Viola M, Sequeira J, Seica R, et al. Subcutaneous delivery of monoclonal antibodies: how do we get there? J Control Release. 2018;286:301–14.
Article CAS PubMed Google Scholar
Haller MF. Converting intravenous dosing to subcutaneous dosing with recombinant human hyaluronidase. Pharm Technol. 2007;31(10):118–32.
CAS Google Scholar
Bolge SC, Goren A, Tandon N. Reasons for discontinuation of subcutaneous biologic therapy in the treatment of rheumatoid arthritis: a patient perspective. Patient Prefer Adherence. 2015;9:121–31.
Article PubMed PubMed Central Google Scholar
Ringe JD, Farahmand P. Improved real-life adherence of 6-monthly denosumab injections due to positive feedback based on rapid 6-month BMD increase and good safety profile. Rheumatol Int. 2014;34(5):727–32.
Article CAS PubMed Google Scholar
Poulos C, Kinter E, Yang JC, Bridges JF, Posner J, Reder AT. Patient preferences for injectable treatments for multiple sclerosis in the United States: a discrete-choice experiment. Patient. 2016;9(2):171–80.
Article PubMed Google Scholar
Kim H, Park H, Lee SJ. Effective method for drug injection into subcutaneous tissue. Sci Rep. 2017;7(1):9613.
Article PubMed PubMed Central Google Scholar
Kreugel G, Beijer H, Kerstens M, Ter Maaten J, Sluiter W, Boot B. Influence of needle size for subcutaneous insulin administration on metabolic control and patient acceptance. Eur Diabetes Nurs. 2007;4(2):51–5.
Article Google Scholar
Guo X, Wang W. Challenges and recent advances in the subcutaneous delivery of insulin. Expert Opin Drug Deliv. 2017;14(6):727–34.
Article CAS PubMed Google Scholar
Karges B, Boehm BO, Karges W. Early hypoglycaemia after accidental intramuscular injection of insulin glargine. Diabet Med. 2005;22(10):1444–5.
Article CAS PubMed Google Scholar
Australian Diabetes Educators Association (ADEA). Clinical guiding principles for subcutaneous injection technique. 2015. //www.adea.com.au/wp-content/uploads/2015/11/Injection-Technique-Final-digital-version2.pdf. Accessed Nov 2018.
Hirsch L, Byron K, Gibney M. Intramuscular risk at insulin injection sites–measurement of the distance from skin to muscle and rationale for shorter-length needles for subcutaneous insulin therapy. Diabetes Technol Ther. 2014;16(12):867–73.
Article CAS PubMed Google Scholar
Gibney MA, Arce CH, Byron KJ, Hirsch LJ. Skin and subcutaneous adipose layer thickness in adults with diabetes at sites used for insulin injections: implications for needle length recommendations. Curr Med Res Opin. 2010;26(6):1519–30.
Article CAS PubMed Google Scholar
Akkus O, Oguz A, Uzunlulu M, Kizilgul M. Evaluation of skin and subcutaneous adipose tissue thickness for optimal insulin injection. J Diabetes Metab. 2012;3(8):2.
Article CAS Google Scholar
Derraik JG, Rademaker M, Cutfield WS, et al. Effects of age, gender, BMI, and anatomical site on skin thickness in children and adults with diabetes. PLoS One. 2014;9(1):e86637.
Article PubMed PubMed Central CAS Google Scholar
Sim KH, Hwang MS, Kim SY, Lee HM, Chang JY, Lee MK. The appropriateness of the length of insulin needles based on determination of skin and subcutaneous fat thickness in the abdomen and upper arm in patients with type 2 diabetes. Diabetes Metab J. 2014;38(2):120–33.
Article PubMed PubMed Central Google Scholar
Arendt-Nielsen L, Egekvist H, Bjerring P. Pain following controlled cutaneous insertion of needles with different diameters. Somatosens Mot Res. 2006;23(1–2):37–43.
Article PubMed Google Scholar
Hanas R, Lytzen L, Ludvigsson J. Thinner needles do not influence injection pain, insulin leakage or bleeding in children and adolescents with type 1 diabetes. Pediatr Diabetes. 2000;1(3):142–9.
Article CAS PubMed Google Scholar
Robb DM, Kanji Z. Comparison of two needle sizes for subcutaneous administration of enoxaparin: effects on size of hematomas and pain on injection. Pharmacotherapy. 2002;22(9):1105–9.
Article PubMed Google Scholar
Hirsch L, Gibney M, Berube J, Manocchio J. Impact of a modified needle tip geometry on penetration force as well as acceptability, preference, and perceived pain in subjects with diabetes. J Diabetes Sci Technol. 2012;6(2):328–35.
Article PubMed PubMed Central Google Scholar
Petersen C, Zeis B. Syringe siliconisation trends, methods and analysis procedures. Int Pharm Ind. 2015;7(2):78–84.
Google Scholar
Jones LS, Kaufmann A, Middaugh CR. Silicone oil induced aggregation of proteins. J Pharm Sci. 2005;94(4):918–27.
Article CAS PubMed Google Scholar
Thirumangalathu R, Krishnan S, Ricci MS, Brems DN, Randolph TW, Carpenter JF. Silicone oil- and agitation-induced aggregation of a monoclonal antibody in aqueous solution. J Pharm Sci. 2009;98(9):3167–81.
Article CAS PubMed PubMed Central Google Scholar
Cooper K, Gosnell K. Foundations of nursing. St. Louis: Elsevier; 2019.
Google Scholar
Candiotti K, Rodriguez Y, Koyyalamudi P, Curia L, Arheart KL, Birnbach DJ. The effect of needle bevel position on pain for subcutaneous lidocaine injection. J Perianesth Nurs. 2009;24(4):241–3.
Article PubMed Google Scholar
Zijlstra E, Jahnke J, Fischer A, Kapitza C, Forst T. Impact of injection speed, volume, and site on pain sensation. J Diabetes Sci Technol. 2018;12(1):163–8.
Article PubMed Google Scholar
Heise T, Nosek L, Dellweg S, et al. Impact of injection speed and volume on perceived pain during subcutaneous injections into the abdomen and thigh: a single-centre, randomized controlled trial. Diabetes Obes Metab. 2014;16(10):971–6.
Article CAS PubMed Google Scholar
Ravi AD, Sadhna D, Nagpaal D, Chawla L. Needle free injection technology: a complete insight. Int J Pharm Investig. 2015;5(4):192–9.
Article CAS PubMed PubMed Central Google Scholar
So J. Improving patient compliance with biopharmaceuticals by reducing injection-associated pain. J Mucopolysacch Rare Dis. 2015;1(1):15–8.
Article Google Scholar
Mathaes R, Koulov A, Joerg S, Mahler HC. Subcutaneous injection volume of biopharmaceuticals-pushing the boundaries. J Pharm Sci. 2016;105(8):2255–9.
Article CAS PubMed Google Scholar
European Medicines Agency. Vidaza, INN-azacitidine. 2013. //www.ema.europa.eu/en/documents/product-information/vidaza-epar-product-information_en.pdf. Accessed Nov 2018.
Jorgensen JT, Romsing J, Rasmussen M, Moller-Sonnergaard J, Vang L, Musaeus L. Pain assessment of subcutaneous injections. Ann Pharmacother. 1996;30(7–8):729–32.
Article CAS PubMed Google Scholar
Berteau C, Filipe-Santos O, Wang T, Rojas HE, Granger C, Schwarzenbach F. Evaluation of the impact of viscosity, injection volume, and injection flow rate on subcutaneous injection tolerance. Med Devices (Auckl). 2015;8:473–84.
Google Scholar
Broadhead J, Gibson M. Parenteral dosage forms. In: Gibson M, editor. Pharmaceutical preformulation and formulation. New York: Informa healthcare; 2009. p. 325–47.
Google Scholar
Wang W. Tolerability of hypertonic injectables. Int J Pharm. 2015;490(1–2):308–15.
Article CAS PubMed Google Scholar
Tangen LF, Lundbom JS, Skarsvag TI, et al. The influence of injection speed on pain during injection of local anaesthetic. J Plast Surg Hand Surg. 2016;50(1):7–9.
Article PubMed Google Scholar
Nema S, Brendel RJ. Excipients for parenteral dosage forms: regulatory considerations and controls. In: Nema S, Ludwig JD, editors. Dosage forms: parenteral medications. Vol 3: regulations, validation and the future. New York: Informa Healthcare; 2010. p. 109–34.
Google Scholar
Botempo JA. Formulation development. In: Bontempo JA, editor. Development of biopharmaceutical parenteral dosage forms. New York: Informa Healthcare; 2007. p. 109–42.
Google Scholar
Fransson J, Espander-Jansson A. Local tolerance of subcutaneous injections. J Pharm Pharmacol. 1996;48(10):1012–5.
Article CAS PubMed Google Scholar
Frenken LA, van Lier HJ, Jordans JG, et al. Identification of the component part in an epoetin alfa preparation that causes pain after subcutaneous injection. Am J Kidney Dis. 1993;22(4):553–6.
Article CAS PubMed Google Scholar
Laursen T, Hansen B, Fisker S. Pain perception after subcutaneous injections of media containing different buffers. Basic Clin Pharmacol Toxicol. 2006;98(2):218–21.
Article CAS PubMed Google Scholar
Gely C, Marin L, Gordillo J, et al. Impact of pain due to subcutaneous administration of a biological drug. J Crohn’s Colitis. 2018;12:S582–3.
Article Google Scholar
Nash P, Vanhoof J, Hall S, et al. Randomized crossover comparison of injection site pain with 40 mg/0.4 or 0.8 ml formulations of adalimumab in patients with rheumatoid arthritis. Rheumatol Ther. 2016;3(2):257–70.
Article PubMed PubMed Central Google Scholar
Food and Drug Administration. Hyrimoz®. Prescribing information. 2018. //s3-us-west-2.amazonaws.com/drugbank/fda_labels/DB00051.pdf?1543522358. Accessed Oct 2018.
Food and Drug Administration. Humira®. Prescribing information. 2016. //www.accessdata.fda.gov/drugsatfda_docs/label/2018/125057s410lbl.pdf. Accessed Oct 2018.
Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48(1):35–45.
Article CAS PubMed Google Scholar
Sandborn WJ, Colombel JF, D’Haens G, et al. One-year maintenance outcomes among patients with moderately-to-severely active ulcerative colitis who responded to induction therapy with adalimumab: subgroup analyses from ULTRA 2. Aliment Pharmacol Ther. 2013;37(2):204–13.
Article CAS PubMed Google Scholar
Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial. Gastroenterology. 2006;130(2):323–33 (quiz 591).
Article CAS PubMed Google Scholar
Blauvelt A, Lacour JP, Fowler JF Jr, et al. Phase III randomized study of the proposed adalimumab biosimilar GP2017 in psoriasis: impact of multiple switches. Br J Dermatol. 2018;179(3):623–31.
Article CAS PubMed Google Scholar
NHS. Regional medicines optimisation committee briefing, best value biologicals: adalimumab update 6. July 2019. //www.sps.nhs.uk/wp-content/uploads/2019/07/Adalimumab-RMOC-Briefing-6.pdf. Accessed 12 Sep 2019.
Best CA, Best AA, Best TJ, Hamilton DA. Buffered lidocaine and bupivacaine mixture—the ideal local anesthetic solution? Plast Surg (Oakv). 2015;23(2):87–90.
Article Google Scholar
Quaba O, Huntley JS, Bahia H, McKeown DW. A users guide for reducing the pain of local anaesthetic administration. Emerg Med J. 2005;22(3):188–9.
Article CAS PubMed PubMed Central Google Scholar
Meyer BK, Ni A, Hu B, Shi L. Antimicrobial preservative use in parenteral products: past and present. J Pharm Sci. 2007;96(12):3155–67.
Article CAS PubMed Google Scholar
Kappelgaard AM, Bojesen A, Skydsgaard K, Sjogren I, Laursen T. Liquid growth hormone: preservatives and buffers. Horm Res. 2004;62(Suppl 3):98–103.
CAS PubMed Google Scholar
Page 2
From: Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site
Adults | |||||||
Both sexes | 2.23 ± 0.44 | 10.77 ± 5.62 | 2.15 ± 0.42 | 13.92 ± 7.26 | 1.87 ± 0.39 | 10.35 ± 5.65 | [21]a |
Male | 2.12 ± 0.39 | 2.81 ± 1.16 | 2.35 ± 0.43 | 9.83 ± 6.67 | 2.11 ± 0.37 | 3.97 ± 2.76 | [1]a |
1.92 ± 0.31 | 3.03 ± 2.27 | 2.36 ± 0.42 | 11.68 ± 9.19 | 1.97 ± 0.33 | 3.48 ± 2.35 | [1]b | |
– | – | 2.10 (1.99–2.21) | 17.88 (15.93–19.83) | 1.89 (1.78–2.01) | 9.84 (8.21–11.48) | [13]a,c | |
2.14 ± 0.31 | 4.06 ± 1.79 | 2.37 ± 0.36 | 7.75 ± 5.03 | – | – | [43]a | |
Female | 2.08 ± 0.44 | 9.14 ± 7.36 | 2.31 ± 0.42 | 20.19 ± 9.73 | 2.12 ± 0.43 | 10.33 ± 7.39 | [1]a |
1.85 ± 0.35 | 7.44 ± 5.87 | 2.27 ± 0.43 | 16.71 ± 9.46 | 1.86 ± 0.44 | 9.64 ± 6.44 | [1]b | |
– | – | 1.99 (1.89–2.09) | 21.26 (19.54–22.99) | 1.65 (1.55–1.76) | 17.68 (16.23–19.12) | [13]a,c | |
1.84 ± 0.29 | 7.19 ± 2.56 | 2.20 ± 0.36 | 13.07 ± 7.03 | – | – | [43]a | |
Children and adolescents | |||||||
Male | – | – | 1.89 (1.75–2.03) | 9.13 (7.75–10.51) | 1.60 (1.50–1.70) | 7.68 (6.25–9.12) | [13]a,c,d |
Female | – | – | 1.83 (1.68–1.97) | 13.06 (11.70–14.42) | 1.57 (1.47–1.68) | 13.39 (11.97–14.82) | [13]a,c,e |
- Data (in millimeters) are the mean value ± standard deviation or the mean value (95% confidence interval)
- aDiabetic patients
- bHealthy volunteers
- cIn this study, ST refers only to dermis
- dAge 6.0–18.0 years
- eAge 6.0–19.0 years