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Chloroprocaine is Less Painful than Lidocaine for Skin Infiltration Anesthesia

Marica, Livia S. MD; O’Day, Terry BS; Janosky, Janine E. PhD; Nystrom, Elisabet U. M. MD, PhD

doi: 10.1213/00000539-200202000-00022

Skin infiltration of local anesthetics causes pain. In a double-blinded protocol, 22 volunteers received random intradermal injections to the volar surface of the forearm with each of the following solutions: normal saline solution 0.9% (NSS), lidocaine 1% (L), lidocaine 1% and sodium bicarbonate 8.4% (L+BIC), 2-chloroprocaine 2% (CP), 2-chloroprocaine 2% and sodium bicarbonate 8.4% (CP+BIC), and NaCHO3 8.4% (BIC). Initially, each volunteer received an open-labeled injection of NSS. A 100-mm visual analog scale (VAS, 1–100) was used to assess pain with each injection. The pH of each solution was stable for the length of the study. Repeated measures of variance were used for analysis. The VAS scores (mean ± sd) for open-label and blinded NSS injections were 15.5 ± 15.9 and 14.0 ± 18.1, respectively. The scores for the studied solutions were as follows: BIC, 47.2 ± 25.5; L, 25.8 ± 27.6; L+BIC, 16.0 ± 14.2; CP, 8.6 ± 7.4; and CP+BIC, 6.8 ± 6.7. No significant difference was found between CP and alkalinized CP, but the injection of both solutions was significantly less painful than that of all other solutions (P < 0.05). The pH of the solutions was not related to the pain score. We found that chloroprocaine caused less pain at injection than the more commonly used lidocaine.

Department of Anesthesiology, The Western Pennsylvania Hospital, Pittsburgh, Pennsylvania

Supported, in part, by the Western Pennsylvania Hospital Research Foundation.

September 26, 2001.

Address correspondence and reprint requests to Livia S. Marica, MD, Department of Anesthesiology, The Western Pennsylvania Hospital, 4800 Friendship Avenue, Suite 459, Pittsburgh, PA 15224. Address e-mail to

Although venous access is required for all anesthesia procedures, insertion of an IV cannula can be painful. Although the intradermal injection of a local anesthetic is often used to provide analgesia for catheter placement, local anesthetics themselves can produce pain at skin infiltration. Lidocaine is the most commonly used local anesthetic, probably because of tradition and availability. Several studies have attempted to identify the best option for skin infiltration, with controversial results regarding chloroprocaine (1–4).

We performed a double-blinded, randomized, prospective study to compare the pain experienced at skin infiltration of lidocaine, chloroprocaine, and buffered solutions of both.

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Materials and Methods

The study was approved by our IRB. After obtaining the informed consent, 22 healthy volunteers (ASA physical status I) were enrolled in the study: 14 women and 8 men, 18–55 yr old (mean age, 30 yr). The number of subjects was determined by power analysis based on the previous published studies (1–3) to achieve statistical significance. Exclusion criteria were any history of allergy to local anesthetics, current use of pain medication or illicit drugs, diabetes mellitus, peripheral neuropathy, alcohol abuse, or psychiatric disorder. There were no health care professionals among the volunteers. The study was designed as a prospective, double-blinded, randomized trial.

Each subject received 7 intradermal injections (0.25 mL per injection). The initial injection was labeled normal saline 0.9% (“open” to investigators and volunteers), followed by 6 injections of double-blinded solutions of normal saline 0.9%, lidocaine 1%, lidocaine 1% + sodium bicarbonate 8.4%, 2– chloroprocaine 2%, 2–chloroprocaine 2%+ sodium bicarbonate 8.4%, and normal saline 0.9% + sodium bicarbonate 8.4%. The manufacturer characteristics of the local anesthetics are summarized in Table 1. In our study, we used the local anesthetics in equipotent concentrations (lidocaine 1% and 2-chloroporcaine 2%) (5).

Table 1

Table 1

A research pharmacist prepared the solutions 30 min before the study and measured the pH of each solution every 30 min for 3 h with a Beckman 3500 digital pH meter (Beckman, Fullerton, CA). Sodium bicarbonate represented 10% of the alkalized solutions. The pharmacist prepared the tuberculin syringes, each containing 0.5 mL of test solution. Each syringe had a randomly assigned number; the content of each syringe was unknown to the investigator as well as to the volunteers. One investigator performed all injections, whereas the second investigator recorded all patient ratings.

The volunteers received the seven total injections in a standardized fashion as follows. One investigator performed all injections: the skin area to be injected was cleansed with 70% isopropyl alcohol and allowed to dry, a 25-gauge hypodermic needle was inserted intradermally on the volar surface of the forearm, 30 s was allowed for the pain from the needle insertion to subside, and the subjects were asked to tell when the pain produced by the needle insertion was gone. Then, the injections were given to each volunteer in a random order 10 min apart, separated by at least 5 cm, three injections on one forearm and four on the other. A skin wheal was raised by using 0.25 mL from each solution. The volunteers were asked to rate the pain produced by the injection of the solution, using a linear visual analog scale (1–100 mm), 0 being a pain-free injection and 100 the most painful injection ever experienced.

A repeated-measures analysis of variance was used to examine the differences in visual analog score responses across each of the conditions of interest. After the significant omnibus test, post hoc pairwise comparisons were performed. Statistical significance was defined as P < 0.05.

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There were no differences in mean pain scores between open and blinded solutions of normal saline (15.5 ± 14.0). The sodium bicarbonate solution had the highest pain score (47.2 ± 25.5), whereas the 2-chloroprocaine 2% + sodium bicarbonate 8.4% solution had the lowest mean pain score (6.8) (Fig. 1). The pain score of lidocaine 1% was not different from that of lidocaine 1% + sodium bicarbonate 8.4% (P = 0.074). There was no statistical difference in mean pain scores between plain and buffered 2-chloroprocaine 2% (8.6 versus 6.8;P = 0.38) (Table 2).

Figure 1

Figure 1

Table 2

Table 2

2-Chloroprocaine 2% (plain or buffered), independent of pH (pH 3.4 or pH 7.7, respectively), had significantly smaller mean pain scores than lidocaine 1% plain (P = 0.011 at acidic pH;P = 0.006 at alkaline pH) (Fig. 1). 2-Chloroprocaine 2% had lower pain scores than buffered lidocaine, approaching statistical significance (P = 0.054).

The pH values of solutions were stable throughout the study (Fig. 2). No local or systemic complications from the injection of solutions occurred during the study.

Figure 2

Figure 2

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Our study indicates that 2-chloroprocaine 2%, independent of pH, causes less pain at intradermal skin infiltration than the more commonly used lidocaine 1% (Figs. 1,3). The mechanism of pain produced by intradermally injected local anesthetic is unclear. Perhaps pH, pKa, lipid solubility, temperature, additives, epinephrine, injection technique, or any combination of these factors may play a role (1–4,6,7). Several studies have suggested that alkalinization of lidocaine may reduce pain at skin infiltration (4,6,8–11). In contrast, increasing the pH of lidocaine did not seem to reduce pain at skin infiltration before hemodialysis in a pediatric group (12). In our study, there was no statistically significantly difference between buffered lidocaine and plain solution (Table 2, Fig. 4).

Figure 3

Figure 3

Figure 4

Figure 4

McKay et al. (6), Morris and Whish (1), and Morris et al. (2) suggested that chloroprocaine may be the local anesthetic of choice for local skin infiltration, based on their analysis of pain scores. Their findings are in contrast with the results of Nuttall et al. (4) and Prien (3). The contradictory results seem to be related to study design, e.g., use of nonequivalent drug concentrations, different manufacturers, different additives, undifferentiated pain score of needle stick versus injection of local anesthetics (7), statistical type II error, or injection technique.

In our study, chloroprocaine 2% was significantly better tolerated than lidocaine 1% (Fig. 1). Plain chloroprocaine had smaller pain scores than buffered lidocaine, approaching the statistical significance (P = 0.054).

We studied, for the first time, the effect of the alkalinizing of chloroprocaine on pain at skin infiltration using an equipotent concentration with lidocaine.

2-Chloroprocaine with bicarbonate had the lowest mean pain score among the tested solutions. There were no differences in pain scores between alkalinized (pH, 7.7) and acidic (pH, 3.4) solutions of chloroprocaine, regardless of the very different pH (Fig. 2).

In our study, pH of the solutions did not correlate with pain scores. Solutions at extreme pH values had similar pain scores, and solutions with similar pH values had extreme pain scores (Fig. 1, Fig. 2). Our results support the hypothesis of other studies that the pain mechanism is not simply related to the pH of the solution (3,10,11).

Alkalinized solutions of local anesthetics would require additional time to prepare, because no commercial preparation is available. Additionally, the short shelf life, chemical instability, photodegradation, and aldehyde formation make the use of buffered lidocaine impractical in a busy emergency room, in an outpatient surgery clinic, or in a pediatric department. Therefore, the choice of local anesthetic, not the pH, may determine pain at injection.

We observed that sodium bicarbonate, the most alkaline solution that we tested, at the same concentration as the one used as additive to local anesthetics, caused the highest pain score among the solutions injected (Fig. 1). Perhaps the experienced pain is not simply an additive function of each substance in the mixture. This finding might support the McKay et al. (6) hypothesis that the pain-reducing effect of sodium bicarbonate results from a shift of the equilibrium between the ionized and unionized form of local anesthetics and factors other than pH, such as intrinsic properties, play a role in pain mechanism.

The similar mean pain scores of labeled and blinded normal saline solutions support the reliability of pain assessment by visual analog scoring. We tried to eliminate the biases of previous studies by using preservative-free local anesthetics manufactured by one drug company, equipotent concentrations, and a standardized technique of injection by a single investigator.

2-Chloroprocaine 2% is an aminoester drug that contains in its molecule a p-aminobenzoic acid ring known to be allergenic. In a MEDLINE search of the years 1966–2001, there are no reports of local or systemic allergic reactions from 2-chloroprocaine. Most of the studies have used procaine as an ester-type local anesthetic. The intradermal injection of procaine resulted in positive skin reactions in up to 30% of patients (13); however, true allergic reactions from local anesthetics are very rare (1%) (10). Because of a lack of data regarding 2-chloroprocaine, it might be safe to assume that 2-chloroprocaine would have local allergic reactions in a certain percentage of patients, in the same manner as procaine does. Because prevention is the best medicine, a careful history of true allergic reactions from factors such as local anesthetic, ester versus amide, and preservatives in drugs and foods would distinguish those patients with a risk of allergic reactions and indicate the safest approach of using local anesthetics. Although aminoamide local anesthetics, such as lidocaine, seemed to be free of allergic reactions, methylparaben contained in the preservative can cause such reactions. In our study, we did not observe any allergic reactions locally or systemically. This can be the result of the small number of patients, “no allergic reactions history” used as exclusion criteria, infrequent incidence of true allergy, or lack of preservatives.

The potential of local nerve damage from chloroprocaine has been questioned in medical literature after reports of prolonged sensory and motor block in patients with chloroprocaine epidural or spinal anesthesia. Chloroprocaine itself does not appear to be neurotoxic (14). The neurotoxic effects reported in the literature might be caused by the sodium bisulfite preservative, large volume, and probably low pH. The reports and studies were performed with 2-chloroprocaine 3% for epidural, spinal, or peripheral nerve block.

In the MEDLINE search of years 1966–2001, we did not find any reports of neurotoxic effects of preservative-free 2-chloroprocaine 2% used for infiltration anesthesia.

In conclusion, we consider that 2-chloroprocaine 2%, independent of pH, causes less pain than the more commonly used lidocaine at skin infiltration.

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