The effect of pH buffering on reducing the pain associated with subcutaneous infiltration of bupivicaine

The Effect of pH Buffering on Reducing the Pain Associated With Subcutaneous Infiltration of Bupivicaine PAUL R. CHENEY, MD,* GEORGE MOLZEN, MDJ DAN TANDBERG, MD* The authors propose that pH buffering of bupivicaine with sodium bicarbonate reduces the pain associated with its local subcutaneous infiltration. In a double-blind, prospective study, 62 healthy adult volunteers received a 0.5 mL subcutaneous infiltration of 0.5% buffered bupivicaine into the dorsum of a randomly chosen hand. The pH was adjusted to 7.0 by adding 0.5 mL of sodium bicarbonate (1 mEq/mL) to 10 mL vials of commercially available bupivicaine (1:200 dilution). The control hand was injected with the same amount of unbuffered agent. Pain was scored after each infiltration using a nonsegmented visual anaiogue scale. Student’s f-test for paired measurements was used to analyze intergroup pain scow differences. Forty-three subjects (69%) reported less pain with buffered buplvicaine and only 17 (27%) noted a modest increase; two subjects (3%) reported no difference. The mean pain score for the buffered agent was 22 mm compared with 30 mm for the control. The mean difference (control-experimental) was 8 mm (f = 4.64, df = 61, P < .OOl). The authors conclude that the addition of sodium bicarbonate to buplvicaine reduces the pain associated with its local infiltration. (Am J

Emery Med 1991;9:147-148.Copyright0 1991 by W.8. Saunders Company) Infiltration of local anesthetic agents into the skin is common in emergency medicine. ‘.’ Bupivicaine, with its potent and long-acting anesthetic properties, is considered by some to be the drug of choice for lengthy procedures3 and is regularly used at our institution. Unfortunately, the burning sensation associated with its infiltration can be quite painful, more so than many other commonly used agents.4 Previous work has shown that the pain associated with cutaneous infiltration of certain acidic short-acting anesthetic agents is diminished by titration towards a pH of 7.4 with sodium bicarbonate prior to use. 5.6 We thought that similar alteration of bupivicaine also might have this effect. We carried out the following study to test this hypothesis. METHODS

In preliminary experiments, the pH of commercially obtained 10 mL single-use vials of 0.5% bupivicaine (Winthrop, New York, NY) was measured using a Model PHM-82 pH meter (Radiometer America, Cleveland, OH). The pH of different lots of drug varied slightly, with a mean of 5.51. Titration with 1.O mEq/mL sodium bicarbonate (Astra Pharmaceutical Products, Inc. Westborough, MA) was carried From the *Division of Emergency Medicine, University of New Mexico School of Medicine; and the tEmergency Department, Presbyterian Hospital, Albuquerque, NM. Address reprint requests to Dr Tandberg, Division of Emergency Medicine, University of New Mexico School of Medicine, 620 Camino de Salud, Albuquerque, NM 87131. Key Words: Bupivicaine, pH, buffers, sodium bicarbonate, analgesia, local anesthesia. Copyright 0 1991 by W.B. Saunders Company 0735-6757/91/0902-0011$5.00/O

out using locally available lots of bupivicaine.

All lots could be alkalinized to a pH of 7.15, but further titration resulted in precipitation. The maximum volume of sodium bicarbonate that could be added to all available lots of bupivicaine without visible precipitation was 0.05 mL; this mixture was selected for subsequent evaluation. Sixty-two healthy adults volunteered to participate in the study. Subjects were excluded if they were pregnant, had a history of allergic or other adverse reaction to local anesthetic agents, or had a history of cardiac disease, dysrhythmias, or epilepsy. The experimental agent was prepared by adding 0.05 mL of I .O mEq/mL sodium bicarbonate to a 10 mL vial of 0.5% bupivicaine with a resulting pH of 7.0. A tuberculin syringe and 25 g needle was used to measure and add the sodium bicarbonate solution. The control agent consisted of unaltered 0.5% bupivicaine with a pH of 5.50. All vials of bupivicaine came from a single lot. Injection sites were first cleaned with 70% isopropyl alcohol and allowed to air dry. Each subject received a 0.5 mL dose of the experimental or control agent into the dorsal skin of each hand with a tuberculin syringe and a 25 g needle. After the needle entered the skin, infiltration was delayed until the patient reported that all pain had ceased; at this point infiltration was initiated. A stopwatch was used to assure that an infiltration time of 5 seconds was achieved. Labels on all syringes were covered with opaque tape to ensure that both subjects and investigators were blinded as to which treatment was being administered. The orders of the two treatments and the first hand to be injected (right v left) were selected randomly. Each author carried out approximately one third of the trials. After each injection, the subject was asked to rate his or her perceived pain by marking a 100 mm horizontal nonsegmented visual analog scale.7-‘0 The left end of the scale was labeled “no pain” and the right end the “worst pain imaginable.” Pain scores were measured to the nearest 0.5 mm. Differences in pain scores for each pair of injections were calculated by subtraction and analyzed using Student’s t-test for paired samples. ‘I A two-tailed test and an a of 0.05 were used throughout. This study was reviewed and approved by the Human Research Review Committee of the University of New Mexico School of Medicine. Written consent was obtained from each subject. RESULTS

Sixty-two subjects were enrolled in and completed the study, with a median age of 34 years (range 21-65). Fortythree subjects (69%) reported less pain with buffered bupiv147

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icaine while only 17 (27%) noted a modest increase; two subjects (3%) reported no difference (Figure 1). The mean pain score for the buffered agent was 22 mm compared with 30 mm for the control. The mean difference (control minus experimental) was 8 mm (95% CI = 4.6 to 11.4 mm, t = 4.64, df = 61, P < .OOl).

These results show that the addition of sodium bicarbonate reduces the pain associated with the local infiltration of bupivicaine. Although the exact mechanism is not known, we presume that the pH change toward neutrality is the likely reason for the pain reduction, either directly5.6 or through indirect effects such as alteration of the lipid solubility characteristics of bupivicaine.4 We designed our study to avoid several potential sources of bias. We used a paired design to nullify the effects of differing pain sensitivity among subjects. This model also avoided disparities attributable to slight differences in injection technique and anatomic differences such as the proximity of cutaneous nerves to the actual injection site. Both subjects and investigators were blinded as to the order of treatments administered to keep preexisting beliefs about efficacy from prejudicing the results. Possible effects of anticipation on subjects’ pain scores were minimized by randomly assigning the treatment given first. Finally. randomization of the hand first injected avoided possible differences in pain perception associated with handedness. We set out to devise a method of alkalinizing bupivicaine that could be performed quickly and easily by practicing clinicians. Our mixing strategy was simple: we used commercially available single-use 10 mL vials of 0.5% bupiviCaine, and added 0.05 mL of standard 1 mEq/mL sodium bicarbonate with a 1 mL tuberculin syringe. Admittedly, this method of measurement is somewhat imprecise: however, our preliminary experiments showed that this method consistently raised the pH of our experimental solution to approximately 7.0 without formation of precipitate in any of the lots tested. More precise titration methods could be used that would yield a slightly greater pH, with theoretically, greater pain reduction. However, we opted for practicality: our method is easily accomplished, avoids precipitation, and results in less pain. Bupivicaine is prepared commercially at a pH of approximately 5.5 to provide stability and prolong its shelf life.” 60

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The authors gratefully acknowledge preparation by Sandra Mirabal.

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FIGURE 1. Pain score differences for 62 subjects.

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The addition of sodium bicarbonate to bupivicaine the pain associated with its local infiltration.

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We found that different lots of bupivicaine varied in acidity (mean 5.51). and therefore each required slightly different amounts of bicarbonate to achieve near-neutrality. We anticipate that actual users of our method may find slight differences in the maximum amount of buffer that can be added without precipitation. It should be emphasized that the amount of buffer required is relatively small for bupivicaine (I:200 dilution in our study) when compared with a I:10 dilution that is recommended with lidocaine.’ The possibility that buffering local anesthetic agents might adversely affect their efficacy has been investigated. It has been shown that the depth of analgesia is not affected by raising the pH to near physiological levels.5.‘3,‘4 In addition, the onset of action is actually lessened and the duration of sensory blockade is increased.‘3“5 Thus, elevating the pH of bupivicaine may offer other clinical advantages above and beyond that of reducing the pain associated with its local infiltration.

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1. Capan LM, Pate1 KP, Turndorf l-l: Regional anesthesia in the emergency department. In Roberts JR, Hedges JR (eds): Clinical Procedures in Emergency Medicine. Philadelphia, PA, Saunders, 1985 pp 430-475 2. Altman RS, Smith-Coggins R, Ampel LL: Local anesthetics. Ann Emerg Med 1985;14:1209-1217 3. Spivey WH, McNamara RM, MacKenzie RS, et al: A clinical comparison of lidocaine and bupivicaine. Ann Emerg Med 1987;16:752-757 4. Morris R, McKay W, Mushlin P: Comparison of pain associated with intradermal and subcutaneous infiltration with various local anesthetic solutions. Anesth Analg 1987;66:1180-1182 5. Christoph RA, Buchanan L, Begalla K, et al: Pain reduction in local anesthetic administration through pli buffering. Ann Emerg Med 1988;17:117-120 6. McKay W, Morris R, Mushlin P: Sodium bicarbonate attenuates pain on skin infiltration with lidocaine, with or without epinephrine. Anesth Analg 1987;66:572-574 7. Huskisson EC: Measurement of pain. Lancet 1974;2:11271131 8. Rosen M: The measurement of pain. In Harcus AW, Smith RB, Whittle BA (eds): Pain-New Perspectives in Measurement and Management. New York, NY, Churchill Livingstone, 1977, pp 13-26 9. Huskisson EC: Visual analogue scales. In Melzack R (ed): Pain Measurement and Assessment. New York, NY, Raven Press, 1983 pp 33-37 10. Revill SI, Robinson JO, Rosen M, et al: The reliability of a linear analogue for evaluating pain. Anaesthesia 1976;31 :11911198 11. Zar JH: Biostatistical Analysis, (ed 2). Englewood Cliffs, NJ, Prentice-Hall, 1984, pp 150-153 12. Ritchie JM, Greene NM: Local anesthetics. In Gilman AG, Goodman LS (eds): The pharmacological basis of therapeutics (ed 7). New York, NY, Macmillin. 1985, pp 305 13. Hilgier M: Alkalinization of bupivicaine for brachial plexus block. Regional Anesth 1985;8:59-61 14. McMorland GH, Douglas MJ, Jeffery WK, et al: Effect of pH-adjustment of bupivicaine on onset and duration of epidural analgesia in parturients. Can Anaesth Sot J 1986;33:537-541 15. DiFazio CA, Carron H, Grosslight KR, et al: Comparison of pH-adjusted lidocaine solutions for epidural anesthesia. Anesth Analg 1986;65:760-764