General Intervention
`
`Reducing the Discomfort of
`Lidocaine Administration
`through pH Buffering!
`
`Alan H. Matsumoto, MD
`Andrew C. Reifsnyder, MD
`Gary D. Hartwell, DSc
`John F. Angle, MD
`J. Bayne Selby, Jr, MD
`Charles J. Tegtmeyer, MD
`
`Index term: Anesthesia
`
`JVIR 1994; 5:171-175
`
`PURPOSE: A prospective, double-blind study was undertaken to evalu(cid:173)
`ate the effect of using a buffered lidocaine solution on the perception of
`pain experienced by a patient during its intradermal injection.
`PATIENTS AND METHODS: One hundred fifty patients undergoing di(cid:173)
`agnostic angiographic and interventional procedures at the authors' in(cid:173)
`stitution were randomly assigned to receive a 1-mL aliquot of one of
`three lidocaine solutions: plain 1% lidocaine, 1% lidocaine diluted with
`normal saline in a 10:1 ratio, and 1% lidocaine diluted with 8.4% sodium
`bicarbonate in a 10:1 ratio. The lidocaine solutions were administered
`intradermallyover 10-15 seconds. A numerical value was placed on the
`patient's perception of pain, separate from that associated with the 25(cid:173)
`gauge needle insertion, with use of a linear visual analog scale.
`RESULTS: Mean pain scores were as follows: for the 1% lidocaine solu(cid:173)
`tion, 2.83 ± 2.60; for 1% lidocaine plus normal saline solution, 2.89 ±
`2.34; and for 1% lidocaine plus sodium bicarbonate solution, 1.37 ± 1.73
`(P = .0018).
`CONCLUSION: Buffering lidocaine significantly decreased the discom(cid:173)
`fort associated with its administration as a local anesthetic.
`
`LIDOCAINE is frequently used in the
`angiography and interventional radi(cid:173)
`ology suite. It is a local anesthetic of
`the amide class and is a weak organic
`base consisting of uncharged and
`charged fractions when in solution
`(1). It is believed that only the un(cid:173)
`charged or nonionized form of the
`local anesthetic is capable of diffusing
`through interstitial tissues, the peri(cid:173)
`neural tissues, and the nerve mem(cid:173)
`brane (1,2). Once within the nerve
`axoplasm, the nonionized molecule
`recalibrates into its ionized and non(cid:173)
`ionized portions, according to the
`axoplasmal pH. The ionized form at(cid:173)
`taches itself within the sodium chan(cid:173)
`nel of the nerve, blocking neurotrans(cid:173)
`mission (3).
`Most commercially available prepa(cid:173)
`rations of lidocaine are marketed in
`an acidic form (pH = 6.2). At this pH,
`the local anesthetic is more soluble
`and has a shelf life of 3-4 years (4). If
`the pH of the anesthetic solution is
`adjusted closer to its pKa of 7.9, an
`
`increasing percentage of the product
`will be in its uncharged, nonionized
`form. When the pH of the lidocaine
`solution is below 6, less than 1% of
`the lidocaine is in its uncharged form,
`whereas at a pH of 7, 11% is un(cid:173)
`charged (5). Unfortunately, most am(cid:173)
`ides are chemically unstable in the
`uncharged form, being subject to photo(cid:173)
`degradation, aldehyde formation, and
`other denaturing reactions (6).
`The administration of lidocaine as
`a local anesthetic causes a character(cid:173)
`istic burning discomfort. A few stud(cid:173)
`ies with a small number of volunteers
`have suggested that the discomfort of
`intradermal lidocaine administration
`can be reduced through pH buffering
`(7-9). The purpose of this study was
`to determine whether a buffered lido(cid:173)
`caine solution can decrease the per(cid:173)
`ception of pain associated with its
`intradermal injection in a large co(cid:173)
`hort of patients undergoing a variety
`of diagnostic and interventional radi(cid:173)
`ology procedures.
`
`171
`
`I From the Division of Angiography and
`Interventional Radiology, Department of
`Radiology, Box 170, University of Virginia
`Health Sciences Center, Charlottesville, VA
`22908 (A.H.M., G.D.H., J.F.A., C.J.T.l; Ra(cid:173)
`diology Consultants, Austin Tex (A.C.R.);
`and Radiology Associates, Everett, Wash
`(J.B.S.). From the 1993 SCVIR annual
`meeting. Received June 25, 1993; revision
`requested July 26; revision received August
`27. Address reprint requests to A.H.M.
`, SCVIR, 1994
`
`ALL 2023
`PROLLENIUM V. ALLERGAN
`IPR2019-01505 et al.
`
`

`

`172 • Journal of Vascular and Interventional Radiology
`January-February 1994
`
`Table 1
`Summary of Pain Scores for All Patients
`
`Mean Pain
`Mean
`Type of Procedure
`No. of
`Score ± SD
`Age (y)
`Angio
`NVI
`Patients
`Group
`2.83 ± 2.60
`52
`37
`13
`50
`Plain solution (lidocaine alone)
`Control solution (lidocaine + saline)
`NS
`2.89 ± 2.34
`50
`23
`27
`50
`Buffered solution (lidocaine + NaHCOa)
`.0018
`1.37 ± 1.73
`51
`27
`23
`50
`Note.-Angio = angiographic, NS = not significant, NVI = nonvascular diagnostic or interventional procedures, SD = standard
`deviation.
`* Versus plain lidocaine.
`
`P
`Value*
`
`25
`
`20
`
`15
`
`~:c:::;:;t83)
`
`•
`
`UDOCAJNE + NORMAL SAUNE
`(mean pain SCOfe = 2.89)
`
`OUDOCAlNE+NaHC03
`(meanpalnscore=l.37)
`
`10 ~~llIJItJJ
`
`5
`
`0
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`0
`
`~D~
`8
`9
`
`10
`
`C/)
`z
`
`0~
`
`>
`a:
`/)
`
`WC
`
`m0u
`
`.
`
`0
`"*'
`
`PAIN SCORE
`Figure. Histographic comparison of pain scores (according
`to the linear visual analog scale) associated with the intrader(cid:173)
`mal administration of each respective lidocaine solution.
`
`until 50 patients were entered into
`each subgroup of the study. The pH
`of the lidocaine solution was mea(cid:173)
`sured as a baseline with a Beckman
`3560 pH meter (Beckman Instru(cid:173)
`ments, Irvine, CaliD. Each lidocaine
`solution was visually inspected for
`the formation of a precipitate.
`A I-mL aliquot of one of the three
`lidocaine solutions was administered
`intradermallyover 10-15 seconds
`into each patient with use of a 25(cid:173)
`gauge needle by a physician (resident,
`fellow, or attending) in a double-blind
`fashion. The pain separate from the
`insertion of the 25-gauge needle was
`graded during infiltration of the lido(cid:173)
`caine solution. The patients were
`asked to place a numerical value to
`the pain sensation from 0 to 10, by
`using a linear visual analog scale,
`
`where 0 represented no pain, 5 repre(cid:173)
`sented moderate pain, and 10 repre(cid:173)
`sented extremely severe pain. The
`linear visual analog scale enabled
`subjects to assign a numerical value
`corresponding to their perception of
`pain associated with the infiltration
`of the lidocaine solution. This device
`has been used as a reproducible
`means to assign different descriptive
`levels of pain along a graphic scale
`from one extreme sensation to an(cid:173)
`other (10).
`The quantification of pain by each
`patient using the linear visual analog
`scale was pooled into one of three
`groups: plain lidocaine, control lido(cid:173)
`caine, and buffered lidocaine solu(cid:173)
`tions. Statistical analysis of the data
`was performed by using an unpaired
`nonparametric Mann-Whitney rank
`
`PATIENTS AND METHODS
`
`One hundred fifty patients (15
`years of age or older) undergoing di(cid:173)
`agnostic angiography or nonvascular
`diagnostic or interventional radiology
`procedures were enrolled into this
`randomized, prospective, double(cid:173)
`blind study according to a protocol
`approved by the institution's Human
`Investigations Committee. A special
`investigational consent to participate
`in the study was obtained from each
`patient. Patients were excluded from
`the study if they had a history of an
`allergic or adverse reaction to lido(cid:173)
`caine, had received prior sedation,
`had an altered mental status, were
`uncooperative or unable to compre(cid:173)
`hend the nature of the study and/or
`the linear visual analog scale, had
`severe trauma, and/or were diabetic.
`The physician administering the local
`anesthetic and the patient were
`blinded to the type oflidocaine solu(cid:173)
`tion that was administered. The lido(cid:173)
`caine solutions (Abbott Laboratories,
`Abbott Park, Ill) were as follows: 1%
`lidocaine (plain lidocaine solution);
`10 mL of 1% lidocaine diluted with 1
`mL of normal saline (control lido(cid:173)
`caine solution); 10 mL of 1% lido(cid:173)
`caine diluted with 1 mL of 8.4% so(cid:173)
`dium bicarbonate (buffered lidocaine
`solution). The lidocaine solution was
`prepared by the technologist immedi(cid:173)
`ately prior to initiation of the proce(cid:173)
`dure. To minimize confusion, only
`one type of lidocaine solution was
`used per day. The lidocaine solution
`chosen for each day was randomly
`determined by the chief technologist
`
`

`

`Matsumoto et al • 173
`Volume 5 Number 1
`
`Mean Pain Score ± SD
`
`PValue*
`
`Table 2
`Pain Score versus Type of Intervention
`Mean Age (y)
`Group
`No. of Patients
`Patients Undergoing Angiography
`
`Plain solution
`Control solution
`Buffered solution
`
`37
`23
`27
`
`59
`60
`58
`
`Patients Undergoing Nonvascular Procedures
`
`13
`Plain solution
`27
`Control solution
`23
`Buffered solution
`Note.-NS = not significant, SD = standard deviation.
`* Versus plain lidocaine.
`
`31
`42
`43
`
`2.54 ± 2.47
`2.28 ± 2.58
`1.04 ± 1.40
`
`3.65 ± 2.90
`3.41 ± 2.02
`1.76 ± 2.00
`
`NS
`.0089
`
`NS
`.0310
`
`there is a significant difference
`(P = .0018) (Table 1). The histogram
`of pain scores demonstrates that 21
`of the 50 patients who received the
`buffered lidocaine solution had no
`pain (pain score = 0) (Figure).
`Since multiple anatomic sites were
`used for the injection of the lidocaine
`solution, the data were analyzed
`based on the type of procedure (Table
`2). All of the angiograms were ob(cid:173)
`tained from the transfemoral ap(cid:173)
`proach. Plain 1% lidocaine was used
`in 37 patients prior to angiography,
`with a mean pain score of 2.54 ±
`2.47. Buffered lidocaine was adminis(cid:173)
`tered to 27 patients prior to angiogra(cid:173)
`phy, with a mean pain score of 1.04 ±
`1.40 (2.54 vs 1.04; P = .0089). In
`preparation for the nonvascular diag(cid:173)
`nostic or interventional procedures,
`13 patients received plain 1% lido(cid:173)
`caine, with a mean pain score of3.65 ±
`2.90. Twenty-three patients were
`given buffered lidocaine before the
`procedure, with a mean pain score of
`1.76 ± 2.00 (P = .0310). When pa(cid:173)
`tient populations are compared, the
`87 patients undergoing angiography
`were significantly older (mean age, 59
`years) than the 63 patients undergo(cid:173)
`ing nonvascular procedures (mean
`age, 40 years) (P < .0001).
`When the data are divided for pa(cid:173)
`tients 40 years of age or younger and
`those older than 40 years, use of buff(cid:173)
`ered lidocaine is still associated with
`a significant reduction in pain percep(cid:173)
`tion compared with the plain lido-
`
`Plain solution
`Control solution
`Buffered solution
`
`Table 3
`Pain Score versus Patient Age
`Mean Pain Score ± SD
`No. of Patients
`Group
`Patients 40 Years Old or Younger
`12
`4.00±2.82
`16
`3.75±2.67
`17
`2.03±2.44
`Patients Older than 40 Years
`2.46±2.45
`38
`Plain solution
`NS
`2.49±2.09
`34
`Control solution
`Buffered solution
`33
`1.03±1. 11
`.0325
`Note.-NS = not significant, SD = standard deviation. *Versus plain lidocaine.
`
`PValue*
`
`NS
`.0417
`
`sum test and a two-tailed unpaired
`Student t test (11); P < .05 was con(cid:173)
`sidered statistically significant.
`
`RESULTS
`
`Fifty patients were entered into
`each subgroup, for a total of 150 pa(cid:173)
`tients. The pH of each lidocaine solu(cid:173)
`tion was as follows: plain lidocaine
`solution pH, 6.2; control lidocaine
`solution pH, 6.2; and buffered lido(cid:173)
`caine solution pH, 7.2.
`The 50 patients receiving the plain
`1% lidocaine solution had a mean age
`of 52 years, with a range of 16-86
`years. They underwent 37 angio(cid:173)
`graphic and 13 nonvascular diagnos(cid:173)
`tic or interventional procedures. The
`50 patients who received the control
`lidocaine solution had a mean age of
`
`50 years, with a range of 15-85 years.
`They underwent 23 angiographic and
`27 nonvascular diagnostic or inter(cid:173)
`ventional procedures. The third
`group of 50 patients received the
`buffered lidocaine solution. They had
`a mean age of 51 years, with an age
`range of 16-78 years, and underwent
`27 angiographic and 23 nonvascular
`diagnostic or interventional proce(cid:173)
`dures (Table 1).
`The mean pain scores for each
`group were as follows: 1% lidocaine
`(plain) solution, 2.83 ± 2.60; 1% lido(cid:173)
`caine plus normal saline (control)
`solution, 2.89 ± 2.34 (2.83 vs 2.89;
`P = not significant); 1% lidocaine
`plus sodium bicarbonate (buffered)
`solution, 1.37 ± 1.73. When the
`mean pain scores for the plain lido(cid:173)
`caine solution and buffered lidocaine
`solution are compared (2.83 vs 1.37),
`
`

`

`174 • Journal of Vascular and Interventional Radiology
`January-February 1994
`
`caine solution. For patients 40 years
`of age or younger, P = .0417; for pa(cid:173)
`tients older than 40 years, P = .0325
`(Table 3).
`There were no obvious clinical con(cid:173)
`sequences or complications related to
`buffering the lidocaine solution. Al(cid:173)
`though it was not objectively as(cid:173)
`sessed, there was no apparent subjec(cid:173)
`tive difference in the effectiveness or
`duration of action of each solution.
`There was no visible precipitation
`within the buffered lidocaine solu(cid:173)
`tion.
`
`DISCUSSION
`
`This prospective, randomized,
`double-blind study of 150 patients
`demonstrates a significant reduction
`in the perception of pain associated
`with the administration of a buffered
`1% lidocaine solution regardless of
`the age of the patient or the anatomic
`location of skin infiltration. This has
`been attributed to the adjustment of
`the pH of the local anesthetic solu(cid:173)
`tion toward a more physiologic range
`of 7.0-7.4. By raising the pH ofa
`commercially available lidocaine solu(cid:173)
`tion from 6.2 to 7.2, there is a 10-fold
`reduction in the hydrogen ion con(cid:173)
`centration in the solution (7). Reduc(cid:173)
`ing the concentration of hydrogen ion
`within the solution apparently de(cid:173)
`creases the local irritation on its
`administration. It has also been sug(cid:173)
`gested that the uncharged, nonion(cid:173)
`ized form of lidocaine disburses much
`more rapidly through the interstitial
`tissues resulting in almost instanta(cid:173)
`neous nerve blockage (5,6,8). It is
`clear that the reduction of pain asso(cid:173)
`ciated with the infiltration of a buff(cid:173)
`ered anesthetic solution is not due to
`a dilutional or volume effect, since
`our control lidocaine solution con(cid:173)
`taining normal saline was just as
`painful on infiltration as the plain 1%
`lidocaine solution and a 1-mL volume
`was administered in all the patients.
`Buffering the lidocaine solution to
`a pH of 7.0-7.4 does not adversely
`affect the degree and duration of local
`analgesia. Indeed, the onset of anal(cid:173)
`gesia may actually be more rapid
`
`with the buffered solution (5,6). A
`number of studies on nerve prepara(cid:173)
`tions, major nerve block, and regional
`nerve block have shown that the du(cid:173)
`ration of the anesthetic effect is un(cid:173)
`changed by buffering the local anes(cid:173)
`thetic (2,5,12,13). Subjectively, we
`did not appreciate a difference in the
`analgesic effect among the three lido(cid:173)
`caine solutions.
`Alkalinization of the lidocaine solu(cid:173)
`tion can be easily accomplished by
`adding 1 mL of an 8.4% NaHC03 so(cid:173)
`lution to a syringe containing 10 mL
`of a 1% lidocaine solution. This gives
`11 mL of a buffered lidocaine solution
`with a pH of 7.2. As previously re(cid:173)
`ported, buffering a lidocaine solution
`to this pH results in no visible pre(cid:173)
`cipitation (7,8). The 8.4% NaHC03
`solution comes in a 50-mL vial (Ab(cid:173)
`bott Laboratories) and costs approxi(cid:173)
`mately $0.50 per vial. Once opened,
`any unused portion of the 50-mL vial
`is discarded at the end of the day.
`Since the NaHC03 solution is inex(cid:173)
`pensive and easy to use, we have not
`found it necessary to neutralize a
`multidose vial of lidocaine. Despite
`this, one study has demonstrated
`that a solution oflidocaine contain(cid:173)
`ing epinephrine buffered to a pH of
`7.0-7.3 and stored at room tempera(cid:173)
`ture for 1 week was just as effective
`as a freshly made buffered solution at
`producing analgesia, while continu(cid:173)
`ing to be less painful on intradermal
`injection (14). These authors recom(cid:173)
`mend that the alkalinized anesthetic
`be discarded within 1 week of prepa(cid:173)
`ration, primarily because epinephrine
`appears to degrade in buffered solu(cid:173)
`tions at a rate of 25% per week (15).
`Other local anesthetics are also
`prepared in an acidic solution (5,8,
`14). One such agent, bupivacaine
`(Sensorcaine; Astra Pharmaceuticals,
`Westborough, Mass), is a local anes(cid:173)
`thetic of the amide group, with a pKa
`of 8.1 (6). This agent has a longer du(cid:173)
`ration of action compared with lido(cid:173)
`caine. We frequently use it with non(cid:173)
`vascular interventional procedures.
`One study has demonstrated that by
`buffering the bupivacaine solution, a
`more rapid onset and a longer dura(cid:173)
`tion of action can be expected (16).
`
`Our current study validates prior
`reports (7,8,9) that buffering lido(cid:173)
`caine (10 mL of 1% lidocaine mixed
`with 1 mL of 8.4% sodium bicarbon(cid:173)
`ate) significantly decreases the dis(cid:173)
`comfort of its intradermal adminis(cid:173)
`tration. Indeed, many patients in this
`study indicated that the buffered an(cid:173)
`esthetic solution was painless on its
`infiltration. Because it is easy, rela(cid:173)
`tively inexpensive, and safe to do,
`buffering the lidocaine solution
`should be routinely performed prior
`to its administration as a local anes(cid:173)
`thetic.
`
`Acknowledgments: The authors
`would like to acknowledge Sherry Deane,
`Shirley Yowell, and Geneva Shifflett for
`their expert help in preparation of this
`manuscript. The authors would also like
`to thank the technical staff in the Division
`of Angiography and lnterventional Radi(cid:173)
`ology for help in preparing the lidocaine
`solutions and maintaining the double(cid:173)
`blind nature of the study.
`
`References
`1. Ritchie JM, Ritchie B, Greengard P.
`The active structure oflocal anes(cid:173)
`thetics. J Pharmacol Exp Ther 1965;
`150:152-159.
`2. Strobel GE, Bianchi CPo The ef(cid:173)
`fects of pH gradients on the distribu(cid:173)
`tion of C14-procaine and lidocaine in
`intact and desheathed sciatic nerve
`trunks. J Pharmacol Exp Ther 1970;
`172:18-32.
`3. Hille B. Local anesthetics: hydro(cid:173)
`philic and hydrophobic pathways for
`the drug-receptor action. J Gen
`Physiol1977; 69:497-515.
`4. Moore DC. The pH oflocal anes(cid:173)
`thetic solutions. Anesth Analg 1981;
`60:833-834.
`5. DiFazio CA, Carron H, Grosslight
`KR, Moscicki JC, Bolding WR, Johns
`RA. Comparison of pH-adjusted
`lidocaine solutions for epidural anes(cid:173)
`thesia. Anesth Analg 1986; 65:760(cid:173)
`764.
`deJong RH. Local anesthetics.
`Springfield, Ill: Charles C Thomas,
`1977; 42-50.
`7. Bancroft JW, Benenati JF, Becker
`GJ, Katzen BT. Neutralized lido(cid:173)
`caine: use in pain reduction in local
`anesthesia. JVIR 1992; 3:107-109.
`8. Christoph RA, Buchanan L, Begalla
`K, Schwartz S. Pain reduction in
`local anesthetic administration
`
`6.
`
`

`

`Matsumoto et al • 175
`Volume 5 Number 1
`
`9.
`
`through pH buffering. Ann Emerg
`Med 1988; 17:117-120.
`Jaques PF, Mauro MA, Agee M,
`Morris S, Stubblebine J. Alkalin(cid:173)
`ized lidocaine in special procedures.
`AJR 1990; 198.
`10. Scott J, Huskisson EC. Graphic
`representation of pain. Pain 1976;
`2:175-184.
`11. Dixon WJ. BMDP statistical soft(cid:173)
`ware manual. Berkeley, Calif: Uni-
`
`versity of California Press, 1985;
`75-77,440-443.
`12. Buckley FP, Neto GD, Fink BR.
`Acid and alkaline solutions oflocal
`anesthetics: duration of nerve block
`and tissue pH. Anesth Analg 1985;
`64:477-482.
`pH-adjusted local anes(cid:173)
`13. Galindo A.
`thetics: clinical experience. Reg
`Anesth 1983; 8:35-36.
`14. Stewart JH, Chinn SE, Cole GW,
`
`Klein JA. Neutralized lidocaine
`with epinephrine for local anesthe(cid:173)
`sia. J Dermatol Surg Onco11990;
`16:842-845.
`15. Stewart JH, Cole GW, Klein JA.
`Neutralized lidocaine for local anes(cid:173)
`thesia. J Dermatol Surg Onco11989;
`15:1081-1083.
`16. Hilgier M. Alkalinization ofbupi(cid:173)
`vacaine for brachial plexus block.
`Reg Anesth 1985; 10:59-61.
`
`