Adjusting the ph of lidocaine for reducing pain on injection (Review)

Transcription

1 Adjusting the ph of lidocaine for reducing pain on injection (Review) Cepeda MS, Tzortzopoulou A, Thackrey M, Hudcova J, Arora Gandhi P, Schumann R This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2010, Issue 12

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY SUMMARY OF FINDINGS FOR THE MAIN COMPARISON BACKGROUND OBJECTIVES METHODS RESULTS Figure Figure Figure DISCUSSION Figure Figure Figure AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES Analysis 1.1. Comparison 1 Mean pain difference in parallel-group studies by presence of epinephrine, Outcome 1 Mean difference in parallel studies with and without epinephrine Analysis 2.1. Comparison 2 Mean pain difference in parallel-group studies by ph of solution, Outcome 1 Mean pain difference in parallel studies by ph of solution Analysis 3.1. Comparison 3 Mean pain difference in crossover studies by presence of epinephrine, Outcome 1 Mean pain difference in crossover studies with and without epinephrine Analysis 4.1. Comparison 4 Mean pain difference in crossover studies by ph of solution, Outcome 1 Mean pain difference in crossover studies by ph of solution Analysis 5.1. Comparison 5 Preference, Outcome 1 Preference in cross over studies Analysis 6.1. Comparison 6 Effect of risk of bias on mean pain intensity in parallel-group studies (low risk versus high risk), Outcome 1 Mean pain difference Analysis 7.1. Comparison 7 Effect of volume on mean pain intensity in parallel-group studies, Outcome 1 Mean pain intensity in parallel studies Analysis 8.1. Comparison 8 Effect of volume on mean pain intensity in crossover studies, Outcome 1 Mean pain difference in crossover studies Analysis 9.1. Comparison 9 Effect of type of procedure on mean pain intensity in parallel-group studies, Outcome 1 Mean pain intensity by type of procedure Analysis Comparison 10 Effect of type of procedure on mean pain intensity in crossover studies, Outcome 1 Mean pain intensity by type of procedure APPENDICES HISTORY CONTRIBUTIONS OF AUTHORS DECLARATIONS OF INTEREST SOURCES OF SUPPORT DIFFERENCES BETWEEN PROTOCOL AND REVIEW INDEX TERMS i

3 [Intervention Review] Adjusting the ph of lidocaine for reducing pain on injection M Soledad Cepeda 2, Aikaterini Tzortzopoulou 1, Michael Thackrey 3, Jana Hudcova 4, Preeti Arora Gandhi 1, Roman Schumann 1 1 Department of Anesthesiology, Tufts Medical Center, Boston, Massachusetts, USA. 2 Pharmacoepidemiology, Johnson & Johnson Pharmaceutical Research and Development, Titussville, NJ, USA. 3 Family and Community Medicine, University of California, San Francisco, San Francisco, California, USA. 4 Department of Surgical Critical Care, Lahey Clinic, Burlington, Massachusetts, USA Contact address: Aikaterini Tzortzopoulou, Department of Anesthesiology, Tufts Medical Center, 800 Washington street, Boston, Massachusetts, 02111, USA. tzortzokat@yahoo.com. Editorial group: Cochrane Anaesthesia Group. Publication status and date: New, published in Issue 12, Review content assessed as up-to-date: 7 November Citation: Cepeda MS, Tzortzopoulou A, Thackrey M, Hudcova J, Arora Gandhi P, Schumann R. Adjusting the ph of lidocaine for reducing pain on injection. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD DOI: / CD pub2. Background Lidocaine administration produces pain due to its acidic ph. Objectives A B S T R A C T The objective of this review was to determine if adjusting the ph of lidocaine had any effect on pain resulting from non-intravascular injections in adults and children. We tested the hypothesis that adjusting the ph of lidocaine solution to a level closer to the physiologic ph reduces this pain. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, to June 2010); Ovid MEDLINE (1966 to June 2010); EMBASE (1988 to June 2010); LILACS (1982 to June 2010); CINAHL (1982 to June 2010); ISI Web of Science (1999 to June 2010); and abstracts of the meetings of the American Society of Anesthesiologists (ASA). We checked the full articles of selected titles. We did not apply any language restrictions. Selection criteria We included double-blinded, randomized controlled trials that compared ph-adjusted lidocaine with unadjusted lidocaine. We evaluated pain at the injection site, satisfaction and adverse events. We excluded studies in healthy volunteers. Data collection and analysis We separately analysed parallel-group and crossover trials; trials that evaluated lidocaine with or without epinephrine; and trials with ph-adjusted lidocaine solutions < 7.35 and To explain heterogeneity, we separately analysed studies with a low and higher risk of bias due to the level of allocation concealment; studies that employed a low and a higher volume of injection; and studies that used lidocaine for different types of procedures. 1

4 Main results We included 23 studies of which 10 had a parallel design and 13 were crossover studies. Eight of the 23 studies had moderate to high risk of bias due to the level of allocation concealment. Pain associated with the infiltration of buffered lidocaine was less than the pain associated with infiltration of unbuffered lidocaine in both parallel and crossover trials. In the crossover studies, the difference was units (95% confidence interval (CI) to -1.34) and in the parallel-group studies it was units (95% CI to -0.47) on a 0 to 10 scale. The magnitude of the pain decrease associated with buffered lidocaine was larger when the solution contained epinephrine. The risk of bias, volume of injection, and type of procedure failed to explain the heterogeneity of the results. Patients preferred buffered lidocaine (odds ratio 3.01, 95% CI 2.19 to 4.15). No adverse events or toxicity were reported. Authors conclusions Increasing the ph of lidocaine decreased pain on injection and augmented patient comfort and satisfaction. P L A I N L A N G U A G E S U M M A R Y Adjusting the ph of lidocaine solution for reducing pain on injection Lidocaine is frequently used to anaesthetize the skin prior to invasive procedures. Its administration produces pain that is thought to be due to the acidic ph of commercial preparations (ph levels between 3.5 and 7.0 compared with the physiologic ph which is between 7.35 and 7.45). The objective of this review was to determine the effect of increasing the ph of a commercial lidocaine preparation on pain associated with its injection in adults and children. We included 23 studies with 1067 participants in the metaanalysis. Increasing the ph of lidocaine reduced pain and improved patients comfort and satisfaction. No adverse events were reported. Therefore, increasing the ph of commercial lidocaine solutions with bicarbonate immediately prior to their use should be considered. 2

5 S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation] Plain lidocaine compared to buffered lidocaine for patients requiring local anaesthesia Patient or population: Patients requiring local anaesthesia Settings: Inpatient Intervention: Plain lidocaine Comparison: Buffered lidocaine Outcomes Illustrative comparative risks*(95% CI) Relative effect (95% CI) No of Participants (studies) Quality of the evidence (GRADE) Comments Assumed risk Corresponding risk Plain lidocaine Buffered lidocaine Pain at injection site VAS.Scalefrom0to10. The mean pain at injection site in the control groups of the parallel studies was 2.99 units The mean pain at injection site in the intervention groups of the parallel studies was 0.95lower(1.42to0.49 lower) compared to control groups. 685 (7 studies) moderate 1,2,3 In 10 crossover studies painwas1.98lowerwith buffered compared to unbuffered lidocaine (2.62 to-1.34 lower) Preference OR 3.01 (1.19 to 4.15) 346 (8 studies) All studies were high 4 crossover. Adverse events See comment See comment Not estimable 182 (3 studies) high With the exception of one study that reported a haematoma (no description in which treatment arm), the studies reported absence of adverse events *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention(and its 95% CI). CI: Confidence interval; OR: Odds ratio; 3

6 GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Lowquality:Furtherresearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandislikelytochangetheestimate. Very low quality: We are very uncertain about the estimate. 1 Subgroupanalysisshowedthattheeffectwas-0.30(95%CI-0.41to-0.19)inlowriskofallocationconcealmentstudies;-1.54(95% CI-2.39 to-0.68) for high risk of allocation concealment studies(analysis 6.1). 2 Highlevelsofheterogeneityoftheresultsbothinparallelandcross-overtrialspersisteddespiteeffortstoexplainit. 3 Lower95%CI0.5isequaltotheminimalimportantdifferenceofhalfauniton0to10scale(Cepeda2003). 4 AlleightstudiesshowedOR>2. xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx 4

7 B A C K G R O U N D Lidocaine is one of the most commonly used local anaesthetics (Corbett 2005; Haas 1995; Koeppe 2005) due to its rapid onset of action, safety profile, low cost and wide availability. It is frequently used in medical care to facilitate a variety of invasive procedures including anaesthetizing the skin prior to venous or arterial cannulation and providing analgesia and anaesthesia for surgical procedures. When lidocaine is used for local, subcutaneous injections patients often complain of pain thought to be related to the ph of most commercial lidocaine solutions, which is between 3.5 and 7.0 (Mosby 2006). This pain, often present as a burning sensation, can be quite severe (McKay 1987; Parham 1996). Since physiologic ph is between 7.35 and 7.45, it is suggested that this pain is likely to result from the increase in hydrogen ions in the local tissue environment due to the acidity of lidocaine. Nociceptors are activated leading to subsequent pain sensation and sometimes sustained pain (Issberner 1996; Reeh 1996; Steen 1992; Steen 1993; Steen 1995). Although increasing the ph of commercial lidocaine solutions with or without epinephrine admixture decreases pain intensity and increases patient preference for the adjusted lidocaine (Brogan 1995), this alkalinization could affect the onset, duration or degree of analgesia (Gaggero 1995). Epinephrine is commonly co-administered with lidocaine. Adding epinephrine to lidocaine potentiates and prolongs lidocaine s action in a dose-related manner (Liu 1995). In addition, the higher ph of the lidocaine-epinephrine solution could influence pain on injection (Colaric 1998). The clinical experiences of care providers in healthcare facilities suggest that alkalinization of lidocaine does in fact reduce the level of pain associated with its injection. However, conclusive evidence for this clinical perception is not available. This knowledge gap contributes to a reluctance to commit additional time and cost for ph adjustment of a lidocaine solution in a busy clinical practice. Although many randomized controlled trials have evaluated the effect of lidocaine alkalinization on pain at the site of injection, this outcome has never been comprehensively reviewed (Burns 2006; Vossinakis 2004; Watts 2004). We performed a systematic review of the literature to fill this knowledge gap. The results of this review could lead to evidence-based practice recommendations for the clinical use of lidocaine and may potentially foster changes in the manufacture of lidocaine. One reason for the current absence of such a ph-adjusted solution from the market could be storage restrictions. There are studies that suggest that buffered lidocaine stays effective for up to one week after preparation and remains less painful on injection than the unbuffered solution over that time (Bartfield 1992). O B J E C T I V E S The objective of this review was to determine if adjusting the ph of lidocaine had any effect on pain in non-intravascular injections in adults and children. We tested the hypothesis that adjusting the ph of lidocaine to a level closer to physiologic ph reduces this pain. M E T H O D S Criteria for considering studies for this review Types of studies We included only double-blinded, randomized controlled trials (RCTs). We included both parallel group and crossover RCTs. Double blinding is essential in studies evaluating subjective outcomes such as pain intensity and RCTs are the best study design to evaluate effectiveness. Types of participants We included studies that evaluated either adults or children. We did not exclude studies because of participants ages, underlying disease, condition or diagnosis. We also included healthy people in need of local anaesthesia like those undergoing dental procedures. Types of interventions We included studies that compared ph-adjusted lidocaine with unadjusted lidocaine solutions for non-intravascular injection. We included studies using plain or epinephrine-containing lidocaine solutions. We excluded studies using lidocaine mixed with other local anaesthetics or studies that evaluated local anaesthetics other than lidocaine. We also excluded studies where there was a temperature difference between the interventions and studies in which none of the study arms used lidocaine or buffered lidocaine. Types of outcome measures The primary outcome was pain intensity at injection of buffered and unbuffered lidocaine administered to adults or children in order to provide local anaesthesia prior to epidural catheter insertion, intravascular cannulation or a small surgical procedure. We excluded studies if pain intensity was not self-reported, if the subjects were healthy volunteers, or if the unit of analysis was not the patient but the site of injection. Secondary outcomes were patient satisfaction and adverse events. 5

8 Search methods for identification of studies We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, to June 2010); Ovid MEDLINE (1966 to June 2010); EMBASE (1988 to June 2010); LILACS (1982 to June 2010); CINAHL (1982 to June 2010); and ISI Web of Science (1999 to June 2010). We developed a specific strategy for each database. The search strategies used for Ovid MEDLINE, CENTRAL, EMBASE, LILACS, CINAHL and ISI Web of Science are found in detail in the appendices (Appendix 1; Appendix 2; Appendix 3; Appendix 4; Appendix 5; Appendix 6). We based each search strategy on that developed for MEDLINE (Appendix 1). We combined the MEDLINE search strategy with the Cochrane highly sensitive search strategy phases one and two as described in the Cochrane Handbook for Reviews of Interventions (Higgins 2005). The Cochrane highly sensitive search strategy was modified to exclude single-blinded trials. We did not apply any language restrictions. In addition, we searched abstracts of the annual meetings of the American Society of Anesthesiologists (ASA) over the last seven years (2002 to October 2009). For each article we checked the references in the full text. We also searched for relevant ongoing trials posted at Data collection and analysis Trial identification Four authors (AT, MT, JH, and PA) independently screened the titles and abstracts of reports resulting from the electronic database search. We retrieved full-text versions of any potentially relevant studies chosen by at least one author. We were not blinded with respect to the journal, study authors, institution or the magnitude and direction of the study results because it has been shown that knowledge of this information by the investigators has no significant impact on the results of systematic reviews (Berlin 1997). Trial selection We included the following. Double-blinded, randomized controlled trials (RCTs). Studies that evaluated adults or children of any age, underlying disease, condition or diagnosis. Studies that compared ph-adjusted lidocaine with unadjusted lidocaine solutions for non-intravascular injection, with or without epinephrine. Studies that assessed self-reported pain intensity at injection, satisfaction or acceptability. We excluded the following. Studies using lidocaine mixed with other local anaesthetics or studies that evaluated local anaesthetics other than lidocaine. Studies where there was a temperature difference between interventions. Studies where the unit of analysis was not the patient. Four authors (AT, MT, JH and PA) independently selected trials that met the inclusion criteria using a checklist designed in advance for that purpose. A separate author (MSC) settled any disagreements. We performed all trial selections in duplicate. Quality assessment We judged the quality of the studies on the basis of the methods of randomization and allocation concealment. We categorized studies into four categories. Category A: low risk of bias - adequate allocation concealment with central randomization (e.g. allocation by a central office unaware of patient characteristics, computer file that could be accessed only after the characteristics of an enrolled participant had been entered, or other description containing elements suggesting adequate concealment). Category B: moderate risk of bias - unclear allocation concealment in which the authors either did not report an allocation concealment approach at all or reported an approach that did not fall into category A. Category C: high risk of bias - inadequate allocation concealment such as alternation or reference to case numbers or dates of birth. Category D: no allocation concealment used - any procedure that was entirely transparent such as an open list of random numbers or other description that contained elements indicating no concealment of allocation. In addition, we considered the similarity of treatment arms at baseline, completeness of follow up, and the use of intention to treat in the analysis as further indicators of good quality studies. All studies were double blinded. The quality assessments were included in the risk of bias tables for each study included in the systematic review. Data extraction Five authors (MT, AT, JH, PA, MSC) independently extracted data using a standardized data extraction form. We resolved conflicts through consultation with one author (MSC). Statistics Primary outcome Pain intensity Measurements using visual analogue scales or numerical scales from 0 to 100 were converted to 0 to 10 values. In the parallel 6

9 group studies, we extracted the mean and standard deviation (SD) of pain intensity after infiltration in each study arm. To pool the data we calculated a weighted mean difference using the randomeffects model. In the crossover studies, we extracted the mean difference in pain intensity and the SD or standard error of the difference. To pool the data we used the generic inverse variance method in RevMan software. In studies reporting the difference in pain intensity without measure of dispersion, we estimated the SD from the P value and the number of participants in the study. Secondary outcomes Patient preference and patient satisfaction In parallel studies reporting patient preference or satisfaction, we extracted the proportion of patients who preferred one treatment over the other, or who were satisfied in each treatment arm. For crossover studies, we calculated the odds ratio (OR) for preferring buffered over unbuffered lidocaine and the 95% confidence interval (CI) using the McNemar test and STATA. This test takes into account the crossover design, and produces correct 95% CIs and the desired M-H OR for crossover studies (Elbourne 2002). We then used the generic inverse variance method to pool the study estimates. Adverse events We extracted the number of patients presenting with adverse events, such as toxicity, skin rash, allergic reactions, or other. Subgroup analysis We separately analysed parallel and crossover trials; paediatric and adult trials; trials that evaluated lidocaine with and without epinephrine; and trials with ph-adjusted lidocaine solutions of ph < 7.35 and To determine if the use of epinephrine augmented the reduction in pain we used the metareg command in STATA. The outcome variable was the mean pain difference with the presence of epinephrine in the solution as an explanatory variable. Heterogeneity We measured heterogeneity by the Higgins test (Higgins 2003). To pool the data we used a random-effects model since I 2 values were higher than 50%. To explain heterogeneity, we separately analysed studies with low risk (category A) and higher risk of bias (categories B, C, D) due to allocation concealment, as well as studies that employed low volumes of injection (< 2.5 ml) and higher volumes for injection (> 2.5 ml). The 2.5 ml cutoff limit was chosen because it was the median volume injected in the studies meeting the inclusion criteria. In addition, we separately analysed trials on different procedures. We divided them into three groups: lidocaine use for intravenous cannulation; lidocaine use for nerve block or epidural catheter insertion; and lidocaine use for minor surgical procedures. R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification. We searched CENTRAL; Ovid MEDLINE; EMBASE; LILACS; CINAHL; ISI Web of Science; and abstracts of the ASA annual meetings. We came up with 2067 studies from which we excluded 1987 in the first cut. We retrieved the remaining 80 studies in full text. From these studies 23 fulfilled the inclusion criteria. We excluded 54 studies. The reasons for exclusion are shown in the Characteristics of excluded studies tables. The flow diagram of included and excluded studies is shown in Figure 1. 7

10 Figure 1. Searching flow diagram We included 23 studies in the review, a total of 1067 patients were included in the meta-analysis. Ten studies were parallel-group design and 13 were crossover studies. Two of the studies included in the meta-analysis had more than two treatment arms. We split those treatments up and referred to them as Carvalho 2007a; Carvalho 2007b and Nakayama 2001a; Nakayama 2001b. This meant that although there were only 23 included studies we refer to 25 references. All studies evaluated pain intensity. However six studies, three parallel-group design (Ernst 1996; Gershon 1991; Martin 1990) and three crossover (Orlinsky 1992; Richtsmeier 1995; Yuen 1999), were not included in the meta-analysis of pain intensity on injection of lidocaine. The study by Orlinsky (Orlinsky 1992) did not report the data on pain intensity. In the studies by Ernst (Ernst 1996), Gerhson (Gershon 1991) and Yuen ( Yuen 1999) no measures of dispersion nor exact P values were provided. The study by Martin (Martin 1990) used medians not means and the study by Richtsmeier (Richtsmeier 1995) used the Oucher scale. In addition, for the Fitton study (Fitton 1996) we excluded the treatment arm that received lidocaine solution at body temperature instead of room temperature (10 patients); for Nuttal s parallel-group study (Nuttall 1993) we excluded five of the seven treatment arms (200 patients), each receiving an anaesthetic other than lidocaine. Data suitable for the analysis of pain intensity were provided by seven parallel-group studies (two with two treatment arms) (Carvalho 2007a; Carvalho 2007b; Fatovich 1999; Nakayama 2001a; Nakayama 2001b; Nuttall 1993; Steinbrook 1993; Watts 8

11 2003; Yiannakopoulos 2004) with 635 patients (from which 321 received unbuffered lidocaine and 314 buffered lidocaine); and 10 crossover studies (Bartfield 1993; Cornelius 1996; Fitton 1996; Masters 1998; Metzinger 1994; Nelson 1995; Samdal 1994; Sapin 1991; Vossinakis 2004; Younis 2004) with 432 patients. Nineteen studies evaluated adults, two studies evaluated both children and adults (Cornelius 1996; Fitton 1996), one study evaluated children (Richtsmeier 1995), and one study did not describe the type of population included (Masters 1998). Following the data extraction process we found that there was a very high agreement among authors in extracted data: for categorical variables the kappa statistics ranged from 0.9 to 1, and for continuous variables the intra-class correlation ranged from 0.9 to 1. The average number of participants in the parallel-group studies was 42 years, range 20 to 95 years, and in the crossover studies the average age was 43 years, range 7 to 98 years. The mean age of participants ranged from 11 to 61 years. All of the studies evaluated the lidocaine solution at room temperature. Eleven of the studies evaluated lidocaine with epinephrine. Eighteen studies measured the ph of the solution; the ph for unbuffered lidocaine was 5.4 ± 1.1 and the ph for buffered lidocaine was 7.3 ± 0.2. All studies used sodium bicarbonate as the buffer agent. Although in each of the included trials patients received the same volume of the corresponding solution, nine studies added normal saline or sterile water to the lidocaine in the control group (Bartfield 1993; Cornelius 1996; Fatovich 1999; Gershon 1991; Nakayama 2001a; Nakayama 2001b; Orlinsky 1992; Samdal 1994; Watts 2003; Yiannakopoulos 2004). Median volume injected was 2.5 ml. Using the median volume as a cutoff point we separated the studies into those injecting a volume equal or lower than 2.5 ml (13 low volume studies) and those injecting a volume higher than 2.5 ml (11 high volume studies). The study by Nelson provided data for both low and high volumes and is included in both groups. The median volume injected in the low dose studies was 1.0 ml and the median volume injected in the high dose studies was 7.0 ml. Seven studies used the local anaesthetic infiltration for intravenous cannulation (Gershon 1991; Martin 1990; Nakayama 2001a; Nuttall 1993; Richtsmeier 1995; Sapin 1991; Steinbrook 1993); four (one with two treatment arms) used it for placement of a nerve block or an epidural needle (Bartfield 1993; Carvalho 2007a; Carvalho 2007b; Cornelius 1996; Nakayama 2001b); and in the remainder of studies it was used to provide local anaesthesia for minor surgical procedures, such as repairing small lacerations (Ernst 1996; Fatovich 1999; Orlinsky 1992), bilateral pinnaplasty (Fitton 1996), bilateral blepharoplasty or other eyelid procedures (Metzinger 1994; Samdal 1994; Yuen 1999), mammoplasty (Samdal 1994), liposuction (Samdal 1994), Norplant injection (Nelson 1995), carpal tunnel decompression (Vossinakis 2004; Watts 2003; Yiannakopoulos 2004), bilateral vasectomy (Younis 2004), or other elective outpatient procedures requiring subcutaneous injection of lidocaine (Masters 1998). The calibre of the needles used for the infiltration ranged from 22 G to 30 G. Three studies used 22 G or 23 G needles (Nelson 1995; Vossinakis 2004; Watts 2003). Risk of bias in included studies Seven of the 23 studies had moderate or high risk of bias due to the lack of allocation concealment or missing information on allocation concealment (see Risk of bias tables, Figure 2, Figure 3). 9

12 Figure 2. Methodological quality summary: review authors judgements about each methodological quality item for each included study.although there are 23 studies included in this meta-analysis in this figure it appears as if there were 25 studies. This is because two of the studies had more than two treatment arms. We have spit these treatments up and refer to them as Carvalho a and b and Nakayama a and b. 10

13 Figure 3. Methodological quality graph: review authors judgements about each methodological quality item presented as percentages across all included studies. Allocation Ten of the 23 included studies (Figure 2) provided an adequate method of sequence generation and 16 mentioned adequate allocation concealment. Blinding All included studies were double blinded. However, upon closer assessment the blinding was unclear in three studies (Gershon 1991; Nuttall 1993; Samdal 1994). Incomplete outcome data All studies had complete outcome data. Selective reporting There was no selective reporting of outcomes in any of the studies. Effects of interventions See: Summary of findings for the main comparison Plain lidocaine compared to buffered lidocaine for patients requiring local anaesthesia Pain intensity All 23 studies evaluated pain intensity. Twenty studies evaluated pain intensity using a numerical or visual analogue scale, two studies used descriptive scales, one used a 4-point scale (Martin 1990), another used a 6-point scale (Yuen 1999), and there was also a study that used the Oucher scale (Richtsmeier 1995). Seven studies were parallel-group design and 10 were crossover studies. In the parallel-group studies 314 participants were exposed to buffered lidocaine and 321 were exposed to unbuffered lidocaine. These numbers are slightly lower than the total numbers in the tables and forest plots (339 and 346 respectively) because the study by Nakayama evaluated a total of 50 patients but reported data separately by site of injection (Nakayama 2001a; Nakayama 2001b). The total number of participants in the meta-analysed crossover studies was 432. Pain associated with the infiltration of buffered lidocaine was lower than the pain associated with the infiltration of unbuffered lidocaine in both crossover and parallel trials (see Summary of findings for the main comparison). In the crossover studies the decrease in pain intensity with buffered compared to unbuffered lidocaine was units (95% CI to -1.34) (see Analysis 3.1; Analysis 1.1); in the parallel-group studies the difference was units (95% CI to -0.49). The results were heterogenous both in the crossover trials (I 2 = 11

14 90%) and the parallel-group studies (I 2 = 87%). Secondary outcomes Subgroup analysis Lidocaine with or without epinephrine Of the 10 crossover studies that evaluated pain intensity, six evaluated buffered lidocaine with epinephrine versus unbuffered lidocaine with epinephrine and four studies evaluated buffered lidocaine without epinephrine versus unbuffered lidocaine without epinephrine. The magnitude of the pain decrease associated with buffered lidocaine was larger when the solution contained epinephrine than when the solution lacked epinephrine (see Analysis 3.1). For the crossover studies that evaluated buffered lidocaine with epinephrine the magnitude of the decrease was units (95% CI to -1.72) (I 2 = 88%). This compared to a decrease of units (95% CI to -0.63) in the studies that evaluated buffered lidocaine without epinephrine. The latter results were homogeneous (I 2 = 50%) (Analysis 3.1 ). In the parallel-group studies the effect of adding epinephrine to buffered lidocaine could not be evaluated because there was only one study that evaluated lidocaine with epinephrine. The magnitude of pain decrease in the parallel-group studies comparing buffered lidocaine without epinephrine to unbuffered lidocaine without epinephrine was units (95% CI to -0.45), however the results were heterogenous (I 2 = 89%) (see Analysis 1.1). ph of buffered lidocaine All studies with the exception of one (Carvalho 2007a; Carvalho 2007b) reported the ph of the buffered lidocaine. The effect of lidocaine solutions with ph of 7.3 or higher on the decrease in pain intensity was not clear as the results were in opposite directions in the crossover and parallel studies. In the crossover studies, trials using solutions with a higher ph produced larger decreases in pain intensity (-2.44 units, 95% CI to -0.92) than trials using solutions with a lower ph (-1.70 units, 95% CI to -1.22) (see Analysis 4.1). However, in parallelgroup trials the solutions with a higher ph were associated with smaller decreases in pain intensity, unit decrease (95% CI to -0.15) versus unit decrease (95% CI to -0.44) in trials using solutions with a lower ph (see Analysis 2.1). The results were heterogeneous in both parallel-group (I 2 = 74% and I 2 = 93%) and crossover studies (I 2 =66% and I 2 = 96%) respectively. Children The study that focused on children (Richtsmeier 1995) included seven participants and reported no difference (P = 0.13) in pain intensity between buffered and unbuffered lidocaine using an Oucher scale. Patient preference Eleven studies with a total of 418 participants reported patient preference (Bartfield 1993; Cornelius 1996; Fitton 1996; Masters 1998; Metzinger 1994; Nelson 1995; Orlinsky 1992; Samdal 1994; Sapin 1991; Vossinakis 2004; Yuen 1999). All of these trials were crossover studies. In three studies (Fitton 1996; Samdal 1994; Vossinakis 2004) the odds ratio (OR) could not be estimated due to the presence of zeros (none of the patients preferred unbuffered lidocaine) and therefore could not be included in the meta-analysis (see Analysis 5.1; Summary of findings for the main comparison). Patients preferred buffered lidocaine over unbuffered lidocaine (OR 3.01, 95% CI 2.19 to 4.15). The results were homogenous (I 2 = 0%). Patient satisfaction The study by Yiannakopoulos was the only study that evaluated patients satisfaction (Yiannakopoulos 2004); 55% of participants in the unbuffered lidocaine group would refuse to undergo the same anaesthetic technique again versus 18% in the buffered lidocaine group (P = 0.01). Adverse events Three of the 23 studies specifically mentioned the assessment of adverse events or complications (Carvalho 2007a; Carvalho 2007b; Fitton 1996; Samdal 1994). With the exception of the study by Fitton (Fitton 1996), which reported a hematoma (no description in which treatment arm), the studies reported an absence of adverse events or toxicity in buffered and unbuffered arms (see Summary of findings for the main comparison). Heterogeneity The risk of bias due to level of allocation concealment in the studies helped explain the heterogeneity of the results. In parallel-group studies with low risk of bias the decrease in pain intensity was units (95% CI to -0.19; I 2 = 0%) versus units (95% CI to -0.68; I 2 = 85%) in parallel-group studies with higher risk of bias (see Analysis 6.1). The volume of injection did not explain the heterogeneity of the results. In low volume parallel-group studies the magnitude of the decrease in pain intensity with buffered lidocaine compared to unbuffered lidocaine was (95% CI to -0.36) and in high volume trials it was (95% CI to 0.01); I 2 = 79% and 91% respectively (see Analysis 7.1). In low volume crossover studies the magnitude of the decrease in pain intensity with buffered lidocaine compared to unbuffered lidocaine was (95% CI to -0.37), in high volume trials it was

15 (95% CI to -1.58); I 2 = 47% and 86% respectively (see Analysis 8.1). Similarly, the reason for using lidocaine did not explain heterogeneity of results. In parallel-group studies that evaluated intravenous cannulation the magnitude of the decrease in pain intensity with buffered lidocaine compared to unbuffered lidocaine was (95% CI to -0.28), in the studies that evaluated nerve block of epidural catheter insertion it was (95% CI to -0.30), and in those that evaluated minor surgical procedures it was (95% CI to 0.32); I 2 = 30%, 62%, and 95% respectively (see Analysis 9.1). In crossover studies that evaluated minor surgical procedures the magnitude of the decrease in pain intensity with buffered lidocaine compared to unbuffered lidocaine was 0.10 (95% CI 0.05 to 0.20; I 2 = 88%) and in the studies evaluating nerve block or epidural catheter placement it was 0.28 (95% CI 0.08 to 0.91; I 2 = 83%). However, the latter analysis involved only two studies. Only one study provided data on intravenous cannulation therefore it was impossible to provide a pooled estimate (see Analysis 10.1). D I S C U S S I O N Increasing the ph of lidocaine decreases the pain associated with its infiltration and increases patient preference for the ph-adjusted lidocaine. With the exception of patient preference the study results were heterogeneous and remained so despite the analysis of factors that could explain the heterogeneity. However, none of the studies showed that buffered lidocaine produced more pain than unbuffered lidocaine. The basis for discrepancy was the magnitude of the decline in pain intensity. In the worst scenario the decrease in pain intensity was 0.3 units, which is considered to be of small clinical importance (Cepeda 2003). However, the fact that patients preferred buffered lidocaine over unbuffered solution (see Figure 4) provides support to the utility of the alkalinization to decrease pain associated with injection and strengthens the clinical importance of the decrease in pain intensity with buffered lidocaine (see Summary of findings for the main comparison). Figure 4. Forest plot of comparison: 5 Preference, outcome: 5.1 Preference in cross over studies. This systematic review did not evaluate the effect of alkalization of lidocaine on the quality of the sensory blockade. Results of studies that have assessed the effect of alkalinization on the quality of sensory blockade range from alkalinization decreasing the onset of analgesia and increasing potency to alkalinization decreasing the degree and duration of the anaesthesia block (Gaggero 1995). In addition, the effect of alkalization on the quality of anaesthetic blockade seems to vary both with the presence of epinephrine and the type of agent used to increase the ph (sodium bicarbonate versus sodium hydroxide) (Sinnott 2000). Clinicians should be mindful of the limitation that this systematic review focused on the pain on injection and did not evaluate the quality of the anaesthetic blockade when interpreting the results of the review. We found that the difference in the magnitude of the decrease in pain intensity between buffered and unbuffered lidocaine is larger when the solution contains epinephrine (Figure 5; Figure 6). This may not be surprising as the ph of these solutions is lower than that of the solutions without epinephrine (ph 4.94 versus 5.09) (Robinson 2000). 13

16 Figure 5. Forest plot of comparison: 1 Mean pain difference in parallel studies, outcome: 1.1 Mean difference in parallel studies by presence of epinephrine. Figure 6. Forest plot of comparison: 3 Mean pain difference in crossover studies with and without epinephrine, outcome: 3.1 Mean pain difference in crossover studies with and without epinephrine. 14

17 Other factors, in addition to the ph of the solution injected, that could affect the pain associated with injection are needle size, speed of injection and temperature of the local anaesthetic solution (Redd 1990); however, these factors were not evaluated in this review. The pain associated with local anaesthetic infiltration may be considered short lived and moderate in intensity, putting into question its clinical relevance and the need for efforts to decrease it. However, multiple attempts or injections at different locations are not uncommonly needed to complete clinical tasks such as intravenous cannulation or anaesthetizing soft tissue. In addition, some patients are likely to require similar procedures in the future. A previous poor experience may increase the patient s anxiety, interfere with the ability to cooperate and may even lead to refusal of a procedure that has proven benefits for them (Siddiqui 2007). Alkalinization of lidocaine is most commonly performed by adding 1 ml of 8.4% sodium bicarbonate to 9 ml of 1% or 2% lidocaine. However, alkalinization of lidocaine could cause precipitation and loss of potency. No precipitation was mentioned in any of the studies, even with higher concentrations of bicarbonate. Buffered lidocaine has been shown to maintain pharmacologic activity when refrigerated for two weeks and to maintain clinical activity when stored for one week at room temperature (Bartfield 1993; Larson 1991; Stewart 1990). As for its antimicrobial activity, buffering lidocaine seems to potentiate the bacteriocidal effects (Thompson 1993). Although the number of studies in some analyses was limited and heterogeneity existed despite our attempts to explain it, the results of this systematic review indicate that increasing the ph of commercial lidocaine solutions admixture immediately prior to clinical use decreases pain intensity and increases patient preference for the adjusted lidocaine. These findings were evident with or without epinephrine. A commercially produced buffered lidocaine would be likely to facilitate wider use. A U T H O R S C O N C L U S I O N S Implications for practice Increasing the ph of commercial lidocaine preparations with bicarbonate should be considered in order to systematically decrease pain on injection and augment patients comfort and satisfaction. The acidic ph of commercial solutions is mostly a consequence of the need for effective preservation of the solution. Manufacturers should be encouraged to search for alternatives for local anaesthetic preservation that permit a more physiologic ph and abolish the need for ph adjustment prior to use. Another alternative is the preparation of double vials. The upper vial will have bicarbonate as a dry substance and the lower vial the anaesthetic solution so that the bicarbonate can be introduced into the local anaesthetic solution at the time of injection. Clinicians need to be aware that although the lidocaine concentration in alkalinized solutions remains constant over time, epinephrine concentrations in alkalinized lidocaine solutions decrease substantially over 24 hours (Robinson 2000). Implications for research We could not explain the large variation in the magnitude of pain decrease with buffered lidocaine. Therefore, we need a better understanding of the conditions or circumstances in which buffered lidocaine has maximum benefits. A C K N O W L E D G E M E N T S This work was in part supported by Saltonstall Fund for Pain Research, USA. We would like to thank Anna Lee, Phil Wiffen, Scott Strassels and Kathie Godfrey for their help and editorial advice during the preparation of the protocol for the systematic review. We would like to thank Anna Lee, Marialena Trivella, Mona Nasser, Scott Strassels, Milli Reddy, Anne Peticolas, Suzanne Cunliffe, Karen Hovhannisyan and Jane Cracknell for their help and editorial advice during the preparation of the current systematic review. R E F E R E N C E S References to studies included in this review Bartfield 1993 {published data only} Bartfield JM, Ford DT, Homer PJ. Buffered versus plain lidocaine for digital nerve blocks. Annals of Emergency Medicine 1993;22(2): [MEDLINE: ] Carvalho 2007a {published data only} Carvalho B, Fuller A, Brummel C, Cohen SE. Local infiltration of epinephrine-containing lidocaine with bicarbonate reduces superficial bleeding and pain during labor epidural catheter insertion: a randomized trial. International Journal of Obstetric Anesthesia 2007;16: [MEDLINE: ] Carvalho 2007b {published data only} Carvalho B, Fuller A, Brummel C, Cohen S. Local infiltration of epinephrine-containing lidocaine with bicarbonate reduces superficial bleeding and pain during labor epidural catheter insertion: a randomized trial. International Journal of Obstetric Anesthesia 2007;16: [MEDLINE: ] 15

18 Cornelius 1996 {published data only} Cornelius P, Kendall J, Meek S, Rajan R. Alkalinisation of lignocaine to reduce the pain of digital nerve blockade. Journal of Accident & Emergency Medicine 1996;13(5): [MEDLINE: ] Ernst 1996 {published data only} Ernst AA, Marvez-Valls E, Nick TG, Wahle M. Comparison trial of four injectable anesthetics for laceration repair. Academic Emergency Medicine 1996;3: [MEDLINE: ] Fatovich 1999 {published data only} Fatovich DM, Jacobs IG. A randomized controlled trial of buffered lidocaine for local anesthetic infiltration in children and adults with simple lacerations. The Journal of Emergency Medicine 1999;17: [MEDLINE: ] Fitton 1996 {published data only} Fitton AR, Ragbir M, Milling MA. The use of ph adjusted lignocaine in controlling operative pain in the day surgery unit: a prospective, randomised trial. British Journal of Plastic Surgery 1996;49(6): [PUBMED: ] Gershon 1991 {published data only} Gershon RY, Mokriski BK, Matjasko MJ. Intradermal anesthesia and comparison of intravenous catheter gauge. Anesthesia and Analgesia 1991;73(4): [MEDLINE: ] Martin 1990 {published data only} Martin AJ. ph-adjustment and discomfort caused by the intradermal injection of lignocaine.[erratum appears in Anaesthesia 1991 Mar;46(3):242]. Anaesthesia 1990;45 (11): [MEDLINE: ] Masters 1998 {published data only} Masters JE. Randomised control trial of ph buffered lignocaine with adrenaline in outpatient operations. British Journal of Plastic Surgery 1998;51(5): [MEDLINE: ] Metzinger 1994 {published data only} Metzinger SE, Rigby PL, Bailey DJ, Brousse RG. Local anesthesia in blepharoplasty: a new look?. Southern Medical Journal 1994;87: [MEDLINE: ] Nakayama 2001a {published data only} Nakayama M, Munemura Y, Kanaya N, Tsuchida H, Namiki A. Efficacy of alkalinized lidocaine for reducing pain on intravenous and epidural catheterization. Journal of Anesthesia 2001;15: [MEDLINE: ] Nakayama 2001b {published data only} Nakayama M, Munemura Y, Kanaya N, Tsuchida H, Namiki A. Efficacy of alkalinized lidocaine for reducing pain on intravenous and epidural catheterization. Journal of Anesthesia 2001;15: [MEDLINE: ] Nelson 1995 {published data only} Nelson AL. Neutralizing ph of lidocaine reduces pain during Norplant system insertion procedure. Contraception 1995;51(5): [MEDLINE: ] Nuttall 1993 {published data only} Nuttall GA, Barnett MR, Smith RL 2nd, Blue TK, Clark K, Payton BW. Establishing intravenous access: a study of local anesthetic efficacy. Anesthesia and Analgesia 1993;77 (5): [MEDLINE: ] Orlinsky 1992 {published data only} Orlinsky M, Hudson C, Chan L, Deslauriers R. Pain comparison of unbuffered versus buffered lidocaine in local wound infiltration. Journal of Emergency Medicine 1992;10 (4): [MEDLINE: ] Richtsmeier 1995 {published data only} Richtsmeier AJ, Hatcher JW. Buffered lidocaine for skin infiltration prior to hemodialysis. Journal of Pain and Symptom Management 1995;10(3): [MEDLINE: ] Samdal 1994 {published data only} Samdal F, Arctander K, Skolleborg KC, Amland PF. Alkalisation of lignocaine-adrenaline reduces the amount of pain during subcutaneous injection of local anaesthetic. Scandinavian Journal of Plastic and Reconstructive Surgery and Hand Surgery 1994;28(1):33 7. [MEDLINE: ] Sapin 1991 {published data only} Sapin P, Petrozzi R, Dehmer GJ. Reduction in injection pain using buffered lidocaine as a local anesthetic before cardiac catheterization. Catheterization and Cardiovascular Diagnosis 1991;23(2): [MEDLINE: ] Steinbrook 1993 {published data only} Steinbrook RA, Hughes N, Fanciullo G, Manzi D, Ferrante FM. Effects of alkalinization of lidocaine on the pain of skin infiltration and intravenous catheterization. Journal of Clinical Anesthesia 1993;5(6): [MEDLINE: ] Vossinakis 2004 {published data only} Vossinakis IC, Stavroulaki P, Paleochorlidis I, Badras LS. Reducing the pain associated with local anaesthetic infiltration for open carpal tunnel decompression. Journal of Hand Surgery - British Volume 2004;29(4): [MEDLINE: ] Watts 2003 {published data only} Watts AC, Gaston P, Hooper G. Randomized trial of buffered versus plain lidocaine for local anaesthesia in open carpal tunnel decompression. Journal of Hand Surgery - British Volume 2004;29(1):30 1. [MEDLINE: ] Yiannakopoulos 2004 {published and unpublished data} Yiannakopoulos CK. Carpal ligament decompression under local anaesthesia: the effect of lidocaine warming and alkalinisation on infiltration pain. Journal of Hand Surgery - British Volume 2004;29(1):32 4. [MEDLINE: ] Younis 2004 {published data only} Younis I, Bhutiani RP. Taking the ouch out - effect of buffering commercial xylocaine on infiltration and procedure pain - a prospective, randomised, double-blind, controlled trial. Annals of the Royal College of Surgeons of England 2004;86: [MEDLINE: ] Yuen 1999 {published data only} Yuen VH, Dolman PJ. Comparison of three modified lidocaine solutions for use in eyelid anesthesia. Ophthalmic Plastic & Reconstructive Surgery 1999;15(2): [MEDLINE: ] 16

19 References to studies excluded from this review Acosta 1997 {published data only} Acosta AE. Clinical parameters of tumescent anesthesia in skin cancer reconstructive surgery. A review of 86 patients. Archives of Dermatology 1997;133(4): [MEDLINE: ] Ball 2006 {published data only} Ball EL, Sanjay P, Woodward A. Comparison of buffered and unbuffered local anaesthesia for inguinal hernia repair: a prospective study. Hernia 2006;10: [MEDLINE: ] Barnett 1992 {published data only} Barnett TA, Kapp DS. Reduction of pain and local complications when buffered lidocaine solution is used as a local anesthetic in conjunction with hyperthermia treatments: results of a randomized trial. International Journal of Radiation Oncology, Biology, Physics 1992;23(3): [MEDLINE: ] Bartfield 1992 {published data only} Bartfield JM. Homer PJ. Ford DT. Sternklar P. Buffered lidocaine as a local anesthetic: an investigation of shelf life. Annals of Emergency Medicine 1992;21(1):16 9. [MEDLINE: ] Benlabed 1990 {published data only} Benlabed M, Jullien P, Guelmi K, Hamza J, Bonhomme L, Benhamou D. Alkalinization of 0.5% lidocaine for intravenous regional anesthesia. Regional Anesthesia 1990; 15(2): [MEDLINE: ] Bowles 1995 {published data only} Bowles WH, Frysh H, Emmons R. Clinical evaluation of buffered local anesthetic. General Dentistry 1995;43(2): [MEDLINE: ] Brown 2004 {published data only} Brown D. Local anesthesia for vein cannulation: a comparison of two solutions. Journal of Infusion Nursing 2004;27(2):85 8. [MEDLINE: ] Burns 2006 {published data only} Burns CA, Ferris G, Feng C, Cooper JZ, Brown MD. Decreasing the pain of local anesthesia: a prospective, double-blind comparison of buffered, premixed 1% lidocaine with epinephrine versus 1% lidocaine freshly mixed with epinephrine. Journal of the American Academy of Dermatology 2006;54(1): [MEDLINE: ] Capogna 1993 {published data only} Capogna G, Celleno D, Costantino P, Muratori F, Sebastiani M, Baldassini M. Alkalinization improves the quality of lidocaine-fentanyl epidural anaesthesia for caesarean section. Canadian Journal of Anaesthesia 1993;40 (5 Pt 1): [MEDLINE: ] Christoph 1988 {published data only} Christoph RA, Buchanan L, Begalla K, Schwartz S. Pain reduction in local anesthetic administration through ph buffering. Annals of Emergency Medicine 1988;17(2): [MEDLINE: ] Connelly 1996 {published data only} Connelly NR, Leonard R. Discomfort associated with regional anesthetic placement in obstetrics: does alkalinization help?. International Journal of Obstetric Anesthesia 1996;5: [MEDLINE: ] DiFazio 1986 {unpublished data only} DiFazio CA, Carron H, Grosslight KR, Moscicki JC, Bolding WR, Johns RA. Comparison of ph-adjusted lidocaine solutions for epidural anesthesia. Anesthesia and Analgesia 1986;65: [MEDLINE: ] Eccarius 1990 {published data only} Eccarius SG, Gordon ME, Parelman JJ. Bicarbonatebuffered lidocaine-epinephrine-hyaluronidase for eyelid anesthesia. Ophthalmology 1990;97(11): [MEDLINE: ] Elhakim 1998 {published data only} Elhakim M, Magady M, Seuam A, Mostafa BE. Alkalinization of lidocaine for multiple level infiltration after tonsillectomy in children. Acta Anaesthesiologica Italica 1998;49: Farrell 1995 {published data only} Farrell HA, Waldman SR, Campbell JP, Jones RO. Duration of buffered lidocaine versus unbuffered lidocaine: a doubleblind, randomized prospective study. Ear, Nose, & Throat Journal 1995;74: [MEDLINE: ] Friedman 1997 {published data only} Friedman HE, Jules KT, Springer K, Jennings M. Buffered lidocaine decreases the pain of digital anesthesia in the foot. Journal of the American Podiatric Medical Association 1997; 87(5): [MEDLINE: ] Gaggero 1995 {published data only} Gaggero G, Meyer O, Van Gessel E, Rifat K. Alkalinization of lidocaine 2% does not influence the quality of epidural anaesthesia for elective caesarean section. Canadian Journal of Anaesthesia 1995;42(12): [MEDLINE: ] Gormley 1995 {published data only} Gormley WP, Hill DA, Murray JM, Fee JP. The effect of alkalinisation of lignocaine on axillary brachial plexus anaesthesia. Anaesthesia 1996;51(2): [MEDLINE: ] Hinshaw 1995 {published data only} Hinshaw KD, Fiscella R, Sugar J. Preparation of phadjusted local anesthetics. Ophthalmic Surgery 1995;26(3): [MEDLINE: ] Iwama 2001 {published data only} Iwama H, Ohmori S, Kaneko T, Watanabe K. Waterdiluted local anesthetic for trigger-point injection in chronic myofascial pain syndrome: evaluation of types of local anesthetic and concentrations in water. Regional Anesthesia and Pain Medicine 2001;26(4): [MEDLINE: ] Jones 1998 {published data only} Jones JS, Plzak C, Wynn BN, Martin S. Effect of temperature and ph adjustment of bupivacaine for 17

20 intradermal anesthesia. The American Journal of Emergency Medicine 1998;16: [MEDLINE: ] Kelsaka 2006 {published data only} Kelsaka E, Guldpgus F, Sarihasan B, Tepe S. Comparison of EMLA and lidocaine with or without sodium bicarbonate in prevention of spinal needle insertion pain. Anestezi Dergisi 2006;14:76 9. Koscielniak-Nielsen {published data only} Koscielniak-Nielsen ZJ, Stens-Pedersen HL, Kjaerbo EJ. Intra-arterial regional anaesthesia for hand surgery with alkalinized 0.5% lignocaine. Acta Anaesthesiologica Scandinavica 1995;39(8): [MEDLINE: ] Larson 1991 {published data only} Larson PO, Ragi G, Swandby M, Darcey B, Polzin G, Carey P. Stability of buffered lidocaine and epinephrine used for local anesthesia. The Journal of Dermatologic Surgery and Oncology 1991;17: [MEDLINE: ] Long 1991 {published data only} Long CC, Motley RJ, Holt PJ. Taking the sting out of local anaesthetics. British Journal of Dermatology 1991;125 (5): [MEDLINE: ] Lugo-Janer 1993 {published data only} Lugo-Janer G, Padial M, Sanchez JL. Less painful alternatives for local anesthesia. Journal of Dermatologic Surgery & Oncology 1993;19(3): [MEDLINE: ] Manka 1991 {published data only} Manka RL, Gast TJ. Sodium bicarbonate reduces pain associated with ophthalmic nerve blocks. Refractive & Corneal Surgery 1991;7(2): [MEDLINE: ] Marica 2002 {published data only} Marica LS, O Day T, Janosky JE, Nystrom EU. Chloroprocaine is less painful than lidocaine for skin infiltration anesthesia. Anesthesia and Analgesia 2002;94(2): [MEDLINE: ] Matsumoto 1994 {published data only} Matsumoto AH, Reifsnyder AC, Hartwell GD, Angle JF, Selby JB Jr, Tegtmeyer CJ. Reducing the discomfort of lidocaine administration through ph buffering. Journal of Vascular and Interventional Radiology 1994;5(1): [MEDLINE: ] McGlone 1990 {published data only} McGlone R, Bodenham A. Reducing the pain of intradermal lignocaine injection by ph buffering. Archives of Emergency Medicine 1990;7(2):65 8. [MEDLINE: ] McKay 1987 {published data only} McKay W, Morris R, Mushlin P. Sodium bicarbonate attenuates pain on skin infiltration with lidocaine, with or without epinephrine. Anesthesia and Analgesia 1987;66(6): [MEDLINE: ] Metzinger 1992 {published data only} Metzinger SE, Bailey DJ, Boyce RG, Lyons GD. Local anesthesia in rhinoplasty: a new twist?. Ear, Nose, & Throat Journal 1992;71: [MEDLINE: ] Minasian 2000 {published data only} Minasian MC, Ionides AC, Fernando R, Davey CC. Pain perception with ph buffered peribulbar anaesthesia: a pilot study. British Journal of Ophthalmology 2000;84(9): [MEDLINE: ] Moharib 2002 {published data only} Moharib MM, Mitra S, Rizvi SG. Effect of alkalinization and/or hyaluronidase adjuvancy on a local anesthetic mixture for sub-tenon s ophthalmic block. Acta Anaesthesiologica Scandinavica 2002;46(5): [MEDLINE: ] Moreno-Jimenez 2008 {published data only} Moreno-Jimenez S, Ibarra Rangel A, Loaeza Zarate C, Gutierrez Aceves GA, Celis MA, Terrazo-Lluch J, et al.comparative study between different dilutions of lidocaine-sodium bicarbonate in local infiltration to the positioning of the stereotactic frame [Spanish]. Archivos de Neurociencias 2008;13(1):3 7. [: CINAHL: ; : ISSN: ] Nevarre 1998 {published data only} Nevarre DR, Tzarnas CD. The effects of hyaluronidase on the efficacy and on the pain of administration of 1% lidocaine. Plastic and Reconstructive Surgery 1998;101(2): [MEDLINE: ] Ng 1999 {published data only} Ng HN, Sim KM, Boey SK. Bone marrow harvesting using EMLA (eutectic mixture of local anaesthetics) cream, local anaesthesia and patient-controlled analgesia with alfentanil. Bone Marrow Transplantation 1999;23(9): [MEDLINE: ] Ong 2000 {published data only} Ong EL, Lim NL, Koay CK. Towards a pain-free venepuncture. Anaesthesia 2000;55: [MEDLINE: ] Ozer 2005 {published data only} Ozer H, Solak S, Oguz T, Ocguder A, Colakoglu T, Babacan A. Alkalinisation of local anaesthetics prescribed for pain relief after surgical decompression of carpal tunnel syndrome. Journal of Orthopaedic Surgery 2005;13(3): [MEDLINE: ] Palmon 1998 {published data only} Palmon SC, Lloyd AT, Kirsch JR. The effect of needle gauge and lidocaine ph on pain during intradermal injection. Anesthesia and Analgesia 1998;86(2): [MEDLINE: ] Parham 1996 {published data only} Parham SM, Pasieka JL. Effect of ph modification by bicarbonate on pain after subcutaneous lidocaine injection. Canadian Journal of Surgery 1996;39(1):31 5. [MEDLINE: ] Primosch 1996 {published data only} Primosch RE, Robinson L. Pain elicited during intraoral infiltration with buffered lidocaine. American Journal of Dentistry 1996;9(1):5 10. [MEDLINE: ] 18