Administration Sites for Long-Acting Injectable Antipsychotics

Key Takeaways

• Most commonly, long-acting injectable (LAI) antipsychotics are administered in the deltoid or gluteal muscle.
• Many healthcare professionals are quick to assume that patients prefer deltoid administration of LAI antipsychotics, although it has been shown that one third of patients opt for the gluteal injection site when given the choice.
• Conversations with potential candidates for LAI antipsychotics should include discussion of administration sites with an explanation of the pros and cons for each, and they should take individual preference into account.

Long-acting injectable (LAI) antipsychotics are an invaluable treatment option for many patients with schizophrenia, schizoaffective disorder, or bipolar disorder. These products offer a multitude of potential benefits over their oral counterparts. Rather than daily oral administration, individuals have the option to receive injections at intervals ranging from every 2 weeks to every 6 months. This confers an advantage in adherence and is a valuable aid in establishing an adequate medication trial and determining potential treatment resistance. Like other parenteral products, LAIs bypass first-pass metabolism and are subject to fewer absorption issues. In addition, the steady release of medication eliminates daily fluctuations in peak and trough drug levels, resulting in better tolerability and fewer adverse effects for some patients. Moreover, the gradual elimination of LAI antipsychotics reduces the risk for abrupt loss in efficacy if a dose is missed. Not surprising, these properties have demonstrated improvements in adherence, reduced hospitalizations, and even decreased mortality vs oral antipsychotics.^1,2  

Although the advantages of LAI antipsychotics may seem evident to most, barriers to their use still exist.³ Many barriers can be overcome through proper education and shared decision-making, but most research has focused on gaining patient acceptance of the injection itself. Still, an important and frequently overlooked piece of this process is determining individual preferences for the injection’s administration site. By far, the 2 most common sites for LAI administration are intramuscularly in the deltoid or gluteal muscles. A commonly held belief is that intramuscular deltoid administration is the superior route when available. Many assume it is much more likely to be preferred by patients and that it offers advantages with absorption, tolerability, and decreased pain. Despite these assumptions, very little data evaluating individual preferences for site of administration actually exist.⁴

For LAI products with the option of being given in either the deltoid or the gluteal muscle, pharmacokinetic differences have been observed. The differences are due in large part to the smaller size and greater perfusion of the deltoid vs the gluteal muscles. Pharmacokinetically, this translates to a more rapid absorption of the antipsychotic, leading to overall higher peak plasma concentrations (C_max) and decreased time to max concentration (T_max) when the LAI is given in the deltoid.^5-7 Conversely, the reduced perfusion of the gluteal muscle produces lower C_max and delayed T_max, but it also yields a longer terminal half-life of the medication. However, these variations in pharmacokinetics are more pronounced when evaluating single doses of LAI antipsychotics and diminish as the drug approaches steady state with repeated injections. In addition, the overall area under the curve representing total drug exposure is similar for LAI antipsychotics regardless of deltoid or gluteal administration. 

Regarding gluteal administration, several other considerations must be taken into account. Although proper administration technique is critical for all LAI antipsychotics, it is even more paramount when giving intramuscular gluteal injections. Because the area has larger amounts of subcutaneous fat, there is a greater potential for injections to inadvertently be administered subcutaneously. It has been predicted that gluteal injection failures may occur in more than 50% of patients receiving LAIs, with a higher proportion of failures in patients with obesity.⁸ The risk of failure, however, can be mitigated with training on needle selection, proper injection angle, and using the ventrogluteal vs dorsogluteal area for administration. LAI antipsychotics typically require wider (18-22 gauge) and longer (1-2 inch) needles with gluteal administration, even in patients who are thin. This necessity for proper drug delivery often causes patients and healthcare professionals to assume that gluteal injections will be more painful than those given in the deltoid. In reality, the opposite has been found to be true, and some patients prefer gluteal administration for this very reason.^6,7,9 The table lists the LAI antipsychotics currently available in the United States and their approved administration sites. 

Table. LAI Antipsychotic Administration Sites

The formulation of LAI antipsychotics plays an important role in their tolerability at the injection site. First-generation antipsychotic LAIs, for instance, are comprised of an esterified compound attached to a fatty acid (decanoic acid) and then dissolved in sesame oil. Due to their oil-based nature and high viscosity, a Z-track injection technique is used to minimize leakage of the compound from the injection site. However, more modern LAIs involving second-generation antipsychotics (SGAs) use nano/microcrystalline salts or biodegradable polymers/microspheres for drug delivery. These water-soluble delivery systems likely contribute to the reduced prevalence of injection-site adverse events. Other factors of individual SGA LAI products, such as thin wall needles, self-contained dosing systems, and reduced injection volumes, have likely also made an impact. Overall, local injection-site complications, such as pain or redness, occur in <10% of patients and seem to decrease with subsequent injections. 

As stated previously, individual preferences for the site of LAI antipsychotic administration should be considered. Most assume that patients will simply prefer the familiarity of deltoid administration. Although several small studies confirm that the majority of patients favor this site, surprisingly, more than one third will select gluteal administration when given the option.^4,10 The overwhelming majority of individuals appreciated being given the choice between sites, and most felt better able to participate in their treatment because they were given the option. By engaging patients in shared decision-making, many individual barriers to LAI antipsychotics, such as lack of awareness, feeling coerced, or fear of injections, can be minimized or overcome. Offering more choices to patients with their LAI medication allows for better engagement and helps lay the foundation for an effective therapeutic alliance. Conversations with potential candidates for LAI antipsychotics should include discussion of administration sites, with an explanation of the advantages and disadvantages for each. 

Your Thoughts?
Do you feel comfortable discussing LAI antipsychotics and their administration site options with your patients? Answer the polling question and join in the discussion in the comments section below. For more information on LAI antipsychotics, watch the on-demand presentation “Changing Minds, Changing Lives: Elucidating the Role of LAI Antipsychotics."

References

1. Kishimoto T, Hagi K, Kurokawa S, et al. Long-acting injectable versus oral antipsychotics for the maintenance treatment of schizophrenia: a systematic review and comparative meta-analysis of randomised, cohort, and pre-post studies. Lancet Psychiatry. 2021;8:387-404.
2. Huang C-Y, Fang S-C, Shoa Y-H. Comparison of long-acting injectable antipsychotics with oral antipsychotics and suicide and all-cause mortality in patients with newly diagnosed schizophrenia. JAMA Netw Open. 2021;4:e218810.
3. Lindenmayer J-P, Glick I, Talreja H, Underriner M. Persistent barriers to the use of long-acting injectable antipsychotics for the treatment of schizophrenia. J Clin Psychopharmcol. 2020;40:346-349.
4. Taylor M. Deltoid versus gluteal: Which intramuscular injection site do mental health patients prefer? Aust N Z J Psychiatry. 2020;55:734-735.
5. Cleton A, Rossenu S, Hough D, et al. Evaluation of the pharmacokinetic profile of deltoid versus gluteal intramuscular injections of paliperidone palmitate in patients with schizophrenia. Presented at: American Society for Clinical Pharmacology and Therapeutics Annual Meeting; April 2-5, 2008. Poster.
6. Turncliff R, Hard M, Du Y, et al. Relative bioavailability and safety of aripiprazole lauroxil, a novel once-monthly, long-acting injectable atypical antipsychotic, following deltoid and gluteal administration in adult subjects with schizophrenia. Schizophr Res. 2014;159:404-410.
7. Raoufinia A, Peters-Strickland T, Nylander A-G, et al. Aripiprazole once-monthly 400 mg: comparison of pharmacokinetics, tolerability, and safety of deltoid versus gluteal administration. Int J Neuropsychopharmacol. 2017;20:295-304.
8. Soliman E, Ranjan S, Xu T, et al. A narrative review of the success of intramuscular gluteal injections and its impact in psychiatry. Bio-Des Manuf. 2018;1:161-170.
9. Zolezzi M, Abouelhassan R, Eltorki Y, et al. Long-acting injectable antipsychotics: a systematic review of their non-systemic adverse effect profile. Neuropsychiatr Dis Treat. 2021;17:1917-1926.
10. Millet B, Gourevitch R, Levoyer D, et al. Study on how schizophrenic patients perceive treatment with injections in the deltoid muscle [French]. Encephale. 2012;38:97-103.