The abstract below details one of the possible benefits of buffering a medication, in this case lidocaine. The authors came to this conclusion following a meta analysis of twenty three studies. By adjusting the pH to more closely match physiological pH, patient reported pain decreased during lidocaine injection.

 

Adjusting the pH of lidocaine for reducing pain on injection.

Cepeda MS, Tzortzopoulou A, Thackrey M, Hudcova J, Arora Gandhi P, Schumann R.

Source

Pharmacoepidemiology, Johnson & Johnson Pharmaceutical Research and Development, PO BOX 200, M/S K304, Titussville, NJ, USA, 08560.

Abstract

BACKGROUND:

Lidocaine administration produces pain due to its acidic pH.

OBJECTIVES:

The objective of this review was to determine if adjusting the pH of lidocaine had any effect on pain resulting from non-intravascular injections in adults and children. We tested the hypothesis that adjusting the pH of lidocaine solution to a level closer to the physiologic pH reduces this pain.

SEARCH STRATEGY:

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, to June 2010); Ovid MEDLINE (1966 to June 2010); EMBASE (1988 to June 2010); LILACS (1982 to June 2010); CINAHL (1982 to June 2010); ISI Web of Science (1999 to June 2010); and abstracts of the meetings of the American Society of Anesthesiologists (ASA). We checked the full articles of selected titles. We did not apply any language restrictions.

SELECTION CRITERIA:

We included double-blinded, randomized controlled trials that compared pH-adjusted lidocaine with unadjusted lidocaine. We evaluated pain at the injection site, satisfaction and adverse events. We excluded studies in healthy volunteers.

DATA COLLECTION AND ANALYSIS:

We separately analysed parallel-group and crossover trials; trials that evaluated lidocaine with or without epinephrine; and trials with pH-adjusted lidocaine solutions < 7.35 and ≥ 7.35. To explain heterogeneity, we separately analysed studies with a low and higher risk of bias due to the level of allocation concealment; studies that employed a low and a higher volume of injection; and studies that used lidocaine for different types of procedures.

MAIN RESULTS:

We included 23 studies of which 10 had a parallel design and 13 were crossover studies. Eight of the 23 studies had moderate to high risk of bias due to the level of allocation concealment.Pain associated with the infiltration of buffered lidocaine was less than the pain associated with infiltration of unbuffered lidocaine in both parallel and crossover trials. In the crossover studies, the difference was -1.98 units (95% confidence interval (CI) -2.62 to -1.34) and in the parallel-group studies it was -0.98 units (95% CI -1.49 to -0.47) on a 0 to 10 scale. The magnitude of the pain decrease associated with buffered lidocaine was larger when the solution contained epinephrine. The risk of bias, volume of injection, and type of procedure failed to explain the heterogeneity of the results.Patients preferred buffered lidocaine (odds ratio 3.01, 95% CI 2.19 to 4.15). No adverse events or toxicity were reported.

AUTHORS' CONCLUSIONS:

Increasing the pH of lidocaine decreased pain on injection and augmented patient comfort and satisfaction.

Poster/Public Service Announcement

Pharmaceutical Company Perspective

          Pharmaceutical companies consider many different factors when designing a new drug. Often, alternative drugs that have a similar effect are first looked at and analyzed with the simple question 'will the benefit of the new drug outweigh the cost?' After all, it would be meaningless to create a new tablet that is inferior to the current gold standard.

          However, the cost of designing a drug from the screening of various chemical molecules and clinical trials all the way to the final product requires an enormous amount of time and money. In addition, the trials may fail to support the effectiveness of the new drug, thus, jeopardizing the entire project and all the billions of dollars spent into it. Because of the inherent risk associated with producing a new drug entity, this task is often limited to large pharmaceutical companies that can afford to take the risk. The pharmaceutical company holds a patent to the drug that they developed and would then often sell their drug at a high price to recover their cost.

Many chemical compounds are all screened and tested, but few make it to the final phase of drug development. Often, many new drugs fail at Phase I and II where unexpected side effects are discovered when tested in human.

          Once the patent expires, other pharmaceutical companies can then use the active ingredients of the original drug to create their own 'generic' drug. Since the safe dosage and side effects of the active ingredient has already been tested for and documented, the cost of creating a generic drug is significantly lower and they are often sold at a lower price. The only clinical evidence required for generic drugs are comparison trials where the original drug is compared with the generic. If they are similar enough with their effects, the generic is then approved and ready to be marketed.

unionized acetylsalicylic acid

ionized acetylsalicylic acid

          It is possible to modify the recipe for the generic drug as long as the active ingredient is the same. One common modification is including a buffer system in drugs that are taken orally. MgO can be added into the tablet to create a buffer system in Aspirin. The buffer system act to stabilize a higher pH in the stomach and prevent HCl in your stomach from lowering it back down for the duration. This is important because the active ingredient in Aspirin (acetylsalicylic acid) contains a carboxylic acid functional group that is unionized at low pH and becomes ionized with the introduction of the buffer. At a low pH, the free hydrogen ions in the stomach forces the equilibrium of the ionization of acetylsalicylic acid to favour its unionized form. Acetylsalicylic acid when unionized is highly fat soluble and diffuses into the capillaries that line the stomach and causes them to rupture, and subsequently blood can be observed in a person's feces. At a higher than normal pH, the lower concentration of hydrogen ions in the equilibrium allows the molecule to ionize, which in turn increases its solubility in water and prevent absorption through the stomach lining.

          Having a buffered tablet can decrease risk of gastrointestinal bleeding which can be observed in the case of unbuffered acetylsalicylic acid. However, these side effects are not life threatening to most people and would generally subside with slight stomach irritation and some blood in stool. Addition of a buffer system may require additional clinical trials that would cost money. From a pharmaceutical company's viewpoint, because the minimal side effects of the unbuffered drug does not warrant a change in the recipe.

          The equilibrium of the ionization of acetylsalicylic acid in the stomach can be explained further explained in this video example of how acetic acid ionizes in water.