Diazepam i. m. – the Most Common, but Inappropriate Medication for Management of Acute Anxiety, Agitation and Aggression

Czech version

Authors: J. Vevera ^1,2; Z. Oktábec ^3,4; F. Perlík ⁵; V. Marešová ³; A. Kopecká ³; J. Raboch ¹; M. Novotná ⁶
Authors‘ workplace: Psychiatrická klinika 1. LF UK a VFN v Praze ¹; 7. polní nemocnice AČR ²; Oddělení toxikologie, Ústav soudního lékařství a toxikologie, 1. LF UK a VFN v Praze ³; Klinika adiktologie 1. LF UK a VFN v Praze ⁴; Farmakologický ústav, 1. LF UK a VFN v Praze ⁵; Therapia VIVA s. r. o., psychiatrická ambulance ⁶
Published in: Cesk Slov Neurol N 2014; 77/110(6): 760-764
Category: Short Communication
doi: https://doi.org/10.14735/amcsnn2014760

Overview

Introduction:
There is a need for intramuscular (IM) administration of benzodiazepines for acute restlessness, anxiety and agitation. In the Czech Republic, diazepam is frequently used. The aim of this study was to determine the variability of serum diazepam concentrations after IM administration and evaluate its clinical effect.

Methods:
We included six men, who were administered 10 mg of diazepam IM in an outpatient setting. Measurements were carried out 30 minutes (T1), 4 (T2) and 24 hours (T3) after diazepam administration. The diagnosis was determined using the Mini-International Neuropsychiatric Interview, anxiety was quantified by the Hamilton Anxiety Rating Scale (HAMA).

Results:
The mean levels of diazepam in the serum were 14.6 ng/ml at T1 (after 30 minutes), 48.6 ng/ml at 4 hours and 28.7 ng/ml at 24 hours after administration. The values at T1 ranged from 0.5 ng/ml to 148.0 ng/ml. We found no relationship between the scores of HAMA and concentrations of diazepam. Anxiety decreased to normal values (HAMA < 13) at the time T1 in all patients.

Conclusions:
Concentrations of diazepam were lower 30 minutes after the administration than after 4 and 24 hours, respectively. We observed the largest variability in concentrations 30 minutes after the administration, when the concentrations between patients differed 280-times. This finding confirms international experience that IM diazepam administration should not be used. We discuss the differences between individual SPCs and guidelines that force inappropriate use of diazepam IM and do not permit other than off-label use of midazolam.

Key words:
diazepam – pharmacokinetics – agitation – aggression – intramuscular administration

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Sources

1. Vevera J, Uhrová T, Jirák R, Žukov I, Ort V. Násilné chování a možnosti jeho ovlivnění. I. díl – výskyt, rozdělení a klinické koreláty. Psychiatr Prax 2002; 3(5): 226– 229.

2. Baudiš P, Kališová L, Kitzlerová E, Petr T, Miloš T.Omezovací prostředky. In: Raboch J, Anders M, Praško J, Hellerová P (eds). Psychiatrie: Doporučené postupy psychiatrické péče II. Praha: Infopharm 2006: 152– 162.

3. Jirák R. Franková V. Demence. In: Raboch J, Anders M, Hellerová P, Uhlíková P (eds). Psychiatrie: Doporučené postupy psychiatrické péče III. Brno: Tribun EU 2010: 20– 53.

4. Kališová L, Vevera J, Nawka A, Raboch J. Zvládání akutního neklidu u nedobrovolně přijatých nemocných v roce 2011 a 2004– 2006. In: Raboch J, Zrzavecká I, Doubek P (eds). Civilizace, čas a duševní poruchy. Sborník příspěvků IX. sjezdu Psychiatrické společnosti ČLS JEP s mezinárodní účastí: 7.– 10. června 2012, Hotel Harmony, Špindlerův Mlýn. Brno: Tribun 2012: 274– 276.

5. Vevera J, Černý M. Zvládání agitovanosti a násilného chování. Psychiatr Prax 2011; 12(2): 69– 71.

6. National Institute for Health and Clinical Excellence (NICE). Violence. The short-term management of disturbed/ violent behaviour in in-patient psychiatric settings and emergency departments. Royal College of Nursing. 2005. ISBN 1- 904114- 21- 0. Available from URL: http:/ / www.nice.org.uk/ nicemedia/ pdf/ cg025fullguideline.pdf.

7. Mandelli M, Tognoni G, Garattini S. Clinical pharmacokinetics of diazepam. Clin Pharmacokinet 1978; 3(1): 72– 91.

8. Rang HP, Dale MM, Ritter JM, Flower RJ. Rang and Dale‘s Pharmacology. 6th ed. Edinburgh: Churchill Livingstone 2007.

9. Vevera J, Jirák R., Uhrová T, Žukov I. Možnosti farmakologického ovlivnění násilného chování u pacientů s demencí. Cs Psychiatr 2003; 99(3): 142– 145.

10. Powney MJ, Adams CE, Jones H. Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation). Cochrane Database Syst Rev 2012; 11: CD009377. doi: 10.1002/ 14651858.CD009377.pub2.

11. Gillies D, Sampson S, Beck A, Rathbone J. Benzodiazepines for psychosis-induced aggression or agitation. Cochrane Database Syst Rev 2013; 9: CD003079.

12. Blass DM, Steinberg M, Leroi I, Lyketsos CG. Successful multimodality treatment of severe behavioral disturbance in a patient with advanced Huntington‘s disease. Am J Psychiatry 2001; 158(12): 1966– 1972.

13. Meehan K, Zhang F, David S, Tohen M, Janicak P, Small J et al. A double-blind, randomized comparison of the efficacy and safety of intramuscular injections of olanzapine, lorazepam, or placebo in treating acutely agitated patients diagnosed with bipolar mania. J Clin Psychopharmacol 2001; 21(4): 389– 397.

14. Taylor D, Paton C, Kerwin R. The Maudsley 2005– 2006 Prescribing Guidelines. 8th ed. London: Taylor & Francis 2005.

15. Wyant M, Diamond B, O’Neal E, Sloan A, Borison RL.The use of midazolam in acutely agitated psychiatric patients. Psychopharmacol Bull 1990; 26(1): 126– 129.

16. Nobay F, Simon BC, Levitt MA, Dresden GM. A prospective, double-blind, randomized trial of midazolam versus haloperidol versus lorazepam in the chemical restraint of violent and severely agitated patients. Acad Emerg Med 2004; 11(7): 744– 749.

17. Ranjan S, Chandra PS. Drug combinations for rapid tranquillisation. Br J Psychiatry 2005; 187: 192– 193.

18. Alexander J, Tharyan P, Adams C, John T, Mol C,Philip J. Rapid tranquillisation of violent or agitated patients in a psychiatric emergency setting. Pragmatic randomised trial of intramuscular lorazepam v. haloperidol plus promethazine Br J Psychiatry 2004; 185: 63– 69.

19. TREC Collaborative Group. Rapid tranquillisation for agitated patients in emergency psychiatric rooms: a randomised trial of midazolam versus haloperidol plus promethazine. BMJ 2003; 327(7417): 708– 713.

20. Mantovani C, Labate CM, Sponholz A jr, de Azevedo Marques JM, Guapo VG, de Simone Brito dos Santos ME et al. Are low doses of antipsychotics effective in the management of psychomotor agitation? A randomized, rated- blind trial of 4 intramuscular interventions. J Clin Psychopharmacol 2013; 33(3): 306– 312. doi: 10.1097/ JCP.0b013e3182900fd6.

21. Mula M. The safety and tolerability of intranasal midazolam in epilepsy. Expert Rev Neurother 2014; 14(7): 735– 740. doi: 10.1586/ 14737175.2014.925398.

22. Javadzadeh M, Sheibani K, Hashemieh M, Saneifard H. Intranasal midazolam compared with intravenous diazepam in patients suffering from acute seizure: a randomized clinical trial. Iran J Pediatr 2012; 22(1): 1– 8.

23. Del Pizzo J, Callahan JM. Intranasal medications in pediatric emergency medicine. Pediatr Emerg Care 2014; 30(7): 496– 501. doi: 10.1097/ PEC.0000000000000171.

24. Hollenhorst J, Münte S, Friedrich L, Heine J, Leuwer M, Becker H et al. Using intranasal midazolam spray to prevent claustrophobia induced by MR imaging. AJR Am J Roentgenol 2001; 176(4): 865– 868.

25. Chiaretti A, Barone G, Rigante D, Ruggiero A, Pierri F,Barbi E et al. Intranasal lidocaine and midazolam for procedural sedation in children. Arch Dis Child 2011; 96(2): 160– 163. doi: 10.1136/ adc.2010.188433.

26. Haschke M, Suter K, Hofmann S, Witschi R, Fröhlich J, Imanidis G et al. Pharmacokinetics and pharmacodynamics of nasally delivered midazolam. Br J Clin Pharmacol 2010; 69(6): 607– 616. doi: 10.1111/ j.1365- 2125.2010.03611.x.

27. Baldaçara L, Sanches M, Cordeiro DC, Jackoswski AP. Rapid tranquilization for agitated patients in emergency psychiatric rooms: a randomized trial of olanzapine, ziprasidone, haloperidol plus promethazine, haloperidol plus midazolam and haloperidol alone. Rev Bras Psiquiatr 2011; 33(1): 30– 39.

28. EpiStop. Soubor minimálních diagnostických a terapeutických standardů u pacientů s epilepsií. Epistop. 2013. ISBN 978- 80- 903979- 6- 5. Dostupné z URL: http:/ / www.clpe.cz/ EPI_standard_2013_web.pdf.

29. Roberts JR, Geeting GK. Intramuscular ketamine for the rapid tranquillisation of the uncontrollable, violent, and dangerous adult patient. J Trauma 2001; 51(5): 1008– 1010.

30. Reich DL, Silvay G. Ketamine: an update on the first twenty five-years of clinical experience. Can J Anaesth 1989; 36(2): 186– 197.

31. Strayer RJ, Nelson LS. Adverse events associated with ketamine for procedural sedation in adults. Am J Emerg Med 2008; 26(9): 985– 1028. doi: 10.1016/ j.ajem.2007.12.005.

32. Green SM, Rothrock SG, Lynch EL, Ho M, Hartus T, Hestdalen R et al. Intramuscular Ketamine for pediatric sedation in the emergency department: safety profile in 1,022 cases. Ann Emerg Med. 1998; 31(6): 688– 697.

33. Melamed E, Oron Y, Ben- Avraham R, Blumenfeld A,Lin G. The combative multitrauma patient: a protocol for prehospital management. Euro J Emerg Med 2007; 14(5): 265– 268.

34. Battaglia J, Moss S, Rush J, Kang J, Mendoza R, Leedom L et al. Haloperidol, lorazepam or both for psychotic agitation? A multicenter, prospective, double-blind, emergency department study Am J Emerg Med 1997; 15(4): 335– 340.