Intravenous lidocaine for the treatment of background or procedural burn pain
Abstract
Background
This is an update of the review on "Lidocaine for pain relief in burn injured patients" first published in Issue 3, 2007, and first updated in 2012. Pain is a major issue for people with many different types of wounds, in particular those people with burn injuries. Prompt, aggressive use of opioid analgesics such as morphine has been suggested as critical to avert the cycle of pain and anxiety, but adverse effects are encountered. It has been proposed that newer agents such as lidocaine could be effective in reducing pain and alleviating the escalating opioid dosage requirements in people with burn injury.
Objectives
To assess the safety and effectiveness of intravenous lidocaine as a means of pain relief versus no therapy, placebo, other drugs, or a combination of these therapies in people with burn injury.
Search methods
For this third update, we searched the Cochrane Central Register of Controlled Trials (Issue 11, 2013), and Ovid MEDLINE, MEDLINE in Process and Ovid EMBASE (up to December 2013).
Selection criteria
We included randomised controlled trials (RCTs) and controlled clinical trials (CCTs), published and unpublished, which assessed the efficacy of intravenous lidocaine in varying doses as a single‐agent therapy with no therapy, placebo, other analgesics (such as opioids), lidocaine plus another drug, or a combination of these therapies as a means of pain relief in people with burn injury.
Data collection and analysis
Two review authors independently abstracted data and assessed the risk of bias of the studies identified.
Main results
In this 2014 update, we found no new studies. The one small randomised double‐blind placebo‐controlled cross‐over trial found in 2012, which included only 45 participants and compared intravenous lidocaine against placebo as a means of pain relief in people with burns still remains central to this review. We assessed this study as being at a high risk of bias due to its small size (fewer than 50 participants per treatment arm). Subjective pain ratings, as measured by the verbal rating scale, increased during procedures for both treatment arms; however, the increase was less in the lidocaine treatment group. There were no significant clinical or statistical differences regarding the effects of lidocaine and placebo on opioid requests and consumption, anxiety or level of satisfaction during a wound care procedure, but the small included study provided insufficient data to draw any conclusions.
Authors' conclusions
As current clinical evidence is based on only one RCT as well as case series and reports, intravenous lidocaine must be considered a pharmacological agent under investigation in burns care, the effectiveness of which is yet to be determined with further well‐designed and conducted clinical trials.
PICOs
Plain language summary
Lidocaine for pain relief in people with burns
Background
Burns are very common and sometimes fatal, and the pain associated with such injury is one of the most difficult types to relieve. The use of high‐dose opioid medications like morphine is common, but side effects are encountered. Alternative agents such as lidocaine, an anaesthetic, have been proposed. This is an update of the review of the same name first published in 2007.
Study characteristics
We searched scientific databases for studies assessing the pain‐relieving effects of intravenous (given into the blood stream through a vein) lidocaine in adults with a burn injury. We included studies comparing lidocaine with no treatment, placebo (a pretend treatment), other analgesics (pain killers), or a combination of these. We wanted to look at (for example) severity of pain, time to requiring more medication, rescue analgesia (where extra pain relief is needed in addition to that planned) and side effects. The evidence is current to December 2013.
Key results
We found one small clinical trial, involving only 45 participants, which showed a benefit from intravenous lidocaine for pain relief in people with burns. The trial did not show a difference in opioid use, participant anxiety or level of participant satisfaction with the use of intravenous lidocaine.
Quality of the evidence
The small included study provided insufficient data to draw any conclusions.
Authors' conclusions
Background
Description of the condition
This is an update of the review on "Lidocaine for pain relief in burn injured patients" first published in 2007 (Wasiak 2007). Burn injuries are a particularly emotive injury with which pain is frequently associated. Burn pain continues to be an ongoing issue of investigation and concern (Dauber 2002; Richardson 2009). Inflammatory reactions pursuant to injured tissue or nerves may result in the overproduction of inflammatory mediators, which may result in allodynia and primary hyperalgesia in injured areas and secondary hyperalgesia in surrounding tissue (Meyer 1981; Richardson 2009). Repetitive painful stimuli can cause neuroplastic adaptations throughout the central nervous system whereby pain afferent sensory impulses undergo facilitation and amplification to a given stimulus, contributing to the generation and maintenance of chronic pain (Richardson 2009). Pain from burn injuries has been associated with several mental health conditions such as depression, anxiety, post‐traumatic stress disorder and suicide (Edwards 2007; Summer 2007).
Opioid analgesics, and in particular intravenous opiates, have long been the mainstay of analgesia for procedure‐related burn pain. However, use of high‐dose opiates can be associated with both short‐term adverse effects, including respiratory depression and constipation, as well as long‐term consequences, such as the development of tolerance and reward‐based behaviour to opiate medication.
Description of the intervention
Lidocaine (also named lignocaine) is a local anaesthetic agent of the amide type that has been used for local anaesthesia and systemically as an anti‐arrhythmic drug. Intravenous lidocaine has been proposed as a means to alleviate the debilitating effects of various types of pain and is currently used in the management of many acute, chronic and neuropathic pain conditions (Edwards 1999; Ferrante 1996; Hand 2000; Koppert 2004; McLeane 2001). The most common timing of use of analgesia tends to be during debridement. Systemic lidocaine has also been reported to be effective in treating burn injury in numerous case series, case studies and experimental studies (Cassuto 2003; Holthusen 2000; Jönsson 1991).
How the intervention might work
Lidocaine reversibly binds to subunits of voltage‐gated sodium channels in the nerve membrane, consequently inhibiting nerve conduction. The depression of conduction in afferent nerves secondary to lidocaine administration may act to modify pain in people with burns, and avoid the adverse effects of high‐dose opiates during procedures associated with burn management likely to elicit repetitive painful stimuli.
Why it is important to do this review
Several clinical trials have attempted to use non‐opioid therapies to treat procedural pain with mixed degrees of success (Finn 2004; Harandi 2004; Konstantatos 2009; Zor 2010). Although many burns units employ several different therapies, there is still no widely accepted alternative or uniform adjunctive treatment to intravenous opioids for the management of procedural burn pain supported by meta‐analysis of randomised controlled trials (RCTs). Given the importance of pain control in acute burn injuries, further evidence should be sought with respect to non‐opioid analgesic agents, particularly in the context of procedural pain control. As systemic lidocaine is safe and effective for the management of some neuropathic conditions that have been refractory to standard interventions, we anticipated that we could establish that systemic lidocaine may help reduce the pain of burns.
Objectives
To assess the safety and effectiveness of intravenous lidocaine as a means of pain relief versus no therapy, placebo, other drugs or a combination of these in people with burn injury.
Methods
Criteria for considering studies for this review
Types of studies
RCTs and controlled clinical trials, published and unpublished, that assessed the analgesic efficacy of intravenous lidocaine in people with burn injury.
Types of participants
Adults (aged over 18 years) with any burn injury who required lidocaine as a means of pain relief. We expected to include studies regardless of the method of burn injury. However, we excluded people with burn injury requiring pain relief measures for multiple treatment regimens such as skin‐grafting procedures.
Types of interventions
Intravenous lidocaine of varying doses as a single‐agent therapy compared with no therapy, placebo, other analgesics (such as opioids), lidocaine plus another drug, or a combination of these therapies regardless of the duration of the treatment.
Types of outcome measures
Primary outcomes
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Pain measured by a visual analogue scale (VAS) or verbal rating scales (VRS), a numerical rating scale, or other validated assessment tool.
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Categorical rating of pain intensity in circumstances in which numerical ratings may be problematic.
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Time to re‐medication.
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Requirements for rescue analgesia.
Secondary outcomes
We did not included studies that reported on secondary outcomes alone such as adverse effects, measures of satisfaction, physical functioning without reference to pain, emotional functioning without reference to pain, participant preference and assessment of quality of life.
Search methods for identification of studies
We ran the original search for this review in March 2007 and undertook a subsequent update in 2012. For this third update in 2014, we searched:
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the Cochrane Central Register of Controlled Trials (Issue 11, 2013) (Appendix 1);
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MEDLINE and MEDLINE in Process (Ovid) (to December 2013) (Appendix 2);
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EMBASE (Ovid) (to December 2013) (Appendix 3).
In MEDLINE, we combined the search strategy with the optimum trial search strategy described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We applied no language restrictions.
Data collection and analysis
Selection of studies
In the original review and with the second update, two review authors (JW and HC) reviewed titles and abstracts to identify potentially relevant trials using the selection criteria. For the 2014 update, the review authors performed a similar screening process with the help of an additional review author (HT). We did not review studies that clearly did not meet the inclusion criteria. Two review authors independently retrieved, scanned and reviewed all potentially relevant studies in full text. In all instances, we resolved differences of opinion by discussion.
Data extraction and management
Three review authors (JW, PM and SMcG) independently extracted data from the eligible studies using standardised forms developed for this review. Data extracted included: study characteristics, participant demographics, intervention and comparison details, outcome measures and results. We contacted primary authors to request missing information. In all instances, we resolved differences of opinion by discussion among the review authors.
Assessment of risk of bias in included studies
We assessed the risk of bias for each study according to the recommendations described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The 'Risk of bias' tool incorporates assessment of randomisation (sequence generation and allocation concealment), blinding (of participants, treatment providers and outcome assessors), completeness of outcome data, selection of outcomes reported and other sources of bias. We resolved discrepancies in ratings by discussion.
For this update, we assessed the included study according to size (low risk of bias: 200 or more participants per treatment arm; unclear risk of bias: 50 to 199 participants per treatment arm; high risk of bias: fewer than 50 participants per treatment arm).
Measures of treatment effect
If possible, we expressed dichotomous data as risk ratios (RR) and 95% confidence intervals (CIs). We expressed continuous data as mean difference (MD) and 95% CIs. We planned all analyses to be made on intention‐to‐treat (ITT) results. However, none of the studies used such analyses.
Assessment of heterogeneity
If possible, we tested statistical heterogeneity using the Chi2 test with significance at P value < 0.10 and a quantification of the degree of heterogeneity using the I2 statistic, and planned to carry out further exploration using subgroup analyses.
Subgroup analysis and investigation of heterogeneity
No subgroup analyses were pre‐specified.
Results
Description of studies
Results of the search
In the original review in 2007, we identified 25 references. Independent scrutiny of the titles and abstracts identified five potentially relevant studies. Of the five potentially relevant studies, we excluded four studies because they did not address primary outcome measures (Holthusen 2000; Mattsson 2000), or used alternative study designs such as case reports (Cassuto 2003), or case series (Jönsson 1991). In the 2012 update, we identified 406 further references, of which one additional study, undertaken by the review authors (JW, AS and HC) met the inclusion criteria (Wasiak 2011); one study was identified for exclusion (Koppert 2004). In this latest update, we examined an additional 18 studies but none were suitable for inclusion. See Figure 1.
Study flow diagram.
Included studies
We included one small cross‐over RCT that we found in 2012 (Wasiak 2011). In Wasiak 2011, 47 participants were initially recruited although only 45 participants had burn injuries (mean per cent total body surface area (TBSA) 12.96%, range 3% to 55%). Participants were undergoing wound care procedures (i.e. dressing changes or debridement, or both) over two consecutive days following split skin‐graft surgery. They were randomised to receive lidocaine 1.5 mg/kg/body weight followed by two boluses of 0.5 mg/kg at five‐minute intervals followed by a continuous infusion or control (0.9% sodium chloride) administered at an equivalent volume, dose and rate to that of lidocaine. The primary outcomes measured were change in VRS scores measured before, during and after the procedure; time to rescue analgesia; opioid requests and consumption using patient‐controlled analgesia (PCA); and overall participant anxiety and level of satisfaction. Subjective pain ratings as measured by the VRS increased during procedures for both treatment arms; however, the increase was less for the lidocaine treatment arm. Table 1 presents the results for the individual study.
| Study ID | Dose of lidocaine | Comparator | Number of participants | Withdrawals | Efficacy | Adverse events (intervention) | Adverse events (placebo) |
| Initial bolus dose of lidocaine 1.5 mg/kg/body weight followed by 2 boluses of 0.5 mg/kg/body weight at 5‐minute intervals and an infusion run at 2 mg/minute throughout duration of dressing | 0.9% NaCl (normal saline) at equivalent dose, rate and volume as intervention | 45 | The authors reported no loss to follow‐up of participants for primary outcome measures | Verbal rating scale scores lower for lidocaine compared with placebo. No difference between groups in time to rescue analgesia, opioid requests and consumption using patient‐controlled analgesia, and overall participant anxiety and level of satisfaction | Pre‐dressing: twitchiness 1/45 and nausea/vomiting 8/45 Dressing: twitchiness 1/45 and nausea/vomiting 5/45 Post‐dressing: nausea/vomiting 8/45 | Pre‐dressing: nausea/vomiting 2/45 Dressing: nausea/vomiting 4/45 and severe pain 1/45 Post‐dressing: nausea/vomiting 4/45 |
Excluded studies
In this update, we added no excluded studies. For previous excluded studies, see the Characteristics of excluded studies table.
Risk of bias in included studies
We based risk of bias assessment on the methods outlined in The Cochrane Collaboration's 'Risk of bias' tool (Higgins 2011) (Figure 2, Figure 3). The authors who were not involved in the RCT (SMcG, SD) commented on the individual study in the 'Risk of bias' section of the Characteristics of included studies table. Using the definitions provided by Higgins (Higgins 2011), the study by Wasiak 2011 described adequate allocation concealment and blinding of participants, staff and study researchers. For this update, we also identified a high risk of bias according to the size of the study (as it only had 45 participants), and updated the summary tables accordingly. Although Wasiak 2011 indicated an ITT analysis, the study had two participants lost to follow‐up as one dressing was changed in the outpatient setting and the other stopped due to uncontrolled pain.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Effects of interventions
Wasiak 2011 reported that VRS scores were significantly lower for lidocaine (0.34) compared with placebo (0.70) when measured before, during and after the procedure (difference 0.36, 95% CI 0.17 to 0.55; P value < 0.001). Rescue analgesia was required during six wound care procedures, all involving the removal of staples. During the six procedures, all participants had required intravenous ketamine during dressing procedures prior to rescue analgesia; four participants during the lidocaine arm, one during the placebo arm and one during both. Comparison of opioid demand and consumption showed no significant clinical or statistical differences between lidocaine and placebo arms. Measures of overall anxiety and satisfaction levels showed no appreciable difference between the groups. There were no significant clinical or statistical differences between the lidocaine and placebo arms with regards to anxiety scores prior to or after the wound care procedures.
Discussion
This review aimed to assess the safety and effectiveness of intravenous lidocaine as a means of pain relief versus no therapy, placebo, other drugs or a combination of these therapies in people with to burn injury.
Intravenous lidocaine has been a well‐documented treatment for other clinical conditions such as cardiac arrhythmias and neuropathic pain. In the setting of burns pain, there has been growing evidence in the form of case reports or case series to suggest that lidocaine can improve the analgesic efficacy, alleviate the deleterious effect of opioid administration and minimise the necessity of escalating opioid dosages in people with thermal injury although we excluded these from our original search (Cassuto 2003; Edwards 1999; Jönsson 1991).
Several mechanisms have been proposed for this action, namely that systemic lidocaine can depress conduction in afferent nerves, inhibit dorsal horn neural transmission and modify the cerebral perception of pain (Abelson 2002; Attal 2000). In addition, it has been postulated that burn injury is likely to trigger the release of inflammatory agents such as histamine, serotonin and prostaglandins, which in turn could trigger nociceptive impulses, making lidocaine's potent anti‐inflammatory properties integral to the suppression of pain (Edwards 1999).
We included only one small study involving the addition of lidocaine infusions to PCA morphine as compared with placebo involving 45 randomised people with burn injury (Wasiak 2011). Outcomes included pain intensity as measured by VRS, time to rescue analgesia, opioid requests and consumption, and overall anxiety and level of satisfaction. There were statistically significant differences in VRS score, which was lower in people treated with lidocaine as compared with placebo; however, there were no statistically significant differences with respect to other primary outcomes. Of importance, lidocaine administration did not result in a significantly lower demand by participants for opioids. The study was conducted in a burns centre in Melbourne, Australia where the authors of the trial acknowledge that the standard opioid‐based pain management regimens of the unit usually lead to a high degree of satisfactory pain control. In this context, it may have been difficult to improve upon an already established baseline of pain control and this limits generalisability of this trial to clinical practice in burn centres where opioid‐based pain management has not been optimised or is contraindicated in certain people.
While the included study did not show a reduction in opioid consumption or demand, or a difference in degree of participant satisfaction while the adjuvant use of intravenous lidocaine for pain relief during burn wound dressing changes was administered, the use of intravenous lidocaine as a form of pain relief at other stages during burn wound management remains unexplored in the form of RCTs. Given that several RCTs in a non‐burn context and case series involving people with burns highlight that intravenous lidocaine may lead to a reduction in participants' procedural and background pain levels, lead to less opiate requirements and consequently fewer associated complications, there is a need for larger RCTs to assess the utility of intravenous lidocaine in people with burns.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
| Study ID | Dose of lidocaine | Comparator | Number of participants | Withdrawals | Efficacy | Adverse events (intervention) | Adverse events (placebo) |
| Initial bolus dose of lidocaine 1.5 mg/kg/body weight followed by 2 boluses of 0.5 mg/kg/body weight at 5‐minute intervals and an infusion run at 2 mg/minute throughout duration of dressing | 0.9% NaCl (normal saline) at equivalent dose, rate and volume as intervention | 45 | The authors reported no loss to follow‐up of participants for primary outcome measures | Verbal rating scale scores lower for lidocaine compared with placebo. No difference between groups in time to rescue analgesia, opioid requests and consumption using patient‐controlled analgesia, and overall participant anxiety and level of satisfaction | Pre‐dressing: twitchiness 1/45 and nausea/vomiting 8/45 Dressing: twitchiness 1/45 and nausea/vomiting 5/45 Post‐dressing: nausea/vomiting 8/45 | Pre‐dressing: nausea/vomiting 2/45 Dressing: nausea/vomiting 4/45 and severe pain 1/45 Post‐dressing: nausea/vomiting 4/45 |
