the brachial plexus were performed following a single-injection technique previously described by one of the authors4 using a 2-inch, 22gauge, insulated needle (Stimuplex; B. Braun, Bethlehem, PA) and a nerve stimulator (StimuplexDig, B. Braun; product code # stim-200 333542). Following the production of a motor response identifying the median, radial, or ulnar nerve obtained at ⱕ 0.5 mA, the local anesthetic solution was incrementally injected. The onset of sensory and motor block was monitored and documented using preprinted score sheets to ensure that anesthesia was adequate for surgery without the need for local anesthetic supplementation or adjuvant analgesics.
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Patients in group I received an axillary perivascular brachial plexus block using 40 mL of the local anesthetic mixture consisting of 1% mepivacaine, 0.2% tetracaine and epinephrine, 1:200,000 (5 g/ mL), to which was added 1 mL of buprenorphine, 0.3 mg (total volume, 41 mL). Additionally, these patients received an IM injection into the substance of the ipsilateral deltoid muscle of 1 mL of Normal Saline Solution (NSS). Group II patients received 40 mL of the same local anesthetic mixture to which was added 1 mL of NSS (41 mL total) for the block, followed by an IM injection of 1 mL of buprenorphine, 0.3 mg. Group III patients received 40 mL of the same local anesthetic mixture to which was added 1 mL of NSS (41 mL total) followed by an IM injection of 1 mL of NSS. Following the completion of surgery, patients were monitored to assess the quality and duration of postoperative analgesia. Visual analog pain score assessment was utilized at each hour for the first 6 hours and at 12, 24, 36, and 48 hours. The timing of each patient’s first reported pain and the actual pain score at that time were documented. Patients who reported pain scores ⱖ 5 were given parenteral opioid analgesics (morphine), and patients who reported pain scores of ⬍ 5 and who requested pain medication were given oral analgesics. Once a given patient had requested and received postoperative analgesics, they were considered to have completed the analgesic phase of the study. All patients, regardless of analgesic medication use postoperatively, were assessed for the presence of complications at the subsequent timing intervals until 48 hours had elapsed from the time of injection of local anesthetic. Thus, at each time interval, patients were observed and/or questioned about any subjective and/or objective side effects (sedation, pruritis, nausea, vomiting, or respiratory depression). Data were analyzed using the unpaired t test (analysis of variance [ANOVA]) to compare demographics; the Kruskal-Wallis test for postoperative data with the Mann-Whitney test for nonparametric data being implemented when significance was noted. In addition, Fisher’s Exact Test was used for frequency analysis. A P value of less than .05 was considered to be statistically significant. The data are presented as mean ⫾ SEM.
Results The study included only those patients who had successful surgical anesthesia from the axillary block alone. Patients who required general or local anesthetic supplementation or intravenous sedatives/hypnotics/analgesics were excluded. There were 6 such patients, represented across all 3 study
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Regional Anesthesia and Pain Medicine Vol. 27 No. 2 March–April 2002 Table 1. Patient Characteristics and Duration of Surgery Parameter Gender n (%) Male Female Age (yr) Mean Range Weight (kg) Mean Range Duration of surgery (min) Mean Range
Group I
Group II
Group III
12 (60) 8 (40)
15 (75) 5 (25)
11 (55) 9 (45)
38.9 ⫾ 2.99 19-70
34.95 ⫾ 2.86 20-61
35.9 ⫾ 3.15 19-68
77.02 ⫾ 2.66 61.4-109
81.41 ⫾ 4.03 45-118.2
84.11 ⫾ 5.73 50-150
67.10 ⫾ 7.73 20-145
82.30 ⫾ 11.8 30-225
77.86 ⫾ 11.1 10-230
NOTE. Values expressed as mean ⫾ SEM.
groups (Group I-2, Group II-1, Group III-3). These 6 patients were eliminated and replaced to maintain 20 patients in each group. There were no significant differences between the 3 groups with respect to age, sex, weight, physical status, or duration of the surgical procedure (see Table 1). Table 2 shows the 3 groups were well matched for the type and number of surgical procedures, suggesting postoperative pain of similar intensity. The mean duration of postoperative analgesia (time from completion of the block to first pain score ⱖ 1) in the 3 study groups is represented in Table 3. The differences in results between groups I and III is statistically significant (P ⬍ .001). There was a more than 3-fold increase in the average duration of postoperative analgesia in group I as compared with group III. Additionally, 25% of the patients in group I had no pain at the longest assessment time of 48 hours (Table 3). Comparing groups I and II, there was an almost doubling of the average duration of postoperative analgesia when buprenorphine was added directly to the local anesthetic solution compared to its use intramuscularly. Once again, these results are both statistically (as well as clinically) significant (P ⫽ .0012). Comparing groups II and III, there was a virtual doubling of postoperative analgesia when buprenor-
phine was given intramuscularly as when both the blocks and IM injections were devoid of opioid. These results, too, are statistically significant (P ⬍ .001). The average first reported pain scores among the 3 groups are listed in Table 3. Patients in group I had lower average visual analog pain scores at their first reported pain than patients in group II or group III. Table 4 depicts parenteral opioid requirements, oral analgesic requirements, and side effects in each of the 3 groups. Thirty percent of patients in group I requested no analgesic medications in the first 48 hours postoperatively compared with 15% in group II and 0% in group III. The need for parenteral opioids was significantly higher in group III as compared with groups I and II, since more patients in this group had first pain scores of ⱖ 5. The incidence of nausea, vomiting, and headache was comparable in the 3 groups and is represented in Table 5.
Discussion Animal studies provided the first evidence that primary afferent nerve terminals have significant numbers of opiate receptor sites on their central processes.1 The neurophysiological evidence sup-
Table 2. Types of Surgical Procedures Type of Surgery
Group I
Group II
Group III
ORIF fracture Finger pinning Tendon repair Carpal tunnel release Excision mass Hardware removal Liposuction of hand Finger amputation Incision & drainage Wrist arthroscopy Wrist fusion DeQuervain’s release
9 1 4 1 3 1 1 0 0 0 0 0
6 3 5 1 2 1 0 1 1 0 0 0
5 1 2 5 2 2 0 0 0 1 1 1
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Table 3. Average Duration of Postoperative Analgesia and First Reported Pain Scores Parameter
Group I
Group II
Group III
Postoperative analgesia (hr) (range) Percentage of patients with “0” pain score up to 48 hr First reported pain score (0-10)‡ (range)
22.3 ⫾ 3.1*† (11-48 hr) 25 2.5 ⫾ 0.54§ (0-7)
12.5 ⫾ 1.5† (4-33 hr) 15 4.4 ⫾ 0.64㛳 (2-10)
6.6 ⫾ 1.02 (5-8.5 hr) 0 6.2 ⫾ 0.58 (2-9)
*P ⫽ .0012 between groups I and II. †P ⬍ .01 between groups I and III and II and III. ‡Visual analog score 0 ⫽ 10; 0 ⫽ “no pain,” 10 ⫽ “worst possible pain.” §P ⬍ .05 between groups I and II and I and III. 㛳P ⬍.05 between groups II and III.
ports the tenet that exogenously administered opioids might mediate analgesia both via peripheral, as well as by central, mechanisms.5,6 In 1993, Stein3 proposed that 4 criteria should be met when evaluating peripherally-mediated opioid effects in any animal research model. The 4 criteria referenced above include: (1) exclusion of central effects; (2) demonstration of opioid receptor interaction (met by demonstrating antagonism of analgesic agonist effects by naloxone); (3) measurement of pain intensity in a standardized fashion, and finally; (4) standardization of the type of tissue insult whereby both tissue injury and inflammation are assured. The inflammatory process was considered to be important for the mediation of peripheral opioid antinociceptive actions. While animal models may address all 4 criteria stated, criteria “2” raises ethical issues in a surgical patient population, since it requires antagonizing opioid-induced analgesia by the administration of naloxone. In the present study, therefore, all the proposed criteria, except “2,” were met. Mays et al.,7 in 1987, demonstrated a prolonged analgesic effect of injecting morphine perineurally in patients with chronic pain when compared with IM morphine or perineural bupivacaine. Several studies that have specifically examined the peripheral site of action of opioids using a brachial plexus model in human subjects, however, have offered conflicting results. While some studies have supported the existence of a peripheral mechanism of opioid analgesia,2 others have failed to provide
compelling evidence of such a mechanism.8-12 The reason for such discrepancy may be that the site of opioid injection near the brachial plexus has not been uniform, with some studies examining an interscalene model, others a subclavian perivascular model, and still others an axillary perivascular one. There are differences between the 3 approaches with respect to the proximity of the central neuraxis to the site of injection. Compared with the axillary approach, opioids administered via supraclavicular techniques are administered closer to the central neuraxis, and opioid injected at this site may theoretically diffuse into the CNS with resultant centrally mediated analgesia. Most of the studies have also differed with respect to the type of opioid analgesic studied, with some investigating hydrophilic agents (i.e., morphine) and others lipophilic opioids (i.e., fentanyl, sufentanil, buprenorphine). Although the opioid used in the present study, buprenorphine, is lipophilic and has a high affinity for receptors, with a half-life for dissociation from the receptor of 166 minutes,13 it was presumed that by depositing it at a site far removed from the central neuraxis, there would be limited central neuraxial antinociceptive effects produced by the drug. In a previous study performed at this institution, a subclavian perivascular brachial plexus block model was used to evaluate peripherally mediated effects of buprenorphine.2 The local anesthetic mixture used for the block in that study was similar to that used in the present study (mepivacaine 1%
Table 4. First Medication Use Postoperatively Type of Medication No medication NSAIDS Opioid Acetaminophen
Group I
Group II
Group III
30% (6/20) 20% (4/20) 30% (6/20)* 20% (4/20)
15% (3/20) 20% (4/20) 40% (8/20)† 25% (5/20)
0% (0/20) 25% (5/20) 70% (14/20) 5% (1/20)
Abbreviation: NSAIDS, nonsteroidal anti-inflammatory drugs. *P ⫽ .026 between groups I and III. †P ⫽ .111 between groups II and III.
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Regional Anesthesia and Pain Medicine Vol. 27 No. 2 March–April 2002 Table 5. Side Effects—First 48 Hours Postoperatively Side Effect Reported
Group I
Group II
Group III
Nausea Vomiting Headache Twitching of hand (lasting 30 min)
5% (1/20) 5% (1/20) 5% (1/20) 0
5% (1/20) 25% (5/20) 5% (1/20) 0
5% (1/20) 10% (2/20) 5% (1/20) 5% (1/20)
and tetracaine 0.2% with epinephrine 1:200,000). The dose of buprenorphine added to the local in the opioid-local group was also similar (0.3 mg). Patients who received blocks with buprenorphine added to the local anesthetic mixture had a tripling of the mean duration of postoperative analgesia when compared with the patients who received blocks performed with local anesthetic mixtures alone. That previous study, however, did not include an IM opioid group nor did it address the fact that the subclavian perivascular brachial plexus block is performed at the level of the 3 trunks of the plexus, which lie in close proximity to the central neuraxis. The present study addressed these 2 potential shortcomings of the previous work by evaluating an IM opioid group and by moving the perivascular brachial plexus block site distally. The data from the present study, similar to the previous one, demonstrate that the addition of buprenorphine 0.3 mg to the local anesthetic mixture for a perivascular brachial plexus block results in a 3-fold increase in the duration of postoperative analgesia when compared with a control block using local anesthetic alone. Also demonstrated was a doubling of postoperative analgesia in comparison to patients who received local anesthetic axillary perivascular blocks and IM buprenorphine. The fact that the group receiving IM buprenorphine (group II) had a longer duration of postoperative analgesia than the control group (group III) supports the concept of systemic pain relief due to the parenteral opioid which, however, is about half the duration observed by adding buprenorphine directly to the local anesthetic solution. In fact, this finding may be the strongest evidence from the present study to support a peripheral mechanism of analgesia when buprenorphine is added to the local anesthetic for plexus block, since it shows that systemic analgesic effects of 0.3 mg given intramuscularly following upper extremity surgery typically last about 12 hours. This is far shorter than the analgesic effect demonstrated by adding the same buprenorphine dose to the local anesthetic for plexus block. Similarly, in previous studies, 0.3 mg of epidurally administered buprenorphine was shown to produce postsurgical analgesia lasting between 3 and 12 hours, with a mean value of 6.5 hours.14,15 This, again, would
tend to negate a centrally mediated antinociceptive effect of buprenorphine in the present study, since buprenorphine-local anesthetic plexus blocks provided postoperative analgesia lasting 2 to 3 times as long as that demonstrated in the epidural buprenorphine studies. We believe a mechanism other than systemic absorption or central antinociception must be responsible for the prolonged duration of postoperative analgesia noted in the group I patients. Finally, in comparison to group II patients or group III patients, group I patients had lower mean first pain scores, and several required no rescue analgesics for the first 48 hours following surgery. The observations made in the present study suggest an opioid-peripheral receptor site of action mediating analgesia. Although the actual neurophysiochemical mode of action involved is speculative at present, the clinical benefits of adding buprenorphine to local anesthetic solutions of mepivacaine, tetracaine, and epinephrine for upper extremity plexus blocks is convincing to us from the results of the present study.
Acknowledgment The authors gratefully wish to acknowledge the indispensable contributions made by Dr. Shameem Sultana and our research volunteers, Venu Madhipatla and Aslam Syed, whose tireless efforts at collecting and organizing data greatly assisted our project.
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