Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site

Abstract

The subcutaneous administration route is widely used to administer different types of drugs given its high bioavailability and rapid onset of action. However, the sensation of pain at the injection site might reduce patient adherence. Apart from a direct effect of the drug itself, several factors can influence the sensation of pain: needle features, injection site, volume injected, injection speed, osmolality, viscosity and pH of formulation, as well as the kind of excipients employed, including buffers and preservatives. Short and thin needles, conveniently lubricated and with sharp tips, are generally used to minimize pain, although the anatomic injection site (abdomen versus thigh) also affects the sensation of pain. Large subcutaneous injection volumes are associated with pain. In this sense, the maximum volume generally accepted is around 1.5 ml, although volumes of up to 3 ml are well tolerated when injected in the abdomen. Injected volumes of up to 0.5–0.8 ml are not expected to increase substantially the pain produced by the needle insertion. Ideally, injectable products should be formulated as isotonic solutions (osmolality of about 300 mOsm/kg) and no more than 600 mOs/kg have to be used in order to prevent pain. A pH close to the physiological one is recommended to minimize pain, irritation, and tissue damage. Buffers are frequently added to parenteral formulations to optimize solubility and stability by adjusting the pH; however, their strength should be kept as low as possible to avoid pain upon injection. The data available recommend the concentration of phosphate buffer be limited to 10 mM and that the concentration of citrate buffer should be lower than 7.3 mM to avoid an increased sensation of pain. In the case of preservatives, which are required in multiple-dose preparations, m-cresol seems to be more painful than benzyl alcohol and phenol.Funding: Sandoz SA.

Understanding and Minimising Injection-Site Pain Following Subcutaneous Administration of Biologics: A Narrative Review

“…TNF) SC formulations containing citrate versus those without. In addition, while it has been suggested that citrate concentration might affect pain sensation, there is no clear evidence to support this statement[31]. Cohen et al…”

Preparedness against pandemic influenza: Production of an oil-in-water emulsion adjuvant in Brazil

“…Osmolality values higher than 600 mOsm/kg has been associated to hypertonicity-induced pain. Our results showed a value lower than this limit and the pH were also at physiological range, desirable parameters in the vaccine design to avoid pain in the local injection site [42].…”

Injectable Lipid-Based Depot Formulations: Where Do We Stand?

“…The administration of volumes larger than 1.5 to 2 mL usually requires multiple injections to minimize the risk of considerably high pain upon injection. For example, it has been shown that incrementing the injected volume from 0.8 to 2.25 mL resulted in an increase of the perceived pain about 1.7-fold [18,19]. The choice of the most suitable drug delivery system has to be carefully considered; the potency of the drug and the dose on the one hand and the encapsulation capacity of the delivery system on the other play a decisive role in this selection.…”

“…The choice of the most suitable drug delivery system has to be carefully considered; the potency of the drug and the dose on the one hand and the encapsulation capacity of the delivery system on the other play a decisive role in this selection. Although it has been reported that the used buffers (pH, osmolarity) in the formulations could influence the pain upon injection [18], no correlation between different lipids and the induction of pain has been investigated so far.…”