When a medication irritates subcutaneous tissue which of the following types of injections should be administered?

  1. 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 

  2. Haller MF. Converting intravenous dosing to subcutaneous dosing with recombinant human hyaluronidase. Pharm Technol. 2007;31(10):118–32.

    CAS  Google Scholar 

  3. 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 

  4. 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 

  5. 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 

  6. 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 

  7. 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 

  8. 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 

  9. 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 

  10. Australian Diabetes Educators Association (ADEA). Clinical guiding principles for subcutaneous injection technique. 2015. https://www.adea.com.au/wp-content/uploads/2015/11/Injection-Technique-Final-digital-version2.pdf. Accessed Nov 2018.

  11. 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 

  12. 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 

  13. 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 

  14. 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 

  15. 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 

  16. 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 

  17. 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 

  18. 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 

  19. 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 

  20. Petersen C, Zeis B. Syringe siliconisation trends, methods and analysis procedures. Int Pharm Ind. 2015;7(2):78–84.

    Google Scholar 

  21. 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 

  22. 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 

  23. Cooper K, Gosnell K. Foundations of nursing. St. Louis: Elsevier; 2019.

    Google Scholar 

  24. 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 

  25. 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 

  26. 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 

  27. 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 

  28. So J. Improving patient compliance with biopharmaceuticals by reducing injection-associated pain. J Mucopolysacch Rare Dis. 2015;1(1):15–8.

    Article  Google Scholar 

  29. 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 

  30. European Medicines Agency. Vidaza, INN-azacitidine. 2013. https://www.ema.europa.eu/en/documents/product-information/vidaza-epar-product-information_en.pdf. Accessed Nov 2018.

  31. 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 

  32. 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 

  33. 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 

  34. Wang W. Tolerability of hypertonic injectables. Int J Pharm. 2015;490(1–2):308–15.

    Article  CAS  PubMed  Google Scholar 

  35. 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 

  36. 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 

  37. Botempo JA. Formulation development. In: Bontempo JA, editor. Development of biopharmaceutical parenteral dosage forms. New York: Informa Healthcare; 2007. p. 109–42.

    Google Scholar 

  38. Fransson J, Espander-Jansson A. Local tolerance of subcutaneous injections. J Pharm Pharmacol. 1996;48(10):1012–5.

    Article  CAS  PubMed  Google Scholar 

  39. 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 

  40. 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 

  41. 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 

  42. 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 

  43. Food and Drug Administration. Hyrimoz®. Prescribing information. 2018. https://s3-us-west-2.amazonaws.com/drugbank/fda_labels/DB00051.pdf?1543522358. Accessed Oct 2018.

  44. Food and Drug Administration. Humira®. Prescribing information. 2016. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125057s410lbl.pdf. Accessed Oct 2018.

  45. 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 

  46. 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 

  47. 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 

  48. 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 

  49. NHS. Regional medicines optimisation committee briefing, best value biologicals: adalimumab update 6. July 2019. https://www.sps.nhs.uk/wp-content/uploads/2019/07/Adalimumab-RMOC-Briefing-6.pdf. Accessed 12 Sep 2019.

  50. 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 

  51. 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 

  52. 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 

  53. 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

  Arm Abdomen Thigh References
ST SCT ST SCT ST SCT
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

  1. Data (in millimeters) are the mean value ± standard deviation or the mean value (95% confidence interval)
  2. aDiabetic patients
  3. bHealthy volunteers
  4. cIn this study, ST refers only to dermis
  5. dAge 6.0–18.0 years
  6. eAge 6.0–19.0 years