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Science of Buffering


It is generally accepted that injecting pH-buffered lidocaine with epinephrine is more comfortable than injecting traditional non-buffered lidocaine with epinephrine. Seventeen peer-reviewed published studies that have specifically evaluated buffered lidocaine with epinephrine demonstrated a significant improvement in injection comfort.1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17 

Only two such studies were unable to demonstrate a significant improvement.18,19

Although experts generally accept that buffering improves the comfort of injections using lidocaine with epinephrine, the mechanisms by which either, (a) local anesthetics cause injection pain,20 or (b) buffering reduces that injection pain, are not well understood.21

Chemistry and pH

Chemically, amide local anesthetics are weak bases. Commercial local anesthetic cartridges are purposefully formulated as relatively acidic solutions (compared with the physiologic pH of 7.4) in order to enhance the solubility of the anesthetic salts and to prolong shelf life.22 Typically, commercial lidocaine solutions have a pH of about 3.9.23,24,25,26,27,28 

The pH of the solution is important because it affects the way anesthetic works. Like most other injectable local anesthetics, lidocaine with epinephrine solution contains two forms of the anesthetic salt:29,30,31,32 

(i) the uncharged, de-ionized, or “active” free base form, which is lipid soluble; and (ii) the charged or ionized cationic form, which is not lipid soluble.

The de-ionized form more readily penetrates the nerve membrane to enter the nerve axon, where the anesthetic attaches to receptors on the sodium channels, resulting in a blockade of nerve conduction.33,34 This biochemical process makes the relative availability of de-ionized anesthetic important in creating clinical analgesia.

According to the Henderson-Hasselbalch equation, in any sample of local anesthetic solution the ratio of the de-ionized species of the anesthetic to the ionized species of the anesthetic is based on the pH of the sample.35 At a more acidic pH, the ionized cationic form predominates. For instance, at a pH of 3.9, a typical cartridge of lidocaine with epinephrine contains only 1 molecule of de-ionized anesthetic for every 10,000 molecules of ionized anesthetic. On the other hand, closer to physiologic pH, more de-ionized anesthetic is present. For instance, at the physiologic pH of 7.4 there is one molecule of de-ionized lidocaine in solution for every 4 molecules of ionized lidocaine. At the physiologic pH, then, there is 2,500x more of the active form of the anesthetic available than at pH 3.9. 

Normally, the body buffers the local anesthetic after injection toward physiologic pH,36 which eventually increases the availability of de-ionized anesthetic.37 Over time, as this in vivo buffering process continues, more and more of the de-ionized or active form of the anesthetic is available. This ultimately leads to nerve blockade. Mehta and colleagues described the process thus: 

 After injection, tissue buffering raises the pH and a percentage of the drug dissociates to become free bases, the amount depending upon the ‘dissociation constant’ of the individual anesthetic. Being lipid soluble, the free base is able to penetrate both the nerve coverings and the lipid cell membrane to reach the interior of the axon where a portion re-ionizes. The re-ionized portion enters the sodium channels and plugs these channels so that sodium ions cannot enter the cell. As a result, action potentials are neither generated nor propagated and conduction block occurs.38 

Onpharma provides the practitioner a way to buffer the anesthetic immediately before the injection in vitro (outside the body) rather than the status quo in vivo buffering process, which relies on the patient’s physiology to buffer the anesthetic. Bringing the pH of the anesthetic toward physiologic before injection may have an important effect on injection comfort.

Talu and colleagues suggested that by creating a higher proportion of de-ionized anesthetic in vitro just prior to injection, buffering may reduce injection pain by blocking the nociceptors before injection pain has even been sensed.39 Richtsmeier and Hatcher wrote that the reduction in injection pain could be a combination of two effects: 

It has been shown in adult volunteers that buffering lidocaine with sodium bicarbonate just prior to skin infiltration can significantly reduce the painful burning sensation without compromising anesthetic efficacy. There are two possible mechanisms by which increasing the pH of lidocaine could decrease the pain associated with its injection. Increasing the pH increases the amount of lidocaine in uncharged form, which could either be less irritating to the tissues than the charged form or, alternatively, be capable of entering the nerve sheath much more rapidly than the charged form, thereby blocking pain transmission almost instantaneously.40

Similarly, Burns and colleagues attributed the improvement in injection comfort through buffering to both: (a) the reduction in acidity of the local anesthetic; and (b) to a shorter duration of any pain signal that the injection might cause. They wrote:

The pain caused by infiltration of anesthetic solutions into the skin is largely attributed to their acidity. Solutions with lower pH cause increased pain by two different mechanisms. The acidity of the solution causes a burning sensation when infiltrated into more neutral tissues due to tissue irritation. In addition, at a lower pH less of the anesthetic is in its active, freely diffusible form, leading to a prolonged time until onset of anesthesia. In a more neutral, buffered solution the area is anesthetized more quickly and further infiltration is less painful.41 

The Role of CO2 in Creating More Comfortable Injections

When sodium bicarbonate solution is mixed with a local anesthetic like lidocaine with epinephrine, the interaction of the sodium bicarbonate (NaHCO3) with the hydrochloric acid (HCL) in the local anesthetic will, among other things, create water (H2O) and carbon dioxide (CO2).42 The CO2 will begin to diffuse out of solution; the diffusion beginning immediately and occuring even after the solution has been injected.43

Condouris and Shakalis44 demonstrated that this CO2 possesses an independent anesthetic effect.45 Catchlove concluded that CO2 in combination with lidocaine potentiates the action of lidocaine by (i) a direct depressant effect of CO2 on the axon; (ii) concentrating the local anesthetic inside the nerve trunk through ion trapping; and (iii) changing the charge of the local anesthetic inside the nerve axon.46 

Catchlove concluded that the independent anesthetic effect of CO2 may provide the most immediate form of analgesia.47 Given that Talu,48 Richtsmeier49 and Burns50 attribute reduced injection pain to the rapidity with which pain signals are blocked when using buffered anesthetic, Catchlove’s finding may also point to a mechanism by which in vitro buffering with sodium bicarbonate reduces injection pain.

Because of the potential loss of CO2 from the solution over time, Ikuta and colleagues recommended that buffering take place immediately before giving the injection, versus allowing a delay between buffering the anesthetic and delivery.51 In one of the seminal local anesthetic buffering studies, Christoph and colleagues make the same recommendation for immediate use of local anesthetic after buffering.52