Opioids as local anesthetic adjuvants for peripheral nerve block

Opioids as Local Anesthetic Adjuvants for Peripheral Nerve Block Robert S. Weller, MD, and John Butterworth, MD

Although the perineural application of opioids with local anesthetics has been of interest to anesthesiologists for years, neither the theoretical mechanism of action nor the effectiveness of this technique have been established. Opioid receptors are evident in the dorsal root ganglia (DRG), and central and peripheral endings of sensory afferents. Inflammation dramatically increases the production and axonal transport of these receptors. Local opioid injection in inflamed tissue is antinociceptive. Nevertheless, there is no evidence of opioid receptors in axonal membranes of afferent nerves in the portions of the axon where regional anesthesia is typically induced. Peripheral opioid injection produces modest analgesia in surgical patients when injected intraarticularly, and prolonged analgesia when injected locally into inflamed dental tissues, but has no effect in the absence of inflammation. Animal studies of perineural opioid application, in typical clinical concentrations, have shown no effect on sensory nerve action potentials. In the setting of acute, postoperative pain, the weight of evidence is against a significant clinical benefit from the addition of morphine, fentanyl, or sufentanil to local anesthetics for peripheral nerve block. Positive studies have often used injection sites close to the neuraxis or have not included systemic control groups. In a limited number of studies, perineural buprenorphine has produced prolonged analgesia. Basic opioid receptor research may ultimately provide a mechanism for perineural opioid activity. Alternatively we may determine that including opioids with local anesthetics for regional anesthesia is illogical and ineffective. © 2004 Elsevier Inc. All rights reserved.

he suggestion that opioids might be effective as analgesics when applied perineurally dates to the 1850s when Wood reported pain relief following injection of perineural morphine and stressed the importance of injection close to the site of pain generation.1 For the next hundred years, the site of action of opioids was thought to be in the brain, until in the 1970s, when the discovery of opioid receptors in the spinal cord of animals quickly led to the demonstration of the efficacy of intrathecal morphine analgesia in cancer patients.2,3 The antinociceptive efficacy of intrathecal and epidural opioids is now well established.4,5 The analgesia produced by neuraxial opioids alone, or as adjuvants to local anesthetics, has been demonstrated for acute postoperative pain, obstetric, pediatric, and cancer

T

From the Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina. Address reprint requests to Dr. Weller, Department of Anesthesiology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1009. Fax: 336-716-1890. E-mail: rweller@ wfubmc.edu. © 2004 Elsevier Inc. All rights reserved. 1084-208X/04/0803-0000$30.00/0 doi:10.1053/j.trap.2004.03.005

pain.6-8 The extensive literature on neuraxial opioids is beyond the scope of this review, which will focus on the more controversial question of the activity of perineural opioids as local anesthetic adjuvants. Research in the last three decades has proven the existence in peripheral tissues at afferent nerve terminals of opioid and other receptors for excitatory and inhibitory peptides. The complex interaction of these receptors with endogenous and exogenous compounds, inflammatory and immune responses, and sympathetic nerve endings continues to be elucidated and promises opportunity for peripheral modulation of nociception at the site of injury. Targeting nociception with peripheral regional anesthetic techniques may also have application for the treatment of acute postoperative pain. This has brought us full circle from the time of Dr. Wood in that peripheral, perineural application of opioids is again of interest to anesthesiologists.

Peripheral Opioid Receptors The three classical subtypes of opioid receptors, ␮, ␦, and ␬, have been demonstrated in peripheral tissues in afferent nerve terminals. In the last decade, molecular cloning and labeling techniques have sequenced, characterized, and localized the various opioid receptors, all of which are transmembrane, Gprotein-coupled receptors (GPCR). Demonstrated effects of opioid binding include inhibition of adenylyl cyclase, increase in K conductance and membrane hyperpolarization, and inhibition of voltage-dependent calcium channels with resultant resistance to action potential propagation or excitatory transmitter release, but effects vary with site and receptor subtype.9 Stimulation of ␮ receptors by (local) exogenous opioid injection results in dose-dependent, naloxone-reversible antinociceptive behavior in rat paw models of inflammation, but not in noninflamed tissue. Hassan and coworkers showed that inflammation induced in a rat paw 48 hours before sciatic nerve ligation resulted in accumulation of ␮-opioid receptor binding sites both proximal and distal to the sciatic nerve ligature, as well as in the cutaneous nerve fibers and inflammatory cells of the inflamed paw. If they induced inflammation but did not ligate the sciatic nerve, however, they found no opioid binding activity along that sciatic nerve. They concluded that inflammation increases opioid receptor transcription in the dorsal root ganglion (DRG) and axoplasmic circulation to the periphery occurring at 48 to 72 hours after induction of inflammation.10 Modern receptor localization and binding experiments in the same rat paw inflammation and sciatic ligation model showed a doubling of ␮-opioid binding sites in the ipsilateral DRG of the inflamed paw without a change in the ligand-binding affinity. Once again, in control rats with unligated sciatic nerves, almost

Techniques in Regional Anesthesia and Pain Management, Vol 8, No 3 (July), 2004: pp 123-128

123

no opioid receptors were detected on the sciatic nerve with or without distal inflammation.11 Fields and coworkers observed ␮- and ␦-receptors in high concentrations in the dorsal horn and dorsal root of spinal nerves, but in “barely detectable” concentrations in the ventral root and peripheral (sciatic) nerve of rats.12 Laduron and Jannsen reported radiolabeled lofentanil binding in nerve segments proximal and distal to, but not between, two vagus nerve ligation sites and were unable to identify any opiate binding in the rat sciatic nerve even with ligation.13

Clinical Evidence of Peripheral Opioid Effect The preponderance of human trials demonstrating peripheral opioid analgesia is studies of intraarticular opiate injection for knee surgery. A meta analysis of this work published by Gupta and coworkers concluded that morphine had a definite but mild benefit lasting 24 hours, exceeding any expected systemic effect.14 In dental pain studies, both Dionne and coworkers and Likar and coworkers measured naloxone-reversible analgesia after injection of morphine into inflamed periodontal tissue.15,16 A significant reduction of visual analog scale (VAS) pain scores and use of supplemental analgesics over 24 hours was seen. There was no effect when morphine was injected with local anesthetic in noninflamed tissue for elective dental surgery. For acute postoperative pain, Reuben and coworkers reported a marked benefit of local injection of 5 mg of morphine into a posterior iliac crest bone graft site in patients undergoing cervical laminectomy. They showed a significantly lower graft site pain score with local injection and much less supplemental morphine use [reduced from 64.3 ⫾ 6.6 to 33.7 ⫾ 8.3 mg (mean ⫾ SD) in 24 hours].17 Tegeder and coworkers investigated various modalities of experimental pain and analgesia from peripheral versus centrally acting opioids. A cryolesion, muscle contraction, or an electrical tetanic stimulus served as different noxious stimuli. Morphine-6-glucuronide (M6G) (without central effect) and morphine both produced analgesia with the first two noxious stimuli which are known to produce inflammation; electrical stimulus pain was reduced only by morphine. They concluded that peripherally opioid-mediated analgesia could be demonstrated only in nociception associated with inflammation.18

Perineural Opioid Effects in Animals There have been two primary lines of animal investigation of the activity of perineural, rather than peripheral, opioids. First, does the perineural application of various opioids have local anesthetic activity, and second, are there behavioral, antinociceptive effects of perineural opioids (Table 1)? Frank and Sudha, using in vitro desheathed amphibian and mammalian nerve segments, demonstrated that extracellular application of met- and leu-enkephalins had no effect on the compound action potential (CAP), but that intracellular enkephalins reduced CAP by 30 to 40%.19 Jurna and Grossman demonstrated an effect of morphine, 2 mg/kg, on sural nerve conduction in a cat by injection into the arterial system of the leg. They showed a naloxone-reversible reduction of CAP of 36% in A ␦, and 19% in C fibers.20 The results were reproduced by jugular vein injection of the same

124

large dose, so it is likely the effect was central rather than a local perineural effect. Fentanyl and sufentanil were used to bathe intact or desheathed rabbit vagus nerve preparations by Gissen and coworkers. At 50 ␮g/mL, there was no effect on intact nerves with either opiate, but a decrease in CAP in A (but not C) fibers of desheathed nerves. At 100 ␮g/mL, CAP was decreased in intact and desheathed nerves, more in A than C fibers. These effects were not naloxone-reversible. They concluded that there was no opioid receptor-mediated action of these opioids on peripheral (intact) nerves, and there was a weak local anesthetic action at higher than clinically relevant concentrations.21 Yuge and coworkers reported no effect of perineural opioids on the superficial radial nerve of a decerebrate, ventilated cat. A central portion of the nerve was bathed with 0.1 mL/kg of morphine (dose of 100 ␮g/kg), fentanyl (dose of 25 ␮g/kg), or saline, and there was no effect of either opiate on the CAP of any fiber type. They speculated the lack of effect could be due to either the absence of a receptor or the inability of the compound to penetrate the nerve.22 The latter explanation seems at variance with known physicochemical properties of these agents. Power and coworkers investigated opioid effects on the CAP of A ␦ and C fibers in rabbit desheathed vagus nerve. They tested increasing concentrations of opiate as well as potentiation of bupivacaine block by fentanyl. Although the commercial preparation of fentanyl produced an irreversible nerve block (also shown by Gissen and colleagues21), fentanyl in saline produced a block only at high concentrations, with complete block at 300 ␮g/mL (EC50 140 ␮g/mL); this effect was not naloxone-reversible. Meperidine produced nerve block at clinically relevant concentrations with an EC50 of 120 ␮g/mL. Diamorphine had no effect at any tested concentration. Of interest, however, fentanyl at 50 ␮g/mL potentiated extremely dilute bupivacaine (⬍0.001%) block, especially in C fibers at high frequencies of stimulation.23 In contrast to studies of effects on action potential propagation, others have tested the ability of perineural opioids to modify nociceptive behavior. Grant and coworkers investigated the percutaneous, perineural application of fentanyl, morphine, and meperidine on the sciatic nerve in rats, using withdrawal latency to radiant heat as indicative of antinociception. The systemic intramuscular (IM) dose-producing maximal possible effect (MPE) was first determined, and the perineural dose was 20% of the MPE dose; these doses for fentanyl, morphine, and meperidine were 6.1, 550, and 6850 ␮g/kg, respectively. Withdrawal latency was equivalent in the injected and noninjected limb from peri-sciatic injection of fentanyl or morphine, but meperidine produced a local anesthetic effect.24 Kayser and coworkers found different results in an earlier study of direct axillary sheath injection of fentanyl on the vocalization threshold to rat paw pressure. Fentanyl doses ranged from 0.5 to 1.5 ␮g/kg. The lowest dose significantly elevated threshold by 60% for 90 minutes; the higher doses also raised threshold on the opposite limb. Low-dose intraplantar naloxone had no intrinsic effect, but reversed the antinociception within 1 hour of axillary fentanyl injection, as did systemic naloxone. They concluded the 0.5 ␮g/kg dose of perineural fentanyl produced nonsystemic antinociception by an opioid receptor-mediated mechanism, but could not rule out central migration of the fentanyl within the plexus sheath. They did not discuss the unexpectedly rapid effect of plantar naloxone in reversing perineural fentanyl.25 WELLER AND BUTTERWORTH

TABLE 1. Perineural Opioids in Animals Author (Date) Nerve Conduction Jurna (1977)

Yuge (1985) Frank (1987) Gissen (1987)

Animal Model

Opioids

Results

In vivo decerebrate cat (21), exposed sural nerve, femoral artery injection

Morphine, 2 mg/kg

In vitro sural, vagus, phrenic In vivo decerebrate cat (15), exposed superficial radial nerve In vitro Frog/guinea pig sciatic, rabbit/guinea pig vagus In vitro Rabbit vagus

Morphine, 5 ⫻ 10⫺5 M

CAP: A␤ increased 90% A␦ decreased 36% C decreased 19% Naloxone reversed all effects CAP decreased 7% Afterhyperpolarization increased 14-26% CAP: A␤, A␦, and C, unchanged

Morphine, 0.1 mg/kg Fentanyl, 25 ␮g/kg D-Ala

met enkephalinamide Leu-enkephalin Fentanyl, 50 ␮g/ml; sufentanil, 50 ␮g/ml

Fentanyl, 100 ␮g/ml; sufentanil, 100 ␮g/ml Power (1991)

In vitro Rabbit vagus

Antinociception Kayser (1990)

In vivo Rat axillary sheath injection Paw pressure vocalization threshold (PPT)

Grant (2001)

In vivo Rat sciatic injection (percutaneous, with nerve stimulation) Hindpaw withdrawal latency to radiant heat

Fentanyl, 50-1000 ␮g/ml Fentanyl, 50 ␮g/ml Bupivacaine, 0.00016% Diamorphine, 10-1000 ␮g/ml Meperidine, 50-500 ␮g/ml Fentanyl, 0.5 ␮g/kg Fentanyl, 1, 1.5 ␮g/kg Fentanyl, 1 ␮g/kg

Perineural—no effect Intraneural—CAP decreased 40% (blocked by naloxone) CAP: intact nerves—A or C fibers, no change CAP: desheathed nerves—A fibers 56-78% decreased; C fibers unchanged No naloxone reversal Intact and desheathed nerves, CAP decreased, A ⬎ C fibers No naloxone reversal CAP decreased, EC50 140 ␮g/ml No naloxone reversal CAP: C fiber decreased 50% at 40 Hz (no block with dilute bupivacaine alone) No effect on CAP CAP decreased, EC50 120 ␮g/ml

Fentanyl, 6.1 ␮g/kg

PPT increased 160% PPT increased both sides (systemic effect) Naloxone, 1 mg/kg IV normalized PPT Naloxone, 1 ␮g intraplantar normalized PPT on axillary fentanyl side Ispilateral Contralateral Latency increased 31% ⫽ 23%

Morphine, 0.55 mg/kg

Latency increased

27%

⫽

28%

Meperidine, 6.85 mg/kg

Latency increased

80%

⬎

27%

CAP ⫽ compound action potential.

In none of the studies on intact nerves was a direct inhibition of action potential generation demonstrated by perineural injection of clinically relevant concentrations of morphine or fentanyl, although opioids potentiated extremely low concentrations of bupivacaine. Much larger opioid concentrations showed a non-opioid-receptor-mediated block, and meperidine showed local anesthetic properties. Behavioral antinociception studies using different noxious stimuli and somatic nerves showed mixed results with perineural fentanyl. None of these studies was done in the setting of peripheral inflammation which, as previously noted, increases axonal transport of opioid receptors to the periphery.

Clinical Studies of Perineural Opioid Effect A case report and small series in the 1980s described prolonged analgesia from perineural morphine in patients with cancer or chronic pain.26 These results should be cautiously applied to acute pain settings, however, since major nervous system changes are likely in patients with long-standing pain. Numerous studies on perineural opioid application in acute pain have provided variable results. The two questions that have been proposed are whether there is a statistically significant benefit of perineural opioid on sensorimotor block (intraoperative anesthesia) or analgesia (postoperative), and, if so, is the effect large enough to matter? OPIOIDS AS LOCAL ANESTHETIC ADJUVANTS

Both questions were addressed in a systematic review of available studies on nonarticular, perineural opioid administration published by Picard and coworkers in 1997. They assessed the quality of clinical studies excluding meperidine, but including morphine, fentanyl, alfentanil, buprenorphine, and butorphanol and identified 26 evaluable trials involving 952 patients. Half of the 10 trials showing intraoperative benefit had statistically significant results, but of a magnitude that was not felt by the authors to be clinically important. Of the 17 postoperative studies, 5 reported statistically significant effects, but again none were felt to be clinically important by Picard and coworkers. Studies of higher quality were found to be less likely to show opioid benefit. Overall, they concluded there was no evidence at that time for clinically significant analgesia from perineural opioid administration.27 Murphy and coworkers published an additional review of analgesic adjuncts for brachial plexus block in 2000. Of the 10 evaluable studies using opioids as local anesthetic adjuncts, the authors concluded, “It is not clear whether opioids added to brachial plexus block provide significant analgesic benefit.”28 Only two of the positive studies included in the reviews by Picard and Murphy were done in such a way as to exclude a systemic opioid effect or central spread of the injectate. The axillary injection site is preferable to supraclavicular or interscalene to exclude direct spread of opioid to receptors on the DRG or the neuraxis.

125

TABLE 2. Recent Clinical Trials of Perineural Opioids (Excluding Buprenorphine) Author (Date) Likar (2001) Bouaziz (1999) Fanelli (2001)

P/G

Block Site

Opioid

LA

SCG

Result

35/2

Inf. alveolar nerve Axillary single shot Axillary multi inject.

Morphine (M), 1 mg Sufentanil (S), 5, 10, 20 ␮g Fentanyl (F), 1 ␮g/kg

Articaine Epinephrine Mepivacaine (M), 1.5% 40 mL Ropivacaine (R), 0.75% 20 mL

No

No difference in 24 hr VAS pain score or diclofenac use

No

Motor block duration decreased by S 20 ␮g Sensory block unchanged Time to first analgesic: 11 hr R; 11.8 hr RF VAS Score at first analgesic: 60 R; 70 RF No difference in onset, success Success 4 nerves: improved radial/mscn w/ F 95% vs. 64% Onset 4 nerves: slower onset with F Sensory duration and time to first analgesic: longer AxF 295⬘ than IV F 210⬘ or placebo 215⬘ F increased sensory duration: 10 hr BF, 6.9 hr B, 5.9 hr DBF F increased analgesia: 20.9 hr BF, 11.6 hr B, 12 hr DBF F increased motor duration: 10.7 hr BF vs. 4.9 hr B Time to first analgesic: Longer, 700⬘ AxM vs. 305⬘ IV M or 295⬘ Ax placebo Decreased 24-hr analgesic use AxM vs. IV M or Ax placebo

92/4 30/2

No

Nishikawa (2000)

66/3

Axillary single shot

Fentanyl (F), 100 ␮g

Lidocaine, 1.5% with 1/200,000 epi; 40 mL

Yes IV

Karakaya (2001)

60/3

Axillary single shot

Fentanyl (F), 100 ␮g

No

Reuben (2000)

82/5

Axillary single shot

Morphine, 5 mg

Bupivacaine (40 mL) B, 0.25% DB, 0.125% Lidocaine, 1.5% with 1/200,000 epi, 40 mL

Yes IV

P/G ⫽ patients/groups; SCG ⫽ systematic control group; Ax ⫽ axillary; B ⫽ bupivacaine; DB ⫽ dilute bupivacaine; F ⫽ fentanyl; M ⫽ morphine; mscn ⫽ musculocutaneous nerve; R ⫽ ropivacaine; S ⫽ sufentanil.

Bourke and coworkers compared axillary injection of 0.1 mg/kg morphine with lidocaine/epinephrine to axillary local anesthetic with IV morphine in 40 patients undergoing upper extremity surgery. They found no significant difference in block duration, or VAS pain scores, but found a significantlyreduced (by half) consumption of analgesic capsules in the first 24 hours in the axillary morphine group.29 Wajima and coworkers evaluated the addition of a continuous infusion of butorphanol at 83.3 ␮g/hr (2 mg/d) through an axillary catheter after axillary mepivacaine 1.5% for surgical anesthesia. They compared VAS pain scores and supplemental analgesic consumption. The control group received the same continuous butorphanol dose by IV infusion. The study included 22 patients. There was a significant reduction of pain scores from 9 to 24 hours, with mean pain scores in the IV group ranging from 1.7 to 3.3, and mean scores in the axillary butorphanol group 0.6 to 0.7. There was no difference in supplementary analgesic consumption or systemic side effects. They concluded butorphanol had beneficial analgesic effects when infused in a perineural sheath.30

Recent Clinical Trials of Perineural Fentanyl, Sufentanil, and Morphine Studies published since the reviews of Picard and Reuben have continued to test various opioids in the acute pain setting, with mixed results (Table 2). In dental pain models, Likar administered 1 mg morphine or saline with articaine/epinephrine for inferior alveolar block in patients with established inflammation of surrounding mandibular teeth. They found no difference between groups in VAS pain scores or diclofenac consumption for 24 hours.16 Local morphine injection reduced pain scores significantly. Two groups have recently found no benefit to axillary fentanyl or sufentanil. Bouaziz and coworkers performed a doseresponse study with sufentanil (0-20 ␮g) added to 1.5% mepivacaine for axillary block. There was no difference in onset of motor or sensory block or in duration of sensory block. Postoperative analgesia was not evaluated. The duration of the motor block was, in fact, reduced in the highest sufentanil dose group to 172 minutes (range 115-260) compared with 234

126

minutes (range 128-305) in the control group.31 Using the longer-acting local anesthetic, ropivacaine 0.75%, Fanelli and coworkers also reported no benefit from adding fentanyl 1 ␮g/kg to a low volume, multi-injection axillary block. The onset time, block success, time to first analgesic, and postoperative analgesic consumption did not differ.32 A positive benefit of morphine on duration of axillary block analgesia following hand surgery was shown by Reuben and coworkers using morphine 5 mg added to lidocaine 1.5% for axillary block. The addition of verapamil was also tested, such that five groups of patients were included. The group receiving axillary morphine 5 mg had significantly longer analgesia (720 ⫾ 270 minutes) than the group that received IV morphine 5 mg (305 ⫾ 56 minutes), and consumed significantly fewer supplemental analgesics (4.1 ⫾ 2.6 tabs) versus (8.0 ⫾ 2.9 tabs). The sensorimotor block duration and the pain scores (VAS) were not different, however.33 One design weakness of this study was that the systemic morphine control patients received an IV bolus, and an IM injection might more closely mirror (and exclude) a systemic effect of a perineural morphine injection. Nishikawa and coworkers added fentanyl 100 ␮g to 1.5% lidocaine with epinephrine for axillary block and included an IV fentanyl systemic control. They showed a slower onset of anesthesia with the addition of fentanyl attributed to a reduced pH of the solution, but an increase in duration of sensory block (230 ⫾ 65 to 323 ⫾ 96 minutes) and time to onset of pain (210 ⫾ 62 to 295 ⫾ 85 minutes) compared with the IV fentanyl control group.34 Karakaya and coworkers showed significant potentiation of dilute bupivacaine for axillary block by adding fentanyl 100 ␮g. They used 0.25 and 0.125% bupivacaine and assessed sensory and motor block as well as time to first analgesic and VAS pain scores. The 0.125% bupivacaine with fentanyl was inadequate for surgical anesthesia, but fentanyl improved the duration of sensory block and duration of analgesia of 0.25% bupivacaine. The sensory block (time to paresthesia) increased from 6.9 ⫾ 0.2 to 10.1 ⫾ 0.7 hours, and the time to VAS ⬎4 increased from 11.6 ⫾ 0.4 to 20.9 ⫾ 0.4 hours when fentanyl was added. They concluded that high concentrations of long-acting local anesthetic studied by others obscured the benefit of adding fentaWELLER AND BUTTERWORTH

TABLE 3. Buprenorphine Trials Author (Date)

P/G

Block Site

Opiate

LA

SCG

Results

Viel (1989)

40/2

Supraclavicular

Bupivacaine, 0.5%, 40 mL

No

Duration of analgeisa longer: 35 hr BBr vs. 18.25 hr BM Duration of sensory block: unchanged

Bazin (1997)

89/4

Supraclavicular

Bupivacaine, 0.5%; Lidocaine, 1% 1/200,000 epi (0.4 mL/kg)

No

Duration of analgesia longer: 24.5 hr S, 21 hr M, 20 hr B vs. 11.5 hr control

Candido (2001)

40/2

Supraclavicular

Buprenorphine, 3 ␮g/kg M, 50 ␮g/kg Buprenorphine, 3 ␮g/kg Sufentanil, 0.2 ␮g/kg M, 75 ␮g/kg Buprenorphine, 0.3 mg

No

Duration of analgesia longer: 17.4 Br vs. 5.3 hr placebo

Candido (2002)

60/3

Axillary single shot

1% mepivacaine 0.2% tetracaine 1/200,000 epi (40 mL) 1% mepivacaine 0.2% tetracaine 1/200,000 epi (40 mL)

Yes IM

Onset of pain: 22.3 hr AxBr, 12.5 hr IMBr, 6.6 hr placebo VAS pain score at first analgesic: 2.5 AxBr, 4.4 IMBr, 6.2 placebo

Buprenorphine, 0.3 mg

P/G ⫽ patients/groups; SCG ⫽ systemic control group; B ⫽ bupivacaine; Br ⫽ buprenorphine; M ⫽ morphine; S ⫽ sufentanil.

nyl.35 The absence of a systemic control group is a major weakness of this study.

Is Perineural Buprenorphine Unique? Buprenorphine is considered a partial ␮-receptor agonist with some unique properties. It has considerably greater (24-fold) receptor affinity than fentanyl or (50-fold) morphine and has intermediate lipid solubility.36,37 Three different groups evaluated the perineural application of buprenorphine with local anesthetic; all demonstrated significant prolongation of analgesia when added to brachial plexus block (Table 3). Viel and coworkers, Bazin and coworkers, and Candido and coworkers all added buprenorphine 0.2 to 0.3 mg to brachial plexus local anesthetics, and all showed markedly prolonged mean duration of postoperative analgesia ranging from 8.5 to 17 hours.38-40 Detracting from these results, however, is the fact that all three studies used a supraclavicular site of injection and failed to include a systemic control group. Candido and coworkers performed another study to address these criticisms and again evaluated buprenorphine, 0.3 mg, or saline added to a mixture of tetracaine/mepivacaine/epinephrine for single injection axillary block. A third group had axillary local anesthetic and IM injection of buprenorphine 0.3 mg. There was a significant prolongation of time to first analgesic in both buprenorphine groups, with the greatest effect in the axillary buprenorphine group. The time to first analgesic was 6.6 ⫾ 1.02 hours in the control, 12.5 ⫾ 1.5 hours in the IM group, and 22.3 ⫾ 3.1 hours in the axillary buprenorphine group. There was no difference in the rate of nausea, vomiting, or headache between groups.41 Clearly, buprenorphine in this dose had systemic analgesic effects and also showed more dramatic additional peripheral analgesic effects.

Discussion and Conclusions The application of opioids to sensory nerve endings in inflammatory conditions has a sound scientific foundation and considerable evidence for clinical effectiveness. On the other hand, despite animal and clinical studies that have demonstrated antinociception from perineural application of fentanyl, morphine, or buprenorphine, there is no current scientific evidence for the existence of mid-axonal opioid receptors in sensory afferent nerves. Opioid receptors are plentiful in the DRG, and OPIOIDS AS LOCAL ANESTHETIC ADJUVANTS

in central and peripheral nerve terminals with inflammation. However, even the latest techniques of receptor localization have failed to demonstrate appreciable ligand binding along the middle portion of the sciatic nerve of a rat with distal inflammation. There is also little evidence that perineural opioids have effects through a non-opioid-receptor-mediated mechanism. With increased concentrations or intraneural application, reductions of CAP have been demonstrated; nevertheless, there is no effect on intact nerve action potentials of typical concentrations of perineural opioids excepting those opioids with known local anesthetic properties. Karakaya and Power demonstrated potentiation of dilute local anesthetic activity, however, and there may be some direct action of opioid molecules on nerve function by another mechanism yet to be identified.42 Is it conceivable that perineural opioids could bind to opiate receptors within the axoplasm in transit to the central or peripheral nerve endings? Diffusion of an opioid into the axoplasm may occur depending on the ionization and lipid solubility of the agent, analogous to the transfer of opioids from epidural space to CSF where intermediate lipophilicity is ideal.43 Although the opioid GPCR is not found on nerve membrane mid-axon, there is evidence that opioid receptors are transported within the membrane of intracellular cytoplasmic vesicles, and the exocytosis of these vesicles leads to the incorporation of the receptor into the nerve membrane.44 It has been suggested that an opioid with high receptor affinity such as lofentanil (or buprenorphine) may bind to a ␮-receptor and circulate proximally and distally within the axoplasm to reach an active site.45 The time course of such a process would be likely to take days, however, and clinical effects demonstrated within 12 to 24 hours cannot be explained by this mechanism. In conclusion, at the present time only a minority of wellcontrolled studies have demonstrated an effect of perineural opioid administration. A credible basic science mechanism, by which such administration would be expected to influence nociceptive nerve transmission, especially by an opioid-receptormediated action, is not available. The recent advances in genomics and in characterizing and localizing opioid receptors may provide us with evidence to choose the correct opioid, apply it to the correct nerve in the most appropriate setting of noxious stimuli to demonstrate an effect, and evaluate the effect at the appropriate time for peak activity. Alternatively, this knowledge may allow us to conclude that this is an illogical site

127

to administer opioids, and focus research on more appropriate adjuvants to local anesthetics for regional anesthesia.

References 1. Wood A: On a new method of introducing medicines into the system, more especially applicable to painful local nervous affections, in Cole F (ed): Milestones in Anesthesia: Readings in the Development of Surgical Anesthesia, 1665-1940. Lincoln, NE, University of Nebraska Press, 1968, pp 133-134 2. Kitahata LM, Kosaka Y, Taub A: Lamina-specific suppression of dorsal horn unit activity by morphine sulphate. Fed Proc 32:693ABS, 1973 3. Wang JK, Nauss LA, Thomas JE: Pain relief by intrathecally applied morphine in man. Anesthesiology 50:149-151, 1979 4. Hamber EA, Viscomi CM: Intrathecal lipophilic opioids as adjuncts to surgical spinal anesthesia. Reg Anesth Pain Med 24:255-263, 1999 5. Cousins MJ, Mather LE: Intrathecal and epidural administration of opioids. Anesthesiology 61:276-310, 1984 6. Ready LB: Spinal opioids in the management of acute and postoperative pain. J Pain Symptom Manage 5:138-145, 1990 7. Sabbe MB, Yaksh TL: Pharmacology of spinal opioids. J Pain Symptom Manage 5:191-203, 1990 8. Jorgensen H, Wetterslev J, Moiniche S, Dahl JB: Epidural local anaesthetics versus opioid-based analgesic regimens on postoperative gastrointestinal paralysis, PONV and pain after abdominal surgery. Cochrane Database Syst Rev (4):CD001893, 2000 9. Sawynok J: Topical and peripherally acting analgesics. Pharmacol Rev 55:1-20, 2003 10. Hassan AH, Ableitner A, Stein C: Inflammation of the rat paw enhances axonal transport of opioid receptors in the sciatic nerve and increases their density in the inflamed tissue. Neuroscience 55:185195, 1993 11. Zo¨llner C, Shaqura MA, Bopaiah CP: Painful inflammation-induced increase in ␮-opioid receptor binding and G-protein coupling in primary afferent neurons. Mol Pharmacol 64:202-210, 2003 12. Fields HL, Emson PC, Leigh BK: Multiple opiate receptor sites on primary afferent fibres. Nature 284:351-353, 1980 13. Laduron PM, Janssen PF: Axoplasmic transport and possible recycling of opiate receptors labelled with 3H-lofentanil. Life Sci 31:457462, 1982 14. Gupta A, Bodin L, Holmstro¨m B: A systematic review of the peripheral analgesic effects of intraarticular morphine. Anesth Analg 93: 761-770, 2001 15. Dionne RA, Lepinski AM, Gordon SM: Analgesic effects of peripherally administered opioids in clinical models of acute and chronic inflammation. Clin Pharmacol Ther 70:66-73, 2001 16. Likar R, Koppert W, Blatnig H: Efficacy of peripheral morphine analgesia in inflamed, non-inflamed and perineural tissue of dental surgery patients. J Pain Symptom Manage 21:330-337, 2001 17. Reuben SS, Vieira P, Faruqi S: Local administration of morphine for analgesia after iliac bone graft harvest. Anesthesiology 95:390-394, 2001 18. Tegeder I, Meier S, Burian M, et al: Peripheral opioid analgesia in experimental human pain models. Brain 126:1092-1102, 2003 19. Frank GB, Sudha TS: Effects of enkephalin, applied intracellularly, on action potentials in vertebrate A and C nerve fibre axons. Neuropharmacology 26:61-66, 1987 20. Jurna I, Grossmann W: The effect of morphine on mammalian nerve fibres. Eur J Pharmacol 44:339-348, 1977 21. Gissen A, Gugino LD, Datta S: Effects of fentanyl and sufentanil on peripheral mammalian nerves. Anesth Analg 66:1272-1276, 1987 22. Yuge O, Matsumoto M, Kitahata LM: Direct opioid application to peripheral nerves does not alter compound action potentials. Anesth Analg 64:667-671, 1985 23. Power I, Brown DT, Wildsmith JA: The effect of fentanyl, meperidine

128

24.

25.

26.

27.

28.

29. 30.

31.

32.

33. 34.

35.

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

and diamorphine on nerve conduction in vitro. Reg Anesth 16:204208, 1991 Grant GJ, Vermeulen K, Zakowski MI: Perineural antinociceptive effect of opioids in a rat model. Acta Anaesthesiol Scand 45:906910, 2001 Kayser V, Gobeaux D, Lombard MC, et al: Potent and long lasting antinociceptive effects after injection of low doses of a mu-opioid receptor agonist, fentanyl, into the brachial plexus sheath of the rat. Pain 42:215-225, 1990 Mays KS, Lipman JJ, Schnapp M: Local analgesia without anesthesia using peripheral perineural morphine injections. Anesth Analg 66:417-420, 1987 Picard PR, Trame`r MR, McQuay HJ: Analgesic efficacy of peripheral opioids (all except intra-articular): a qualitative systematic review of randomised controlled trials. Pain 72:309-318, 1997 Murphy DB, McCartney CJ, Chan VW: Novel analgesic adjuncts for brachial plexus block: a systematic review. Anesth Analg 90:11221128, 2000 Bourke D, Furman WR: Improved postoperative analgesia with morphine added to axillary block solution. J Clin Anesth 5:114-117, 1993 Wajima Z, Nakajima Y, Kim C: IV compared with brachial plexus infusion of butorphanol for postoperative analgesia. Br J Anaesth 74:392-395, 1995. Bouaziz H, Kinirons BP, Macalou D, et al: Sufentanil does not prolong the duration of analgesia in a mepivacaine brachial plexus block: a dose response study. Anesth Analg 90:383-387, 2000 Fanelli G, Casati A, Magistris L: Fentanyl does not improve the nerve block characteristics of axillary brachial plexus anaesthesia performed with ropivacaine. Acta Anaesthesiol Scand 45:590-594, 2001 Reuben SS, Reuben JP: Brachial plexus anesthesia with verapamil and/or morphine. Anesth Analg 91:379-383, 2000 Nishikawa K, Kanaya N, Nakayama M: Fentanyl improves analgesia but prolongs the onset of axillary brachial plexus block in peripheral mechanism. Anesth Analg 91:384-387, 2000 Karakaya D, Bu¨yu¨kgo¨z F, Baris¸ S: Addition of fentanyl to bupivacaine prolongs anesthesia and analgesia in axillary brachial plexus block. Reg Anesth Pain Med 26:434-438, 2001 Gutstein H, Akil H: Opioid analgesics, in Hardman J, Limbird L (eds): Goodman & Gilman’s The Pharmacologic Basis of Therapeutics (10th ed). New York, McGraw-Hill, 2001, p 601 Lanz E, Simko G, Theiss D: Epidural buprenorphine—a double-blind study of postoperative analgesia and side effects. Anesth Analg 63:593-598, 1984 Viel E, Eledjam JJ, De La Coussaye JE: Brachial plexus block with opioids for postoperative pain relief: comparison between buprenorphine and morphine. Reg Anesth 14:274-278, 1989 Bazin JE, Massoni C, Bruelle P: The addition of opioids to local anaesthetics in brachial plexus block: the comparative effects of morphine, buprenorphine and sufentanil. Anaesthesia 52:858-862, 1997 Candido KD, Franco CD, Khan MA: Buprenorphine added to the local anesthetic for brachial plexus block to provide postoperative analgesia in outpatients. Reg Anesth Pain Med 26:352-356, 2001 Candido KD, Winnie AP, Ghaleb AH: Buprenorphine added to the local anesthetic for axillary brachial plexus block prolongs postoperative analgesia. Reg Anesth Pain Med 27:162-167, 2002 Yaksh T: Pharmacology and mechanisms of opioid Analgesic activity, in Yaksh T, Maze M, Lynch C, et al (eds): Anesthesia Biological Foundations. Philadelphia, PA, Lippincott-Raven, 1998, p 929 Bernards CM, Shen DD, Sterling ES: Epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidural opioids (part 1): differences among opioids. Anesthesiology 99:455-465, 2003 Shuster S, Riedl M, Li X: Stimulus-dependent translocation of ⌲ opioid receptors to the plasma membrane. J Neurosci 19:26582664, 1999 Laduron PM, Janssen PF: Retrograde axonal transport of receptorbound opiate in the vagus and delayed accumulation in the nodose ganglion. Brain Res 333:389-392, 1985

WELLER AND BUTTERWORTH