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Preventive Analgesia by Local Anesthetics: The Reduction of Postoperative Pain by Peripheral Nerve Blocks and Intravenous Drugs

Barreveld, Antje MD*; Witte, Jürgen MD; Chahal, Harkirat MD*; Durieux, Marcel E. MD, PhD; Strichartz, Gary PhD*

doi: 10.1213/ANE.0b013e318277a270
Pain Medicine: Review Article
Continuing Medical Education

The use of local anesthetics to reduce acute postoperative pain has a long history, but recent reports have not been systematically reviewed. In addition, the need to include only those clinical studies that meet minimum standards for randomization and blinding must be adhered to. In this review, we have applied stringent clinical study design standards to identify publications on the use of perioperative local anesthetics. We first examined several types of peripheral nerve blocks, covering a variety of surgical procedures, and second, we examined the effects of intentionally administered IV local anesthetic (lidocaine) for suppression of postoperative pain. Thirdly, we have examined publications in which vascular concentrations of local anesthetics were measured at different times after peripheral nerve block procedures, noting the incidence when those levels reached ones achieved during intentional IV administration. Importantly, the very large number of studies using neuraxial blockade techniques (epidural, spinal) has not been included in this review but will be dealt with separately in a later review. The overall results showed a strongly positive effect of local anesthetics, by either route, for suppressing postoperative pain scores and analgesic (opiate) consumption. In only a few situations were the effects equivocal. Enhanced effectiveness with the addition of adjuvants was not uniformly apparent. The differential benefits between drug delivery before, during, or immediately after a surgical procedure are not obvious, and a general conclusion is that the significant antihyperalgesic effects occur when the local anesthetic is present during the acute postoperative period, and its presence during surgery is not essential for this action.

Published ahead of print February 13, 2013 Supplemental Digital Content is available in the text.

From the *Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Boston, Massachusetts; and Department of Anesthesiology, University of Virginia, Charlottesville, Virginia.

Accepted for publication October 4, 2012.

Published ahead of print February 13, 2013

The authors declare no conflicts of interest.

Drs. Antje M. Barreveld and Jürgen Witte contributed equally to this work.

Dr. Jürgen Witte is currently affiliated with the Department of Anesthesiology and Intensive Care, University of Muenster, Muenster, Germany.

Reprints will not be available from the authors.

Address correspondence to Gary Strichartz, PhD, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Pain Research Center, BWH/MRB611, 75 Francis St., Boston, MA 02115-6110. Address e-mail to

The perioperative use of analgesic drugs to reduce postoperative pain is properly termed “preventive analgesia.”1,2 (In contrast, the term “preemptive analgesia” is limited to describing effects from drugs that are administered before any surgical manipulations.) Reduced postoperative pain hastens functional recovery and hospital discharge, decreases acute morbidity, and may well reduce the probability of developing chronic postoperative pain. However, it appears that the incidence of postoperative pain is underreported and that the symptoms are undertreated.3 Anesthesia & Analgesia is dedicated to a relatively exhaustive review of articles from the past 5 to 10 years that report criteria-documented clinical studies of preventive analgesia.4 The present work reviews the results of studies where local anesthetics were used for peripheral nerve blocks or intentionally given IV, during or after the surgical procedure. Results are organized by surgical procedure, inasmuch as we think that this information is best used as a resource for anesthesiologists and surgeons who are interested in reducing postoperative pain from specific procedures. The literature searches for this article extend through May 2012. We encourage the interested reader/practitioner to conduct a search of the more recent publications for a complete collection, keeping in mind the importance of inclusion criteria for discerning among clinical studies.1

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Studies on the use of peripheral nerve blocks for acute postoperative pain control after lower and upper extremity procedures and transversus abdominis plane (TAP) blocks were identified using the following search criteria on PubMed:

Search limits: 01/01/2005 to 06/01/2012, clinical trial, randomized controlled trial, humans, English language.

Search terms: “local anesthetic AND femoral nerve block AND pain”; “local anesthetic AND lumbar plexus block AND pain”; “local anesthetic AND psoas compartment block AND pain”; “local anesthetic AND sciatic nerve block AND pain”; “local anesthetic AND intraarticular AND pain”; “local anesthetic AND periarticular AND pain”; “local anesthetic AND brachial plexus block AND pain”; “local anesthetic AND interscalene nerve block AND pain”; “local anesthetic AND transversus abdominis plane block AND pain”; “local anesthetic AND TAP block AND pain”; “local anesthetic AND nerve block AND dexamethasone AND pain”; “local anesthetic AND nerve block AND clonidine AND pain”; “local anesthetic AND nerve block AND dexmedetomidine AND pain”; “local anesthetic AND nerve block AND ketorolac AND pain”; “local anesthetic AND nerve block AND benzodiazepine AND pain”; “local anesthetic AND intraarticular AND dexamethasone AND pain”; “local anesthetic AND intraarticular AND clonidine AND pain”; “local anesthetic AND intraarticular AND dexmedetomidine AND pain”; “local anesthetic AND intraarticular AND dexamethasone AND pain”; “local anesthetic AND intraarticular AND ketorolac AND pain”; “local anesthetic AND intraarticular AND benzodiazepine AND pain.”

The use of IV local anesthetics to reduce postoperative pain was searched on PubMed by the following criteria:

Search limits: randomized controlled trial, clinical trial, humans, English language (no date limits were set because there exists only a small number of published studies on this subject).

Search terms: “intravenous AND local anesthetic”; “intravenous AND lidocaine”; “intravenous AND local anesthetic AND pain”; “intravenous AND local anesthetic AND postoperative pain”; “intravenous AND lidocaine AND postoperative pain”; “intravenous AND lidocaine AND pain”; “intravenous AND local anesthetic AND preventive analgesia”; “intravenous AND lidocaine AND preventive analgesia.”

All studies identified using the above search criteria were evaluated for the following inclusion criteria:

  1. Randomized controlled trials (except in a few instances as is noted)
  2. Postoperative pain evaluation and/or rescue analgesic use
  3. Methodologically sound design1

References of articles thus selected were also searched for relevant studies. The studies excluded primarily investigated variations in block techniques or included opioid adjuvants in the local anesthetic mixture and were therefore not examined in this review. All nerve block studies identified were organized by surgical type to assist readers’ decision-making in choosing nerve block technique(s) and local anesthetic(s).

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Peripheral Nerve Blocks

The nerve block searches led to 471 journal articles. Duplicated studies were removed and all remaining studies and the references were screened for eligibility, revealing 89 studies that met inclusion criteria (Table 1, overview).

Table 1

Table 1

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Total Knee Arthroplasty

Thirty-five studies in total knee arthroplasty (TKA) surgery examined the following local anesthetic injection or infusion techniques: (1) single-shot femoral nerve blocks (SSFNBs); (2) continuous femoral nerve block (CFNB) catheters; (3) sciatic nerve blocks combined with other blocks; (4) single-shot lumbar plexus block (SSLPB) or continuous lumbar plexus block (CLPB); (5) intraarticular (IA)/periarticular injections or infusions. Of these 35 studies, 20 compared a specific intervention with IV patient-controlled analgesia (PCA) or “no block” control or with a placebo injection/infusion or sham block; all 19 demonstrated a positive analgesic effect of the local anesthetic(s), except one study that found no analgesic benefit of an IA infusion of 0.25% bupivacaine versus placebo.5

The remaining 15 studies compared different local anesthetics, local anesthetic concentrations, or techniques. For instance, the administration of a preoperative versus postoperative SSFNB did not impact pain or opioid use.6 Bupivacaine versus ropivacaine showed similar efficacy in SSFNB with or without a single-shot sciatic nerve block.7–9 As might be predicted, a local anesthetic injection decreases pain for the expected duration of the anesthetic and most studies examine acute postoperative pain up to 24 to 48 hours after surgery. With single injections, this effect did not seem to persist beyond postoperative care unit discharge,10,11 although opioid use was shown to be decreased up to 48 hours after the injection in elderly patients.11 An additional study comparing a low-dose bupivacaine plus hydromorphone epidural infusion combined with an SSFNB demonstrated decreased pain versus an epidural alone.12

A continuous femoral nerve catheter is often placed for knee arthroplasty and the resulting CFNB shows improved pain control versus SSFNB.13 When administered with or without a single-shot sciatic nerve block, CFNB consistently demonstrated decreased pain and/or opioid use when compared with PCA control or placebo infusion,14–17 and continuous sciatic nerve block proved to be superior to a single-shot nerve block.18,19 Ropivacaine infusions for 24 to 48 hours, and up to 96 hours, were primarily studied, although there was no difference between ropivacaine or levobupivacaine.20 When compared with an epidural infusion, the epidural provided superior pain control, as might be predicted given that a femoral block does not cover the entire surgical area.21 However, if a sciatic nerve block was performed in addition to a CFNB and compared with an epidural, pain scores and/or opioid use were unchanged,22 and as predicted a single-shot or continuous sciatic nerve block administered in addition to a CFNB was superior to a CFNB or CLPB alone.22–25

CFNBs have also been compared with IA infusions or injections and have been shown to be superior26 or have no difference when a bolus is delivered by femoral catheter every 4 hours;27 however, the addition of an IA injection to CFNB improved analgesia when compared with a CFNB alone.28 The majority of studies examining IA injections or infusions administered exclusively do, however, demonstrate improved analgesia versus placebo or PCA control or intrathecal morphine29–32 (one negative study is mentioned above).5 There was no difference noted between IA or periarticular infusion.33

Finally, 4 studies using lumbar plexus blocks (also referred to as “psoas compartment blocks”) in TKA were identified. A CLPB with a sciatic block decreased pain when compared with a PCA34 and even was shown to be as effective as an epidural.35 One study using ropivacaine did not show a difference in analgesia between a CLPB versus SSLPB when both were combined with a sciatic block,36 although another study using levobupivacaine that also used a placebo infusion did demonstrate improved pain control with a CLPB versus SSLPB37 (Table 1, Refs. 38 and 39, regarding TKA but not included in the text).

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Anterior Cruciate Ligament Reconstruction and Arthroscopic Knee Surgery

Four studies on anterior cruciate ligament reconstruction were identified and 2 of the 3 did not show an analgesic benefit of bupivacaine given by SSFNB or IA infusion versus placebo,40,41 whereas one study using ropivacaine and bupivacaine versus placebo did show a positive analgesic effect of SSFNB.42 One study compared CFNB with a sciatic nerve block versus a SSFNB with a sciatic nerve block and IA infusion and found that the CFNB provided improved pain control.43 In arthroscopic knee surgery, 6 studies meeting our search criteria were identified.44–49 Four of the 6 compared SSLPB or IA injection to placebo or no block and showed a positive analgesic effect.44–47 SSLPB with sciatic block was superior to SSFNB with sciatic block in arthroscopic knee surgery.48

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Total Hip Arthroplasty

Eight studies meeting search criteria were identified (Table 1); 4 of these were compared with placebo or control and showed a positive analgesic effect of IA bolus or infusion or CLPB.50–53 The choice of local anesthetic for CLPB or SSLPB did not affect preventive analgesia,54,55 and extending a ropivacaine infusion beyond 24 hours did not provide additional benefit.56 CLPB versus CFNB did not show a difference in pain control but CFNB decreased time to first ambulation.57

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Foot and Ankle Surgery

Four studies meeting search criteria were identified, all using sciatic or popliteal blocks (Table 1). Only 1 study compared popliteal block with PCA control and found a positive analgesic effect.58 Two studies demonstrated that 0.5% or 0.75% levobupivacaine was more effective than 0.5% ropivacaine,59,60 and as long as the total dose of ropivacaine is constant, the concentration and infusion rate can be varied.61

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Arthroscopic Shoulder Surgery

Ten studies meeting search criteria were identified and 6 of the 10 studies compared the nerve block with a control and the remaining 4 studies compared nerve block techniques (Table 1). Of the 6 controlled studies, 2 did not demonstrate an analgesic effect of local anesthetic administered by subacromial infusion versus placebo or PCA control.62,63 Clinicians have tried adding subacromial catheters to interscalene block (ISB) to prolong the analgesic effect of ISB but this has not been shown to be superior to ISB alone.64,65 ISB is well accepted as effective pain management in arthroscopic shoulder surgery. A 2004 study comparing IA injection, ISB, and suprascapular block versus control demonstrated most effective pain control at 24 hours with ISB,66 whereas a 2011 study did not demonstrate any analgesic benefit after single-shot ISB (SSISB) beyond 6 hours.65 Five of the 6 studies examined for this review have shown that ISB provides improved analgesia versus an IA/subacromial infusion or block,64,65,67–69 whereas 1 study demonstrated similar pain control with continuous IA infusion for 48 hours when compared with SSISB, although this study could have compared continuous infusions of both interventions to ensure a more accurate comparison.70

Two studies in patients undergoing arthroscopic acromioplasty and/or rotator cuff repairs comparing SSISB with continuous ISB (CISB) showed significant reduction in visual analog scale (VAS) scores and opioid consumption with CISB.58,71 Using lower volumes of local anesthetic has been shown to provide effective analgesia with minimal postoperative motor dysfunction in patients undergoing arthroscopic shoulder surgery.72 Therefore, in arthroscopic shoulder surgery, an IA injection or infusion does not definitively improve pain control versus no intervention and is inferior to ISB. Moreover, concerns have been raised about local anesthetics impeding wound healing in the case of subacromial catheters.69 There are also case reports of glenohumeral chondrolysis after IA pain pumps and IA local anesthetic injection,73–75 and subacromial catheters are not routinely recommended at this time.

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Major/Open Shoulder Surgery

Eight studies meeting search criteria were identified and 4 studies comparing ISB versus placebo or no block demonstrated improved analgesia.76–79 One study showed that CISB with a patient-controlled catheter (PCISB) is superior to SSISB but the benefits were noted only in the first 24 hours.77 PCISB also was beneficial in early rehabilitation.78

The remaining 4 studies examined varying volumes and concentrations of local anesthetics in ISB for open shoulder surgery.80–83 ISB is associated with a 100% incidence of hemidiaphragmatic paresis from block of the phrenic nerve.84,85 It is contraindicated in patients with moderate to severe chronic obstructive pulmonary disease.86 Low volume blocks, down to 5 mL from the conventional 20 to 30 mL, decrease the incidence of hemidiaphragmatic paresis to 45%80 and even 0%87 with no difference in analgesic effect. Three studies compared 0.2%, 0.3%, 0.4% ropivacaine infusion.81–83 The need for running a high concentration, low-volume infusion is especially important in ambulatory patients who are discharged home with a fixed reservoir of local anesthetic with limited capacity; however, a higher concentration can lead to a denser sensory block but with unwanted motor block and side effects leading to overall lower patient satisfaction.83 Patients receiving 0.2% received similar analgesia to 0.4% ropivacaine with less motor block and higher patient satisfaction.81,83 There was no difference in pain scores between 0.2% and 0.3% ropivacaine; however, opioid requirements were less in the 0.3% group.82

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Hand and Forearm Surgery

A 2004 study showed improved pain control with axillary block versus general anesthesia on the day of surgery but no difference in analgesic effect measured on postoperative day 1, 7, or 14.88 Only 1 study in hand surgery patients met inclusion criteria for this review and examined low-dose anesthetic mixture with axillary block versus general anesthesia and also showed improved pain scores and decreased opioid use up to 24 hours postoperatively but not beyond.89

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TAP Block

TAP block is a relatively new technique first described by Rafi90 in 2001 and deserves briefly mentioning because it is gaining in popularity for use in pain control after laparoscopy or other open lower abdominal procedures. A 2011 meta-analysis examined 4 studies using TAP block.91 Twelve studies on TAP block were identified for this review and 10 of the 12 studies showed a benefit of TAP block for postoperative pain control (Table 1).92–101 The procedures studied included laparoscopic surgery, open appendectomy and abdominal surgery, cesarean delivery, and total abdominal hysterectomy. In 3 studies, surgery was completed under spinal anesthesia whereas the other 9 used general anesthesia. One study compared TAP block with epidural analgesia and found similar pain scores between groups but decreased opioid use in the epidural group, suggesting that TAP block, although not superior to epidural analgesia, may be a reasonable alternative where epidural analgesia is contraindicated or not performed.93 TAP block did not provide additional analgesic benefit in children undergoing laparoscopic appendectomy; all children received local anesthetic infiltration of port sites.102 TAP block was also ineffective in 1 study in which patients underwent cesarean delivery and all received intrathecal morphine, which by itself is effective pain control.103 Intrathecal morphine, however, can cause side effects such as respiratory depression, pruritus, and nausea. TAP block therefore seems to be a valuable tool in treating postoperative lower abdominal surgical pain after general anesthesia but not after receiving intrathecal morphine. TAP block seems to be safe, can minimize side effects of traditional opioid therapy (although further studies are needed to substantiate this claim) and can be used when a neuraxial technique is contraindicated.

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Local Anesthetic Nerve Block Adjuvants

Peripheral Nerve Blocks and Local Anesthetic Adjuvants

Various adjuvants have been tried to improve the analgesic effects of nerve blocks. The use of epinephrine to prolong the block has been well established in clinical practice. We excluded opioid adjuvants because opioids already have an inherent strong analgesic effect and any benefit from peripheral administration could be attributed to systemic plasma effects, for instance. One study examining naloxone added to a mix of lidocaine and fentanyl or lidocaine alone in axillary nerve block for forearm surgery demonstrated prolonged sensory and motor block versus placebo or fentanyl alone.104 The study is limited by the fact that epinephrine was not used.

Additional adjuvants have been studied in peripheral nerve blocks. A 2009 meta-analysis examined the effect of clonidine on peripheral nerve and plexus blocks and concluded that only a brief prolongation of analgesia was achieved, but with additional prolonged motor block and increased risk of side effects such as hypotension, fainting, and sedation.105 Dexmedetomidine is also an α2 agonist but with α2 selectivity 8 times that of clonidine. When added to local anesthetics such as levobupivacaine, it extends the sensory/motor block and analgesia duration but may lead to side effects such as hypotension and bradycardia, which are expected after IV administration.106 Its long-term effects have not been studied.

Dexamethasone has also been shown to prolong analgesia with upper extremity nerve blocks.107–111 Its use has been recommended when epinephrine is contraindicated. Midazolam has been added to bupivacaine for brachial plexus block and showed improved postoperative analgesia, but data to support its use are limited and it caused additional sedation in subjects, likely secondary to systemic absorption.112 Magnesium 100 to 150 mg when added to prilocaine in axillary plexus block prolonged sensory and motor block and was more effective than IV magnesium,113 but one additional study examining magnesium added to bupivacaine for ISB did not demonstrate prolonged block or decreased opioid use versus placebo although decreased pain scores in the magnesium group were observed.114 Tramadol when added to levobupivacaine for ISB also demonstrated improved analgesia when compared with receiving placebo or even intramuscular tramadol.115 In summary, many adjuvants have been successfully added to local anesthetics to improve pain control but none of the adjuvants has been studied long term and there are insufficient data on their safety in perineural injection.

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Intraarticular Local Anesthetic Adjuvants

Various adjuvant medications to local anesthetics administered in IA infusions or IA single-shot injections for arthroscopic knee surgery have been studied. IA tramadol116 and magnesium sulfate,117 in addition to local anesthetics, seem to decrease pain scores and total analgesic requirements versus local anesthetics alone. IA dexmedetomidine in addition to local anesthetic showed decreased 24-hour opioid use as well as VAS scores, but this was significant only up to 6 hours postoperatively.118 IA ketamine with local anesthetic demonstrates conflicting effects on pain scores and opioid use when compared with local anesthetics alone in arthroscopic knee procedures.119,120 IA morphine and ketorolac in addition to ropivacaine improved pain control versus ropivacaine alone121 but not versus bupivacaine alone.31 In hip surgery, IA clonidine injection in addition to local anesthetic did not, however, show a difference in pain scores or opioid consumption versus local anesthetic alone.122 The use of adjuvant medications in IA local anesthetic solutions needs to be studied further to justify routine use.

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IV Use of Local Anesthetics as Preventive Analgesics

Although many different local anesthetics have been used in clinical practice, only lidocaine has been considered safe for IV use because of its long history of systemic administration as an antiarrhythmic drug. Investigation of any neurologic or cardiovascular toxicity after prolonged, low-dose infusion of other local anesthetics would be of great interest, because these compounds might offer some benefits.

Perioperative IV lidocaine for postoperative analgesia was examined in a 2010 review123 and additional recently published studies meeting our search criteria were identified. For this review, 16 randomized, double-blind, placebo-controlled studies were identified that examined the IV use of local anesthetics in humans and its effect on postoperative pain (Table 2). In the majority of these studies, patients received an initial bolus of lidocaine or equal amounts of saline at induction, followed by a continuous infusion of lidocaine or saline, which was maintained during surgery and, in some studies, for additional time periods of 30 minutes up to 24 hours postoperatively. Surgical procedures that were studied included open and laparoscopic cholecystectomy,124–126 radical prostatectomy,127 major abdominal surgery such as prostatectomy, cystectomy, abdominal nephrectomy, and colectomy, all combined with lymph node dissection,128 open and laparoscopic colorectal surgery,129–132 total hip arthroplasty,133 ambulatory surgery,134,135 abdominal hysterectomy,136 inguinal herniorrhaphy,137 laparoscopic appendectomy,138 and breast surgery.139 A total of 678 patients were enrolled and randomized to lidocaine or placebo administration. The bolus amount was 100 mg in 2 studies and 1.5 mg/kg in all other studies. Infusion rates ranged from 1.5 to 3 mg/kg/h intraoperatively and, when given postoperatively, from 1.33 mg/kg/h to 3 mg/min.

Table 2

Table 2

Ten of 13 clinical trials reported a preventive analgesic effect of lidocaine that lasted longer than 8.5 hours, which is 5.5 times the half-life of IV lidocaine (the definition of preventive effect as used by Katz et al.1). After laparoscopic cholecystectomy, administration of lidocaine for 24 hours reduced pain medication use in the first 2 postoperative days.124,125 When given during radical prostatectomy and maintained for 1 hour postoperatively, a two-thirds reduction in total pain score index could be demonstrated, although the amount of pain medication used and patient satisfaction were not different from the control group.127 After major abdominal surgery, lidocaine administration led to reduced morphine usage and lower pain scores during movement in the first 72 hours after the procedure.128

A preventive analgesic effect could also be demonstrated after laparoscopic colectomy. The intra- and postoperative administration of a continuous lidocaine infusion for 24 hours slightly reduced the use of pain medication and pain scores during movement between the 24th and 48th postoperative hours, compared with the control group.129 When given this treatment during ambulatory surgery and for 1 hour after, patients used less morphine in the first 24 hours after hospital discharge compared with patients who were treated with placebo. After 24 hours, however, there was no difference in the consumption of pain medication or in the pain scores.134 The use of IV lidocaine in ambulatory laparoscopic surgery was also examined by De Oliveira et al.135 The intraoperative administration of lidocaine improved quality of recovery and decreased pain scores in the postanesthesia care unit and opioid consumption in the first 24 hours after surgery. When given during inguinal herniorrhaphy, lower pain scores until 12 hours after surgery were reported, and fentanyl consumption and frequency of PCA pushes were also significantly reduced.137 In addition to intraperitoneal instillation of lidocaine or saline, Kim et al.138 compared intraoperative infusion of lidocaine with intraoperative infusion of saline during laparoscopic appendectomy. Patients who received lidocaine had lower pain scores for 8 hours and lower fentanyl consumption until 24 hours after the end of surgery. Preventive analgesia was also demonstrated when IV lidocaine was given during breast surgery and maintained for 1 hour after the end of the procedure.139 Although there was no significant difference in the consumption of analgesics, a decreased incidence of persistent postsurgical pain was reported.

Three studies with a similar study design failed to demonstrate a preventive analgesic effect of lidocaine. When lidocaine was administered IV during total hip arthroplasty and an infusion was maintained for 60 minutes postoperatively, no difference in pain scores and consumption of analgesics could be detected.133 In a study in patients with colorectal surgery, intraoperative lidocaine administration that was continued for 4 hours postoperatively did not reduce overall piritramide consumption or pain intensities at rest and during coughing, although there was a trend for lower VAS scores in the lidocaine group.130 A preventive analgesic effect could also not be demonstrated after abdominal hysterectomy. Patients who received lidocaine intraoperatively had similar opioid consumption and numeric pain ratings at all time points to those who were treated with placebo.136

A different study design compared thoracic epidural with IV infusion.131 On the day before surgery, an epidural catheter was placed in 60 patients scheduled for open colonic surgery. On the day of surgery, patients were randomized to 1 of 3 groups. One group received a lidocaine bolus of 2 mg/kg followed by a continuous infusion of 3 mg/kg/h via epidural catheter and received saline IV; a second group received the same dose of lidocaine via peripheral IV catheter and saline via the epidural catheter; and the third group received saline IV as well as via the epidural catheter. Postoperative pain was managed with morphine/ropivacaine patient-controlled epidural analgesia (PCEA). In the group treated with IV lidocaine, patients had lower pain scores at rest for 4 hours postoperatively compared with the saline group, and lower pain scores during coughing for 12 hours. The IV group also had higher first PCEA trigger times and lower total PCEA consumption than the control group. However, the group that received lidocaine via an epidural catheter had the best pain relief of all groups.

Swenson et al.132 compared the effect of IV and epidural administration of local anesthetics. In this trial, 42 patients undergoing open colon surgery were enrolled and divided into 2 groups. One group received an IV lidocaine bolus of 1.5 mg/kg during induction, followed by a continuous infusion of lidocaine, which was maintained until return of bowel function or postoperative day 5. The other group received a lidocaine bolus at induction only. Postoperative pain was managed using a thoracic epidural catheter with an infusion of bupivacaine and hydromorphone that was started within 1 hour of the end of surgery and maintained in the same way as the lidocaine infusion in the other group. Although IV lidocaine was as effective as epidural bupivacaine for postoperative pain control, the study design (in particular the absence of a placebo group) does not allow a determination of whether a preventive analgesic effect was present. Five adverse events were recorded in this trial. Two patients of the IV lidocaine group developed typical side effects of local anesthetics such as disorientation and perioral numbness, and one of them had increased lidocaine levels. After these events, the dose in the remaining patients was reduced from 3 to 2 mg/min for patients with a body weight more than 70 kg and from 2 to 1 mg/min for patients with a body weight of less than 70 kg.

Drug interactions with lidocaine were examined in patients scheduled for laparoscopic cholecystectomy randomized to 4 groups.126 The first group received a single dose of the N-methyl-D-aspartate receptor antagonist, dextromethorphan, 30 minutes before skin incision and a continuous lidocaine infusion during surgery. The second group received dextromethorphan before and saline during surgery. The third group received the H1 histamine receptor blocker and serotonin-norepinephrine reuptake inhibitor chlorpheniramine before skin incision and lidocaine during surgery. The fourth group received chlorpheniramine before and saline during surgery. All infusions were terminated at the end of the procedure. Postoperative pain was treated with meperidine. Although VAS scores at rest did not demonstrate a preventive analgesic effect of lidocaine, VAS scores during coughing in patients who were treated with lidocaine were lower in the first 12 hours in the lidocaine/chlorpheniramine groups and lower in the first 24 hours in the lidocaine/dextromethorphan groups. In addition, both lidocaine groups had lower total meperidine consumption than the control groups. These results also suggest a preventive analgesic effect.

In conclusion, 13 of 16 studies demonstrated preventive analgesia by IV administration of lidocaine. This effect, however, could not be associated with a specific regimen or dosage.

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IV Local Anesthetic Drug Levels Resulting from Peripheral Nerve Blocks

Given the large doses of local anesthetics administered for major nerve blocks, and the frequent occurrence of nearby vascular structures, reasonable concern has been expressed about potential systemic drug levels and resulting toxicity. Data from studies examining these levels can also inform us about the therapeutic potential of intra- and postoperative local anesthetic. In one study in which cervical plexus block was accomplished by slow injections of lidocaine (320–460 mg) plus bupivacaine (80–115 mg), arterial lidocaine reached a peak level of approximately 5 μg/mL at 5 to 10 minutes after injection, and then slowly declined to a value of 2 to 3 μg/mL at 3 hours after the block.140 Bupivacaine levels in these same patients had a similar time course, with peak values of 1 to 2 μg/mL and 3-hour levels of approximately 0.5 μg/mL. It is noteworthy that a different study, of local anesthetic mixtures for femoral and sciatic nerve blocks, showed that the presence of lidocaine hastened the decline and reduced the peak levels of coinjected bupivacaine or ropivacaine.8 Lidocaine levels such as these are in the range achieved for treatment of chronic pain by intentional IV delivery,141 and are consonant with the levels resulting from the perioperative delivery of lidocaine for minimizing postoperative pain (see preceding section).

Few studies report the fraction of local anesthetic in plasma that is bound to protein. Although rapid drug dissociation from this protein-bound pool in response to the uptake of free drug by circulated tissues will almost certainly provide a larger “free fraction” than is measured at equilibrium, at least some of the total local anesthetic in plasma is unavailable. Depending on their affinity for and their dissociation rate from plasma proteins, such binding will reduce both the therapeutic and the toxic potential of IV drugs. Particularly relevant in the postoperative context is the increase that follows surgery of α1-acid glycoprotein, the protein that binds local anesthetics with a high affinity. Future studies of local anesthetic levels in plasma would be more informative and useful if bound as well as total local anesthetic were reported.

Although there have been no studies of the therapeutic actions of IV longer-acting local anesthetics, these might have benefit at plasma levels 0.1 to 0.25 that of lidocaine, assuming an action at Na+ channels that results in inhibition of abnormal action potentials.142 Cervical plexus blocks with bupivacaine (80–115 mg) or levobupivacaine (125-mg dose) result in peak plasma levels of approximately 1 to 2 μg/mL140 and 0.4 to 0.8 μg/mL,143 respectively. Brachial plexus blocks with ropivacaine, dose approximately 250 mg, resulted in plasma levels of 2.6 to 3.3 μg/mL144 whereas the same local anesthetic used for femoral nerve block (0.75%, 225 mg)43 or TAP block (150 mg)145 resulted in peak plasma levels of approximately 1.5 and 2 μg/mL, respectively. Relative to the known “therapeutic” concentrations of plasma lidocaine, these values of the longer-acting local anesthetics may well have therapeutic benefit, particularly when their plasma decay occurs over 3 hours or longer, as is the case for most after bolus injections for the block. Therefore, it seems probable that at least part of the reduction of postoperative pain by local anesthetics given for peripheral nerve block results from the systemic distribution of these drugs, which might be acting on the central nervous system (CNS) as well as the peripheral nervous system.

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This review documents “preventive analgesia” by local anesthetics in a large majority of randomized clinical studies. Preventive analgesia is defined as a reduction of postoperative pain that persists for more than 5.5 half-lives of a drug,1 which is approximately 8 hours for lidocaine, and 12 to 16 hours for bupivacaine.146 Most of the cited studies examined pain scores and/or opioid consumption for at least 24 hours after surgery and local anesthetic administration, thus meeting the criteria for preventive analgesia.

Nerve blocks by local anesthetics improve postoperative analgesia compared with placebo or PCA. Peripheral nerve blocks seem to have better analgesic efficacy than IA infusions for both upper and lower extremity procedures. Some of the effects of peripheral nerve block procedures may be attributed to CNS effects from the systemic distribution of these drugs secondary to peripheral nerve block. IV administration of lidocaine has demonstrated a postoperative analgesic benefit but this effect is not associated with a specific regimen or dose and no studies compared IV lidocaine with a regional anesthetic technique such as an epidural or peripheral nerve block. Therefore, IV lidocaine administration may be a reasonable analgesic approach when regional techniques are contraindicated or not performed.

The volume and concentration of the local anesthetic used does not seem to affect the efficacy of the block, but what seems to be important is the total dose (mass) of local anesthetic.61,147 The timing of the block, pre- or postincision, also does not appear to be of clinical significance,6 and this has been discussed at length by Katz and Clarke.148 This suggests that either postoperative nerve impulse activity or slower changes in synaptic neuroplasticity in the CNS, or changes in the signaling properties of non-neuronal cells, such as microglia, in the CNS are affected by local anesthetics given for peripheral nerve block.149,150

What are the limitations in assessing clinical trials that validate the preventive analgesia by local anesthetics? One limitation in studying the effect of peripheral nerve blocks is the difficulty in designing double-blind, placebo-controlled studies. Such a design necessitates a sham block, which is often clinically and ethically unacceptable, and therefore many studies compare the effects of different treatments but do not use a true, drug-free “control.” In addition, all studies are powered to examine different primary outcomes that were not necessarily pain scores or analgesic use, for instance. Furthermore, all studies used different local anesthetics, different drug doses and concentrations, and in the case of infusions, different rates and durations of infusions. Finally, surgical techniques are variable and procedures performed at different institutions cannot be assumed to cause similar pain in patients.

The longer-term outcomes from local anesthetics used perioperatively are rarely assessed. Because chronic pain, persisting for more than 3 months after surgery, is an increasingly recognized syndrome, and acute pain intensity has a positive correlation to the occurrence of such chronic pain,151,152 one predicts that acute pain management would be an effective preventive treatment for chronic pain. Further study is desired in order to examine the long-term analgesic effects of peripheral nerve blocks or IV-administered local anesthetics.

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Dr. Marcel Durieux is the Section Editor for Anesthetic Pre-Clinical Pharmacology for the Journal. This manuscript was handled by Dr. Spencer S. Liu, Section Editor for Pain Medicine, and Dr. Durieux was not involved in any way with the editorial process or decision.

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Name: Antje Barreveld, MD.

Contribution: This author helped write the manuscript and perform literature search and review.

Attestation: Antje Barreveld approved the final manuscript.

Name: Jürgen Witte, MD.

Contribution: This author helped write the manuscript and perform literature search and review.

Attestation: Jürgen Witte approved the final manuscript.

Name: Harkirat Chahal, MD.

Contribution: This author helped write the manuscript and perform literature search and review.

Attestation: Harkirat Chahal approved the final manuscript.

Name: Marcel E. Durieux, MD, PhD.

Contribution: This author helped write the manuscript.

Attestation: Marcel E. Durieux approved the final manuscript.

Name: Gary Strichartz, PhD.

Contribution: This author helped write the manuscript and perform literature search, writing, and editing.

Attestation: Gary Strichartz approved the final manuscript.

Supported partially by NIH grant(s) (NIH/NCI CA080153) and by departmental funds.

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