A limitation in the administration of parenteral products is the pain caused upon injection. Injection site pain has been predominately associated with intravenous, intramuscular, and subcutaneous administration. It becomes important for the formulation scientist to have a basic understanding of the physiology underlying the pain process, as well as the pharmaceutical factors associated with injection site pain. Initially, this review will provide the reader with a primer on the mediation of pain in the periphery and a compilation of those drugs that have been associated with pain on injection. In addition, this review will present important considerations and general formulation approaches or methods that have been used to overcome pain on injection. Finally, a brief overview of the various experimental systems used to investigate injection site pain is discussed.

The purpose of the present study was to investigate the myotoxicity of three buffers containing carboxylic acid groups (i.e., acetate, succinate, and citrate) as a function of their pH, capacity, and tonicity. The myotoxicity of these buffers in the range of pH 2-6 and 0.001-0.1 M buffer capacity was assessed using cumulative creatine kinase (CK) release from an isolated rodent muscle model following injection. Phenytoin and 0.9% NaCl injection were used as positive and negative controls, respectively. Buffer solutions were prepared. A lower pH and higher buffer capacity was linked to increased myotoxicity for the acetate buffers. However, for succinate and citrate buffers, pH appeared to influence the extent of myotoxicity, whereas buffer capacity did not seem to have an effect. When either NaCl or trehalose was used as a tonicity-adjusting agent at pH 6, isotonic 0.01 M buffer solutions dramatically lowered the cumulative CK release compared to those that were not isotonic. Isotonic succinate buffers displayed the lowest myotoxicity, whereas citrate buffers displayed the highest values. Citrate buffers containing three carboxylic acid groups showed higher myotoxicity than succinate buffers and acetate buffers at 0.001 and 0.01 M buffer capacities, whereas acetate buffer produced higher cumulative CK release than citrate and succinate buffers at 0.1 M buffer capacity. The myotoxicity of pharmaceutical buffers containing carboxylic acid groups appears to be directly affected by lowering the pH of the solution.