Document Type : Review Article

Authors

Department of Forensic Toxicology, Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran

Abstract

Background: The analysis of morphine in biological samples is pivotal in clinical and forensic toxicology and indicates drug exposure, metabolism, and toxicological profile.
Method: This systematic review explores the recent analytical techniques that have used the detection and quantification of morphine in forensic toxicological investigations. Articles were collected from PubMed, Scopus and Google Scholar electronic databases from  2011 until 30th September 2024. They were searched using a systematic search of English keywords including: “Morphine” OR “Analysis” OR “Analytical techniques” OR “Analytical innovations” OR “Methods” AND “Biological samples” OR “Biological matrices”. The selection criteria were based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta- Analyses).
Results: From 1200 articles detected in the early systematic search, 30 articles met the inclusion criteria and included in this study. The results showed that the advanced hyphenated analytical methods couple with mass spectrometry (MS) such as Gas Chromatography- Mass Spectrometry (GC-MS), Liquid Chromatography-Mass Spectrometry (LC-MS) and related tandem GC-MS and LC-MS with recent sample preparation methods such as Quick Easy Cheap Effective Rugged Safe (QuEChERS) and Dispersive Liquid-Liquid Micro Extraction (DLLME) are the most common analytical methods for detection of morphine in biological samples.
Conclusion: Due to increase of morphine abuse as a worldwide concern, use of advanced analytical techniques with high sensitivity and precision in forensic toxicology setting should be recommended.

Keywords

Main Subjects

  1. Scendoni R Bury E ,  Buratti E Froldi R Cippitelli M Mietti G, et al. Detection of morphine and opioids in fingernails: Immunohistochemical analysis and confirmation with Ultra-High-Performance Liquid Chromatography Coupled with High-Resolution Mass Spectrometry. Toxics. 2022; 10(8):420.
  2. Pinto E, Gonçalves F, Sacarlal J, Castro L, Rego G. Pain management in cancer patients in the main hospitals in Mozambique. Annals of Palliative Medicine. 2021; 10(4): 4069-79.
  3. United Nations Office of Drugs and Crime (UNODC). World Drug Report. 2022.
  4. European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Drug-related deaths and mortality in Europe. July 2019; 10-22.
  5. Momtazi S, Rawson RA. Substance abuse among Iranian high school students. Curr Opin Psych. 2010; 23(3):221–26.
  6. United Nations Office of Drugs and Crime (UNODC). Drug trafficking and border control. Country Programme for Islamic Republic of Iran 2011-2014, Sub-Programme 1. Available from: https://www.unodc.org/islamicrepublicofiran/drug-trafficking-and-border-control.html. 2024-11-10.
  7. Boroujerdi R, Butt A, Paul R, Majumde S. Unveiling morphine: A rapid and selective fluorescence sensor for forensic and medical analysis. Sensors. 2024; 24: 1722.
  8. Cao J,  Chen XY,  Zhao WR. Determination of morphine in human urine by the novel competitive fluorescence immunoassay. J Analytical Method Chem. 2019; https://doi.org/10.1155/2019/7826090.
  9. Santos V, Vera López KJ, Santos LM, Yonamine M, Carmona MJC, Jorge Santos SRC. Determining plasma morphine levels using GC-MS after solid phase extraction to monitor drug levels in the postoperative period. Clin Sci.2008; 63: 307-14.
  10. Freiermuth M, Plasse JC. Determination of morphine and codeine in plasma by HPLC following solid phase extraction. J Pharm Biomed Anal. 1997; 15(6): 759-64.
  11. AminiRRahimpour EJouyban A. Determination of morphine and its metabolites in the biological samples: An updated review. Bioanalysis. 2020; 12(16):1161-94.
  12. Arndt C, Huestis MA, Jarvis HC, Gray TR. Assessment of urine drug screen utility at autopsy to predict laboratory postmortem blood toxicology. J Forensic Sci. 2024; 69(5): 1815-25.
  13. D’Ovidio C, Bonelli M, Rosato E, Tartagila A, Ulusoy HI, Samanidou V, et al., Novel applications of microextraction techniques focused on biological and forensic analyses. Separations, 2022; 9(1):18.  https://doi.org/10.3390/separations9010018.
  14. Ebrahimi Rahmani M, AnsariMKazemipourMNateghi M. Selective extraction of morphine from biological fluids by magnetic molecularly imprinted polymers and determination using UHPLC with diode array detection. J Sep Sci. 2018; 41(4): 958-65.
  15. Manca A, De Nicolo A, De Vivo ED, Ferrara M, Oh S, Khalili S, et al. A Novel UHPLC-MS/MS method for the quantification of seven opioids in different human tissues. Pharmaceuticals. 2023; 16(6):903. doi: 10.3390/ph16060903.
  16. OrfanidisAGikaHGTheodoridis G,  Mastrogianni ORaikos N. A UHPLC–MS-MS method for the determination of 84 drugs of abuse and pharmaceuticals in blood. J Anal Toxicol. 2021; 45(1): 28-43.
  17. Tahmasebi M, Esmaeili A, Bambai B. New method of identifying morphine in urine samples using nanoparticle-dendrimer-enzyme hybrid system. Arab J Chem. 2022; 15(2): 1-12.
  18. Kang M, Xue J, Zhang Y, Ouyang Z, Zhang W. On-site quantitation of morphine in urine by fast derivatization and miniature mass spectrometry analysis. Green Anal Chem. 2022; 1:100013.
  19. Yan H, Xiang P, Shen M. Current status of hair analysis in forensic toxicology in China. Forensic Sci Res.2021; 6(3): 240–49.
  20. Kintz P. Hair analysis in forensic toxicology: An updated review with a special focus on pitfalls. Curr Pharm Des. 2017; 23(36):5480-86.
  21. Usman M, Naseer A, Baig Y, Jamshaid T,  Shahwar M, Khurshuid S. Forensic toxicological analysis of hair: a review. Egy J Forensic Sci. 2019; 9(17): 1-12.
  22. Soltaninejad K, Shiri-Ghaleh V, Koohi MK, Hassan J. Development of a GC-MS method for the analysis of selected opioids in human hair samples. Intern J Med Toxicol Forensic Med. 2024. 14(03). https://doi.org/10.32598/ijmtfm.v14i03.44185.
  23. GürlerM ,Yılmazcan P,  Doğan, KarkınŞ, İşiner Kaya  B. Development of a LC-MS/MS method for the determination of narcotic drugs and psychotropic substances in human hair. Anal Bioanal Chem Res. 2022; 9(4): 401-09.
  24. Suárez-García A, Álvarez-Freire I, Bermejo-Barrera AMCabarcos-Fernández P Tabernero-Duque  MJ. Disappearance of codeine, morphine and 6-MAM in hair after cessation of abuse. Forensic Sci Int. 2023; 352: 111855.
  25. Barroso M, Gallardo E, Vieira DN, QueirozJA, López-RivadullaM. Bioanalytical procedures and recent developments in the determination of opiates/opioids in human biological samples. Anal Bioanal Chem. 2011; 400:1665-90.
  26. Raggam R, Santner B, Kollroser M, Goessler W. Evaluation of a novel standardized system for collection and quantification of oral fluid. Clin Chem Lab Med. 2008; 46(2): 287-91.
  27. Akçan R, Şerif YildirimMIlhan HGüven BTamer USağlam  N. Surface enhanced Raman spectroscopy as a novel tool for rapid quantification of heroin and metabolites in saliva. Turk J Med Sci. 2020; 50(5): 1470-79.
  28. Truver MT, Swortwood MJ. Quantitative analysis of novel synthetic opioids, morphine and buprenorphine in oral fluid by LC–MS-MS. J Anal Toxicol. 2018; 42(8):554-61.
  29. Bévalot F,  Cartiser N,  Bottinelli C,  Fanton L, Guitton  J. Vitreous humor analysis for the detection of xenobiotics in forensic toxicology: a review. Forensic Toxicol. 2015; 3412-40.
  30. Metushi IG, Fitzgerald RL, McIntyre IM. Assessment and comparison of vitreous humor as an alternative matrix for forensic toxicology screening by GC–MS. J Anal Toxicol.2016; 4:243-247.
  31. ScottKSOliver JS. Vitreous humor as an alternative sample to blood for the supercritical fluid extraction of morphine and 6-monoacetylmorphine. Med Sci Law. 1999; 39(1):77-81.
  32. Moody DE. Immunoassays in forensic toxicology. In: Encyclopedia of Analytical Chemistry 2006. DOI:10.1002/9780470027318.a1109.
  33. KeH,  Du X,   Wang L, Wang X,   Zhu  J,   Gao Y et al.  Detection of morphine in urine based on a surface plasmon resonance imaging immunoassay. Anal Method. 2020; 12:3038-3044.
  34. Freiermuth M, Plasse JC. Determination of morphine and codeine in plasma by HPLC following solid phase extraction. J Pharm Biomed Anal. 1997; 15(6): 759-64.
  35. ZhangX, ChenM, Cao G, Hu G. Determination of morphine and codeine in human urine by gas chromatography-mass spectrometry. J Anal Methods Chem. 2013; 2013:151934.
  36. Lee HM, Lee CW. Determination of morphine and codeine in blood and bile by gas chromatography with a derivatization procedure. J Anal Toxicol. 1991; 15: 182-87.
  37. Alahyari E, Setareh M,  Shekari A,  Roozbehani G,  Soltaninejad K. Analysis of opioids in postmortem urine samples by dispersive liquid-liquid microextraction and high performance liquid chromatography with photo diode array detection. Egypt J Forensic Sci. 2018; 8:13. https://doi.org/10.1186/s41935-018-0046-x.
  38. Meatherall R. GC-MS Quantitation of codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, and oxymorphone in blood. J Anal Toxicol. 29(5); 2005:301-08.
  39. Simão Y, Monteiro C, Marques H, Rosado T, Margalho C, Barroso M, et al. Analysis of opiates in urine using microextraction by packed sorbent and gas Chromatography- Tandem mass spectrometry. J Chromatogr B. 202; 1207:123361.
  40. Van BocxlaerJF Clauwaert KM,  Lambert WE,  Deforce DL, Van den Eeckhout EG,  De Leenheer AP. Liquid chromatography-mass spectrometry in forensic toxicology.
    Mass Spectrom Rev. 2000; 19(4):165-214.
  41. Peters FT. Recent advances of liquid chromatography–(tandem) mass spectrometry in clinical and forensic toxicology. Clin Biochem. 2011; 44(1): 54-65.
  42. Franzin M, Ruoso R, Peruch M, Stocco G,  D’Errico  S,  Addobbati R. Quantification of 108 illicit drugs and metabolites in bile matrix by LC–MS/MS for the toxicological testing of sudden death cases. Anal Toxicol. 2024; 98:135-49.
  43. Lu Q, Guo H, Zhang Y, Tang X, Lei W, Qi R. et al. Graphene oxide-Fe3O4 nanocomposite magnetic solid phase extraction followed by UHPLC-MS/MS for highly sensitive determination of eight psychoactive drugs in urine samples. Talanta. 2020; 206: 120212.
  44. Hansen ST. Sample preparation and separation techniques for bioanalysis of morphine and related substances. J Sep Sci. 2009; 32:825-34.
  45. MalacaSBusardòFGottardi MPichini SMarchei E. Dilute and shoot ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC–MS/MS) analysis of psychoactive drugs in oral fluid. J Pharm Biomed Anal. 2019; 170: 63-67.
  46. Zhuo Y, Wang X,  Wu J, Zhang  S, Deng H. et al. Simultaneous quantitative determination of amphetamines, opiates, ketamine, cocaine and metabolites in human hair: Application to forensic cases of drug abuse. J Forensic Sci. 2020; 65(2): 563-69.
  47. HansenSL NielsenMKK Linnet KRasmussen BR. Simple implementation of muscle tissue into routine workflow of blood analysis in forensic cases - A validated method for quantification of 29 drugs in postmortem blood and muscle samples by UHPLC-MS/MS. Forensic Sci Int. 2021; 325:110901.
  48. Akhunov SD, Kasimov BS, Ashurov KB, Usmanov D. Development of a surface ionization mass spectrometry method for the highly sensitive and highly selective analysis of morphine in biofluid. J Anal Chem. 2021; 76(13): 1499-504.
  49. Zhang R, Fu K, Zou F, Bai H. Highly sensitive electrochemical sensor based on Pt nanoparticles/carbon nanohorns for simultaneous determination of morphine and MDMA in biological samples. Electrochimica Acta. 2021; 370: 137803.
  50.  Isbell TA, Strickland EC, Hitchcock J, McIntire G, Colyer CL. Capillary electrophoresis-mass spectrometry determination of morphine and its isobaric glucuronide metabolites. J Chromatogr B. 2015; 980: 65-71.
  51. Wang L,  Ni C, Shen H, Sheng Z, Liang C, Wang R, Zhang Y. Comparison of the detection windows of heroin metabolites in human urine using online SPE and LC–MS/MS: Importance of Morphine-3-Glucuronide. J Anal Toxicol. 2020; 44(1): 22-28.
  52. Boonchaleaw B, Tansrisawad N, Hoonwijit U. Modified QuEChERS in blood sample preparation for drug abuse determination by LC-MS/MS. Chula Med J. 2021; 65(1); 51-55.
  53. BurattiECippitelliMMietti GScendoni RFroldi RCerioni ACingolani M. Validation of an HPLC-HR-MS method for the determination and quantification of six drugs (Morphine, Codeine, Methadone, Alprazolam, Clonazepam and Quetiapine) in nails. J Anal Toxicol. 2023; 47(5): 488-93.
  54. Baciu T, Borrull F, Neusüß C, Aguilar C, Calull M. Capillary electrophoresis combined in-line with solid-phase extraction using magnetic particles as new adsorbents for the determination of drugs of abuse in human urine. Electrophoresis. 2016; 37(9): 1232-44.
  55. Kovatsi L, Rentifis K, Giannakis D,  Njau S, Samanidou V. Disposable pipette extraction for gas chromatographic determination of codeine, morphine, and 6-monoacetylmorphine in vitreous humor. J Sep Sci. 2011; 34(14): 1716-21.
  56. JúniorEFCaldas ED. Determination of new psychoactive substances and other drugs in postmortem blood and urine by UHPLC-MS/MS: method validation and analysis of forensic samples. Forensic Toxicol. 2022; 40(1):88-101.