ORIGINAL ARTICLE
Efficacy of Bicarbonate in Decreasing Pain on Intradermal
Injection of Local Anesthetics
A Meta-Analysis
Marie N. Hanna, MD, Amir Elhassan, MD, Patricia M. Veloso, MD, Maggie Lesley, BS,
Jon Lissauer, MD, Jeffrey M. Richman, MD, and Christopher L. Wu, MD
Objective: Intradermal injection of local anesthetic often results in pain
on injection due in part to the acidic pH of commercially prepared
solutions, which are optimized to prolong shelf life. Although there
are other possible explanations (eg, noxious properties of local anes-
thetics, pressure effect of infiltration), the etiology is most likely multi-
factorial. Although addition of bicarbonate to local anesthetics may
decrease pain on intradermal injection, the extent of this analgesic effect
is uncertain. We performed a meta-analysis of available trials investi-
gating pain during intradermal injection of buffered local anesthetic
preparations.
Methods: We searched the National Library of Medicine’s PubMed
database for all relevant articles published on the topic through
November 2006. Inclusion criteria included double-blind, randomized
controlled trials and use of a visual analog scale to measure pain on
infiltration of local anesthetic buffered with sodium bicarbonate
compared with that of unbuffered local anesthetic. Meta-analysis was
performed using the Review Manager 4.2.7 (The Cochrane Collabo-
ration, 2004). A random-effects model was used.
Results: Our search resulted in 86 abstracts, of which 12 articles met
all inclusion criteria. Overall, there were 609 observations for buffered
local anesthetic and 615 for unbuffered local anesthetic. Use of buff-
ered local anesthetic resulted in a statistically lower weighted mean
difference in visual analog scale of j1.17 (95% confidence interval,
j1.68 to j0.67) compared with unbuffered local anesthetic.
Conclusions: Our systematic review suggests that the use of buff-
ered local anesthetics seems to be associated with a statistical decrease
in pain of infiltration when compared with unbuffered local anesthetic.
(Reg Anesth Pain Med 2009;34: 122Y125)
T he pain from subcutaneous or intradermal injection of lo-
cal anesthetic, which is used in a number of procedures
ranging from minor wound repair to extensive plastic surgical
procedures, may be the most painful aspect of some proce-
dures. Most local anesthetics are commercially prepared at an
acidic pH to enhance shelf life. Occasionally, health care pro-
viders may add sodium bicarbonate to buffer local anesthetics
before subcutaneous injection in an attempt to reduce the pain
of infiltration. Although there have been several studies in-
From the Department of Anesthesiology and Critical Care Medicine, The
Johns Hopkins University and School of Medicine, Baltimore, MD.
Accepted for publication June 20, 2008.
Address correspondence to: Christopher L. Wu, MD, The Johns Hopkins
Hospital, Carnegie 280; 600 N Wolfe St, Baltimore, MD 21287 (e-mail:
chwu@jhmi.edu).
Copyright * 2009 by American Society of Regional Anesthesia and Pain
Medicine
ISSN: 1098-7339
DOI: 10.1097/AAP.0b013e31819a12a6
122 Regional Anesthesia and Pain Medicine
Copyright @ 2009 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
vestigating the analgesic efficacy of bicarbonate in this setting,
the overall efficacy is uncertain because a prior systematic re-
view1 did not provide a pooled estimate (ie, did not provide any
quantification of the effect). We have undertaken a systematic
review of randomized trials and performed a meta-analysis to
quantify the analgesic efficacy of adding bicarbonate to local
anesthetics before intradermal injection.
METHODS
Studies were identified by searching the National Library
of Medicine PubMed database using the keywords Bbicarbon-
ate[ and Blocal anesthetic or local anesthesia.[ These searches
were combined, and the results were further narrowed by
adding the keyword Bpain[ and limiting to Bhumans, random-
ized controlled trials, English (language).[ Inclusion criteria
for a study to be considered for analysis were (a) randomized,
double-blind controlled trial; (b) comparison of pain between
buffered and unbuffered intradermally administered local anes-
thetics, and (c) measurement of pain scores using a visual analog
scale (VAS) with SD or an equivalent method assessed during
injection of local anesthetic. To be included in this meta-analysis,
studies had to provide a clear comparison between buffered and
unbuffered local anesthetics intradermally without concurrent
use of both regimens. Exclusion criteria included articles where
VAS scores were not recorded, use of buffered local analgesics
intravenously or in regional anesthesia/analgesia, or failure to
meet any of the other mentioned inclusion criteria. The primary
outcome investigated was pain of infiltration using buffered and
unbuffered solutions of local anesthetics.
The full article of each accepted abstract was then re-
viewed by the authors for inclusion into the meta-analysis.
Accepted articles were hand searched for additional references.
No minimum sample sizes were invoked for inclusion of studies
in the analysis. Data were extrapolated from figures as needed.
Visual analog scale or numeric pain scores were converted to a
0- to 10-point scale. All statistical analyses were performed with
the Cochrane Collaboration’s Review Manager version 4.2.9
(October 2006). A random-effects model was used. The level of
significance for all tests was set at an > level of 0.05.
RESULTS
Our search yielded a total of 86 articles, of which 12
articles2Y13 met all inclusion criteria. A total of 74 articles
were rejected for the following reasons: 14 did not record pain
scores or lacked usable data (eg, lack of SD), 4 measured pain
after injection, 2 were not randomized controlled trials, 1
study had buffered analgesics in both arms, 13 did not study
buffered local anesthetics, and 42 articles did not evaluate
intradermal injection of local anesthetics (eg, studied regional/
nerve block administration of buffered local anesthetics). No
studies were excluded for measuring pain as a variable and
& Volume 34, Number 2, March-April 2009
Regional Anesthesia and Pain Medicine & Volume 34, Number 2, March-April 2009 Bicarbonate for Pain in Intradermal Injection

including healthy volunteers, plastic surgery candidates, and

TABLE 1. Characteristics of Included Studies patients receiving angiographic procedures. However, despite the
fact that there was a statistical decrease in weighted mean VAS
Total no. subjects 801
pain with addition of bicarbonate to local anesthetics, it is not
Total no. unique observations 1224
clear whether this difference is clinically meaningful.
Study location (no. studies) There are several reasons why there may be pain on intra-
United States 7 dermal injection of local anesthetics. Although only the non-
Europe 4 ionized form of local anesthetic is able to cross nerve membranes
Asia/Australia 1 and exert its sodium channelYblocking effect, most commercially
Sex (no. studies) prepared local anesthetic solutions are acidic. Protons from the
Male only 0 acidic solution may activate acid-sensing ion channel receptors
Female only 0 or polymodal nociceptors14 causing pain.
Both 6 Addition of bicarbonate may theoretically decrease activa-
tion of these nociceptors. In addition, the actual needle puncture
Not specified 6
may contribute to pain on intradermal injection, as may rapid
Local anesthetic used (no. studies)
distention of tissue.
Lidocaine 12 An important factor in determining the accuracy of the
Chloroprocaine 1 data we used is the concentration and volume of sodium
bicarbonate used and thus pH of the preparations used for infil-
tration. The concentrations of bicarbonate used varied among
not showing efficacy of buffering of local anesthetics in atten- the studies, which may have contributed to the heterogeneity
uation of pain of infiltration. Table 1 shows the characteristics observed in the results. Table 2 shows the methods of prep-
of the articles included. A total of 855 patients with 1224 aration of the buffered lidocaine solutions used in each of the
unique observations (ie, some subjects were studied more studies included.
than once) were available for analysis. Lidocaine was the Whether a weighted mean difference (WMD) of j1.2 on a
most commonly studied local anesthetic (11/12 studies). The VAS score of 0 to 10 is clinically meaningful is somewhat
pooled analysis of all available trials is shown in Figure 1. uncertain. Our meta-analysis revealed an overall approximate
Addition of bicarbonate was associated with a statistical sig- 30% reduction (which is consistent with values that have
nificant decrease in pain (P G 0.0001), with a decrease in been suggested to be a clinically relevant reduction in pain
weighted mean VAS of j1.17 (95% confidence interval, j1.68 scores15,16) in overall VAS pain on intradermal injection with
to j0.67). addition of bicarbonate. No study actually correlated a change
in VAS pain score to a clinically important difference in pain
DISCUSSION (eg, concurrently assessing pain with categories such as ‘‘not
Our systematic review showed that, when compared with improved,’’ ‘‘improved,’’ ‘‘much improved,’’ ‘‘very much im-
unbuffered local anesthetic, the addition of bicarbonate to local proved’’).17 Furthermore, the pain scores recorded for the
anesthetics is associated with a decrease in pain during subcu- unbuffered group were rather low and the pain likely to have
taneous injection. This effect was observed in a variety of patients been very brief.

FIGURE 1. Effect of adding bicarbonate to local anesthetic on pain of subcutaneous infiltration: meta-analysis. Measured by weighted
VAS pain. ‘‘N’’ represents the number of individual data points in each experimental group. The entire diamond at the bottom of the
figure represents the pooled estimate (WMD = j1.17) and is entirely to the left of the WMD = 0, suggesting that administration of
buffered local anesthetic is associated with lower pain scores.

* 2009 American Society of Regional Anesthesia and Pain Medicine 123

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Hanna et al Regional Anesthesia and Pain Medicine & Volume 34, Number 2, March-April 2009

TABLE 2. Local Anesthetic Solutions of Studies Included in the Meta-analysis

Population,
Study, Year No. Subjects (Total) Nonbuffered Group (LA; pH) Buffered Group (LA; pH)
Marica, 200211* Volunteer, 22 1% Lido or 2% chloro; chloro pH 3.4 1% Lido + 8.4% bicarb or 2% chloro + 8.4%
bicarb; chloro/bicarb pH 7.7
Martin2 Mix, 150 1% Lido or 1% lido/epi; 1% lido 1% Lido + 8.4% bicarb or 1% lido/epi +
pH 5.0, 1% lido/epi pH 3.8 8.4% bicarb; 1% lido/bicarb pH 7.5, 1%
lido/epi/bicarb pH 7.4
Masters10 Mix, 40 2% Lido/epi; pH 3.5 2% Lido/epi + 8.4% bicarb; pH 7.0
Matsumoto et al7 Interventional 1% Lido; pH 6.2 1% Lido + 8.4% bicarb; pH 7.2
radiology, 150
Palmon et al9* Volunteer, 40 2% Lido; pH 6.2 2% Lido + 8.4% bicarb; pH 7.3
Richtsmeier and Hemodialysis, 7 1% Lido; n/a 1% Lido + 8.4% bicarb; n/a
Hatcher4*
Samdal et al5* Mix, 35 1% Lido/epi; pH 4.1Y4.4 1% Lido/epi + bicarb; pH 7.1Y7.3
Scarfone et al8* Volunteer, 42 1% Lido; n/a 1% Lido + 8.4% bicarb; n/a
Steinbrook et al6 Mix, 184 1% Lido; n/a 1% Lido + bicarb; n/a
Stewart et al3 Volunteer, 100 1% Lido/epi; pH 4.0 1% Lido/epi + 7.5% bicarb; pH 7.3
Vossinakis et al13 Ortho, 21 1% Lido/epi; n/a 1% Lido/epi + 8.4% bicarb; n/a
Watts et al12 Ortho, 64 2% Lido; pH 6.4 2% Lido + 8.4% bicarb; pH 7.4
*Multiple groups or interventions within each study.
Abbreviations: BICARB, sodium bicarbonate; CHLORO, chloroprocaine; EPI, epinephrine; LA, local anesthetic; LIDO, lidocaine; MIX, mixed;
N/A, not available; ORTHO, orthopedic.

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